Red Cell Transfusion and the Immune System S

Anaesthesia 2015, 70 (Suppl. 1), 38–45 doi:10.1111/anae.12892 Review Article

Red cell transfusion and the immune system S. Hart,1 C. N. Cserti-Gazdewich2 and S. A. McCluskey3

1 Fellow, 3 Consultant, Department of Anaesthesia and Pain Management, 2 Consultant, Department of Haematology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada

Summary Understanding the complex immunological consequences of red cell transfusion is essential if we are to use this valu- able resource wisely and safely. The decision to transfuse red cells should be made after serious considerations of the associated risks and benefits. Immunological risks of transfusion include major incompatibility reactions and transfusion-related acute lung injury, while other immunological insults such as transfusion-related immunomodulation are relatively underappreciated. Red cell transfusions should be acknowledged as immunological exposures, with consequences weighed against expected benefits. This article reviews immunological consequences and the emerging evidence that may inform risk-benefit considerations in clinical practice...... Correspondence to: S. A. McCluskey; Email: [email protected]; Accepted: 21 August 2014

Introduction In 1901, Karl Landsteiner established that not all The decision to transfuse red cells should be made blood was the same, identifying what is now known as after serious considerations of the associated risks and the ABO system; he received a Nobel prize for this benefits. Immunological risks of transfusion include discovery in 1930. These antigens consist of precursor major incompatibility reactions and transfusion-related H-substance on carrier molecules; the highest density acute lung injury (TRALI), while other immunological is on the red cell membrane, and lower densities are insults such as transfusion-related immunomodulation present on other tissues. The A and B genes encode (TRIM) are relatively underappreciated. enzymes that add N-acetylgalactosamine (A) or galac- Immunological risks of red cell transfusions may tose (B) respectively to H-substance. Plasma contains be classified according to host and donor interactions. antibodies formed against these antigens after confron- In this review, we discuss these complications and tations with similar moieties on bacteria in the gastro- strategies to reduce them. intestinal tract and food substances [6]. Group O individuals (unmodified H-substance Red cell antibodies alone) develop anti-A and anti-B re-activities, while The International Society of Blood Transfusion recog- group AB individuals do not. The A types are further nises > 300 red cell antigens from > 30 systems [1]. classified serologically as A1 (80%) and non-A1 (typi- The most important points of compatibility lie within cally A2, 20%). The latter may naturally gain anti-A1 the ABO system [2, 3]. Many of these antigens may activity, which is not usually reactive at 37 °C, but provoke acute or delayed haemolytic transfusion reac- can rarely result in a haemolytic transfusion reaction tions, as well as haemolytic disease of the foetus and [4, 7, 8]. newborn, while others are clinically insignificant despite The Rhesus system includes up to 50 different their potential to corrupt compatibility tests [4, 5]. antigens, of which D, C, c, E and e are the most clini-

38 © 2014 The Association of Anaesthetists of Great Britain and Ireland Hart et al. | Immunological consequences of transfusion Anaesthesia 2015, 70 (Suppl. 1), 38–45 cally significant. Rh factor or positivity refers to the D dence of immune recognition of approximately 20 sig- antigen, which is a large membrane protein (MW nificant minor antigens relevant to cross-matching. If 30 000 Da). Numerous polymorphisms account for the antibodies appear, then specificity investigations are RhD-negative (non-expression) state. The RhD+ phe- performed. In some conditions at higher risk of screen notype is most frequent (85% in Caucasians, 95% in positivity (allo-immunisation), matching beyond ABO Sub-Saharan Africa, 99.5% in Eastern Asia) [9]. An and RhD may include typing for Kell and RHCE type increasing number of variants are also now recognized, [12, 13]. including ‘weak D’, ‘partial D’ and ‘Del’. A second The antibody screen may miss dynamic serocon- gene encodes the RHCE protein (expressing C/c and versions or antibody re-activations that are relevant to E/e antigens) [9]. forthcoming cross-matches if not re-assessed (e.g. every three days) after recent red cell exposure, for Haemolytic transfusion reactions example during pregnancy or after transfusion in the The goal of the group, screen and cross-match is to previous three months. Re-examination intervals may prevent haemolytic incompatibility with red cells, but be extended in the chronically transfused or those with the importance of adhering to transfusion protocols no history of recent pregnancy or transfusion, accord- and positive patient identification to avoid incompati- ing to local blood bank policy [11]. ble transfusion cannot be overstressed (Table 1) [7]. Cross-matching is the final step in assuring red cell Transfusion reactions due to ABO incompatibility compatibility. It may either be abbreviated or represent would occur in 1/3rd of transfusions without ABO a full serological cross-match. Abbreviated testing may typing [3]. Haemolytic transfusion reactions can be be either an immediate spin or electronic cross-match, acute, delayed or serological, without clinical manifes- depending on the established laboratory protocols. tations, and range from mild to severe and possible • Immediate spin: donor red cells are mixed with death. recipient plasma at room temperature for 5 min. The group and screen is conducted differently in This is unpopular due to sensitivity to insignificant different countries, but the objective of insuring a safe IgM (cold) antibodies and insensitivity to signifi- red cell transfusion is the same. It has three compo- cant IgG antibodies already discoverable by screen- nents: ABO and RhD grouping; antibody screening; ing [11], or and review of historical records. Patients’ red cells are • Electronic/computer cross-match: institutions with examined with commercially prepared anti-A, anti-B approved information systems favour virtual cross- and anti-D, and agglutination is assessed by visual matching. This relies on confirmed ABO and RhD inspection on forward typing [10, 11]. Known A and typing with serially negative antibody screens (on B group red cells are then added to the patient’s at least two independent samples) [10, 14]. How- plasma, and again checked for agglutination on reverse ever, some centres issue units to some patients or back-typing, therein also verifying conformity with despite known antibodies [15]. Landsteiner’s Law [10, 11]. Other antibodies are identified by adding patient A manual or serological cross-match should be plasma to commercially characterised red cells for evi- performed if screening is positive, or the patient is

Table 1 Summary of ABO frequency and transfusion compatibility.

Antigen on red Antibodies in Can receive Can receive Blood group % blood cell the plasma blood from plasma from O 44 0 Anti-A O All Anti-B A 43 A Anti-B A, O A, AB B 9 B Anti-A B, O B, AB AB 4 A and B None All AB

© 2014 The Association of Anaesthetists of Great Britain and Ireland 39 Anaesthesia 2015, 70 (Suppl. 1), 38–45 Hart et al. | Immunological consequences of transfusion known to have had red cell antibodies in the past. This as group O platelets may be suspended in plasma with includes an indirect antiglobulin test that is sensitive high isohaemagglutinin titres that may bind to recipient to IgG, not detectable otherwise or at room tempera- red cells to induce haemolysis. Some blood banks assess ture [11]. Some laboratories perform this serological titres in platelets, so that high-content concentrates are cross-match prior to issuing any red cells [15]. given only to matched recipients or undergo plasma volume reduction [22, 23]. Titres may increase after Acute haemolytic transfusion reaction vaccination or probiotic ingestion [24]. This is a potentially life-threatening event and occurs The reaction itself manifests typically with fever, within 24 h of a transfusion; it is due to red cell immune chills, chest or flank pain, shortness of breath, tachy- destruction. Destruction affects incompatible red cell cardia, hypotension, and haemoglobinuria/haemosider- antigens or comes from haemolytic antibodies in inuria. Progression to renal failure, disseminated plasma-containing products. The incidence is 1 in 38– intravascular coagulation (DIC) and death may occur. 76 000, with fatalities rare at < 1 per million [16–18]. Laboratory evidence includes a failure of increase or Between 2008 and 2012, the US FDA reported 53 deaths even a fall in haemoglobin, with an increase in biliru- due to haemolytic transfusion reaction, acute and bin and lactate dehydrogenase, while haptoglobin delayed, representing 27% of transfusion-related deaths reciprocally falls. Management includes stopping the (second after TRALI), however the incidence is decreas- transfusion and providing supportive care. Fortunately, ing [19]. AB- incompatibility accounted for three out of mortality is < 10% [16], and correlates with the vol- eight cases of acute haemolytic transfusion reaction in ume of incompatible blood transfused. 2012. Of the remaining five cases, three were acute reactions by laboratory error (misinterpreted screen/misfiled Delayed haemolytic transfusion reaction records), and two were emergency transfusions given to The onset of delayed haemolytic reaction is > 24 h patients with known antibodies and insufficient prepa- after transfusion, and arises most often because of the ration time. Australia reported 14 cases between 2008 missed detection of an antibody on screening [25, 26]. and 2011, with no fatalities, representing 1.8% of all Antibodies are usually IgG isotypes, with some more events reported [18]. In the UK, there were nine cases in prone than others to severe delayed reactions and/or 2012, all after red cell transfusion, with no deaths [20]. waxing and waning expression (e.g. Kidd-Jka [27], Acute haemolytic transfusion reactions commonly stem Duffy-Fya, and Kell-K [28]. After the first confronta- from clerical error or other lapses in patient identification, antibody levels eventually dissipate. On re-expo- tion, culminating in administration of properly labelled sure, the anamnestic response manifests a prompt rise blood to the wrong patient [16]. in antibody levels. These antibodies bind to the red The pathophysiology involves complement-fixing cell, with haemolysis occasionally following. Frequency antibodies in recipient plasma binding to mismatched is 1 in 2500–11 000 [18, 28]. The FDA reported two red cells, thereby activating the classical complement fatal cases in 2012 – both failed to determine the pathway, with membrane attack complex-mediated implicated antibody before transfusion. intravascular haemolysis over a period of minutes. Delayed reactions present 1–4 weeks after transfu- Recipient IgG may also bind to incompatible red cells sion with fever, chills, jaundice and laboratory evidence to induce antibody-dependent cell cytotoxicity, wherein of haemolysis. The post-transfusion screening and/or splenic and hepatic macrophages engage in extravascu- direct antiglobulin test reveals the allo-antibody, which lar haemolysis. The acuity of the reaction may reflect in the early stages may only be detected by blind eluates the level of preformed antibody in the plasma. It may from the recipient’s circulating red cells. To varying occur if these antibodies are missed in error or by the degrees, alloantibodies may be adsorbed onto the urgent need for uncross-matched blood [21]. incompatible subpopulation of red cells. These reactions Plasma antibodies in products may conversely react are usually less severe than an acute reaction, and may with recipient red cells, and while the amount of plasma be missed entirely, especially with reduced hospital in packed red cells is limited, other blood products such length of stay [28]. Severity depends on antibody quality

(subclass, affinity, thermal range), quantity (titre), and 34% to 4% (7% if RhD mosaics were included) with this target antigen density. approach. Immune provocation is important in sickle Treatment is usually unnecessary, although further cell disease, as a delayed transfusion reaction may pre- red cells should be selected for their antigen- negativ- cipitate a vaso-occlusive crisis or potentially fatal hyper- ity. Archiving and review of serologic records in cen- haemolysis syndrome [43, 44]. Broadening the ‘better tralised databases mitigates risk [29–31]. Delaney et al. match’ strategy is not yet known to be cost-effective in noted that > 13% of patient records were amended lower-risk populations. Meanwhile, leukoreduction has with historical data that otherwise would have been not affected red cell allo-immunisation rates [45]. unknown to the primary care staff had there not been Allo-immunisation to other blood product anti- data centralisation in King County, Washington [32]. gens, such as human leukocyte antigen or human platelet antigen, may provoke other sequelae such as Serological transfusion reaction and platelet refractoriness, post transfusion purpura, febrile allo-immunisation non-haemolytic transfusion reactions, TRALI, and allo- A serological transfusion reaction describes the positive graft rejection [46]. screen or direct antiglobulin test after transfusion, and may or may not correlate with a delayed transfusion Non-haemolytic immunological reaction. It spans not only the post-red cell reaction, but response to transfusion the subclinical primary sensitisation that may be inci- A febrile non-haemolytic transfusion reaction is dentally detected in the laboratory 1–3 months later defined as a > 1 °C rise in temperature and/or rigors/ [33]. These antibody-only responses are between two chills with or without other symptoms such as nausea and five times more common than delayed transfusion or discomfort not attributable to other causes. These reactions, featuring specificities such as anti-E or -K [34, were the most frequent adverse events reported in 35]. Allo-immunisation, as a term, encompasses all sero- Australia and New Zealand [18, 47]. Reporting rates conversions, including, but not limited to, those discov- vary widely, but occur in approximately 1 in 300 red ered as a serological reaction through testing, although cell transfusions and 1 in 20 platelet transfusions [48]. many authors use the terms interchangeably [20, 36]. Two mechanisms may account for such a response Serological reaction rates vary, being as low as to transfusion. Soluble factors in the supernatant may 0.2–0.4% in healthy donors and soldiers [21, 37], 4% be pyrogenic, including cytokines released during stor- in inpatients [32] and up to 76% in transfusion-depen- age, particularly at room temperature [49, 50]. Lin dent patients [21, 38–40]. Harm et al. [29] found et al. [51] demonstrated higher levels of IL-6 and -8 in screen-positivity in 44% of sickle cell patients, and in post-red cell patients, including baseline IL-6 levels in 63.3% of these at least one of the detected antibodies cases vs controls, although cytokine levels did not vary evanesced over the study period of 15 years. accordingly in transfused products. Alternatively, reci- Allo-immunisation risk depends on red cell quan- pient leuko-agglutinins interact with donor antigens tity, presence and antigenicity of foreign antigens, and [50], thereby explaining lower rates with pre-storage whether the host is prone to seroconversion or not. leukoreduction [52, 53]. Febrile non-haemolytic Rhesus D is one of the most immunogenic antigens. transfusion reactions are not dangerous, but are Post-exposure seroconversion rates as high as 80% uncomfortable for the patient and may result in the have been reported in healthy volunteers [41], early discontinuation of a transfusion. although others suggest lower rates of 30% [42]. Rates King et al. [52] demonstrated a reduction of feb- have decreased significantly since the use of anti-D im- rile non-haemolytic transfusion reactions following munoprophylaxis for RhD-negative pregnant women. pre-storage luekodepletion from 0.37% to 0.19%. Yazer Allo-immunisation can be minimised by more et al. [53] also observed a reduction in red cell and extensive matching in transfusion-dependent popula- platelet responses (0.33% to 0.19% for red cells and tions at high seroconversion risk. LaSalle-Williams et al. 0.45% to 0.11% for platelets). Many centres premedi- [12] reported reduced allo-immunisation rates from cate the patient to further decrease risk, although this

© 2014 The Association of Anaesthetists of Great Britain and Ireland 41 Anaesthesia 2015, 70 (Suppl. 1), 38–45 Hart et al. | Immunological consequences of transfusion practice may be declining [54] as many question its of this claim [69]. Transfusion of allergens may be benefit [48]. more likely to induce an allergic reaction in atopic recipients via primed mast cells and basophils [70]. Allergic reactions Conversely, passive transfer of IgE from donor to Allergic reactions vary from mild urticarial skin rashes to recipient can occur, with harm if the protein is subse- life-threatening anaphylaxis. Their incidence varies quently ingested. The half-life of IgE in plasma is rela- between 1% and 3% [48]. In a single-institution series tively short (1.1 days), but once bound to a mast cell or examining adverse events, 17% were allergic with 1.3% basophil it may persist for up to 7 weeks [71]. Arnold anaphylactic [55]. Overall, severe allergic reaction fre- et al. [72] describe this scenario in a recipient of two quency was 1 in 53 612 components (highest for platelets units of plasma, whose peanut ingestion 2 days later met and lowest for red cells). Anaphylaxis accounted for 5% with anaphylaxis. Peanut-specificIgEwasfound,witha of transfusion-related fatalities in the US between 2009 normalising disappearance 3 months later and a non- and 2013 (nine cases overall and none in 2013 [19]). reactive peanut re-exposure. The donor was found to be Several mechanisms can explain allergic reactions: peanut allergic and further product collection/compo- passive donor allergens or anaphylatoxins; passive nent preparation demonstrated that the IgE level was donor IgE, host or donor anti-IgA IgG; and other acti- unaffected by storage. Similar reports followed [73]. IgE vators, such as biologic response modifiers, of comple- antibodies to common food substances were found in ment or mast cells [56]. Wild-type plasma proteins 2.2% of Norwegian and 11.1% of Swedish blood donors. may sensitise recipients with inherited deficiencies or Note was made in this study of peanut allergy frequency variations therein. For example, IgA-deficient recipi- andquality,inthatoveraquarterofthosewithanti- ents may develop anti-IgA IgG antibodies capable of peanut IgE had moderate to high levels [74]. reacting with IgA [57, 58]. It is unclear why anti-IgA Domen et al. [55] found storage-dependent biologi- IgG sensitisation occurs in those without known expo- cal response modifiers associated with allergic reactions sures [59]. IgA deficiency varies in different popula- after observing five events in autologous donations and tions; up to 1 in 300 in the US or Canada and 1 in a disproportionate amount in platelet transfusions [75]. 32 000 in Japan [59]. IgA-mediated anaphylaxis is However, Savage et al. [76] concluded that recipient and rare, with incidence estimates hampered by the lack of donor factors are more important than product factors standardized diagnostic criteria or laboratory tests rele- in allergic pathogenesis. Indeed, rates have not changed vant to allergy testing [60], such as histamine and with leukoreduction [52]. tryptase quantification or assays for basophil activation [61]. Analogous inherited protein deficiency that may Transfusion-related acute lung injury act as a passive donor allergens include haptoglobin Transfusion-related acute lung injury was once thought [62, 63], C4 and Von Willebrand factor [64]. to be a rare complication, but it is now recognised as a Transfused anti-IgA IgG within IgA deficient leading cause of transfusion-related morbidity and donors could theoretically cause reactions in non-IgA mortality [20, 77–80]. In 2004, the US National Heart, deficient recipients. However, increased rates of allergic Lung and Blood Institute Working Group formulated reactions have not been seen when IgA deficient donor adefinition for TRALI (Table 2) [77, 78]. Transfusion- products are used, implying that dilution of IgG in the related acute lung injury remains under-reported due recipient reduces the risk [65, 66]. to incomplete acceptance of this definition and the Methylene blue has been reported to cause ana- voluntary nature of haematovigilance [81–83]. UK case phylaxis [67], and this is relevant in countries using review also incorporates correlative serology [84]. this agent for pathogen inactivation. Food allergens The incidence of TRALI is between 0.08% and 15% conveyed by the donor may also play a role, as sug- [85]. It has decreased in the UK, with 11 suspected gested in a case [68] of peanut protein initiating ana- cases in 2012 (none fatal), compared with 36 suspected phylaxis in a recipient with the allergy, although the cases and 7 deaths in 2003 [34]. However, it remains a protein was not tested for and some refute the veracity leading cause of US transfusion fatalities [80].

A proposed mechanism for TRALI is the ‘two hit’ patients require supplementary oxygen and up to 70% model [86, 87]. The first hit lies in the extent to which require ventilatory support [90]. Symptoms usually host neutrophils are activated and marginated on pul- resolve within 72–96 h. Mortality is estimated at 10– monary endothelium. Transfusion introduces the sec- 15% [84, 91]. ond ‘hit’ in an antibody- or non-antibody-mediated The mainstay of prevention is transfusion avoid- manner. In the former, passive transfer of donor anti- ance. Given that anti-HNA and anti-HLA antibodies bodies against Human Leukocyte Antigens (HLA) or occur at higher frequency in multiparous females [92, Human Neutrophil Antigens (HNA) react with targets 93], implementation of male-only plasma in compo- in the recipient or, less commonly, leuko-agglutinins nent therapy began in the early 2000s, with the UK in the recipient react with donor leukocytes (reverse- starting in 2003. The incidence of TRALI has TRALI). There are several reported cases of reverse decreased markedly in these risk-mitigating nations TRALI, but this is now rare through pre-storage leuko- [94], prompting attempts to minimise plasma in cellu- reduction [86]. High-titre, cognate encounters do not lar components. Because male-only plasma restrictions guarantee TRALI, and antibody-negative TRALI cases may reduce supply, some propose either reactive exclu- occur, thereby suggesting alternative mechanisms, such sions (only excluding donors implicated in TRALI) or as pro-inflammatory mediators, as the second hit. proactive exclusions (multiparous females, those previ- The second hit arises from transfusion factors. It is ously transfused or those with leukocyte antibodies). dose-dependent and typically associated with plasma, Most often, female plasma is subjected to fractionation although low volumes of plasma, such as the quantity (except in the UK [84]) for production of albumin and within red cell units (2–100 mL), cryoprecipitate, and immunoglobulin. Leukoreduction reduces TRALI inci- intravenous immunoglobulin [88] may be sufficient to dence [95], as does solvent detergent plasma [94, 96]). cause TRALI. A threshold model [86] describes who Controversially and less practically, washed and/or does, or does not, develop TRALI [88, 89]. fresh products may be considered. Manifestations of TRALI include dyspnoea, hypoxaemia and hypotension. There may be a transient Transfusion related immunomodulation leukoneutropenia and then leucocytosis. Nearly all Transfusion related immunomodulation is often cited as a non-infectious consequence of transfusion and yet its mechanism remains unclear. It was first deliberately Table 2 Definition of transfusion-associated lung exploited in renal transplantation through the anti- injury (TRALI). rejection effects of non-leukoreduced red cell transfusions [97]. Subsequently, observations of immunosup- TRALI (suspected) pression and/or cancer recurrence led to abandonment Acute lung injury Temporally related to transfusion: within 6 h of this tactic [98]. No other risk factors for acute lung injury Transfusion related immunomodulation probably Acute lung injury results from cell-mediated and humoral hits in stored Acute onset Hypoxaemia: one of red cells. There may be limits to what factors can be < PaO2/FIO2 40 kPa attenuated by pre-storage leukoreduction due to other Oxygen saturation < 90% on room air Other clinical evidence byproducts in red cells (e.g. lipopolysaccharides and free Bilateral lung infiltrates iron) [99]. Postoperative clinical consequences of TRIM No evidence of circulatory overload may result in increased morbidity due to infectious (PAOP < 18 mmHg, CVP < 15 mmHg) Possible TRALI complications and cancer recurrence [100]. Same as TRALI but when another risk factor for acute lung injury is present Red cell storage lesion ° – PaO2, partial pressure of oxygen in arterial blood; FIO2, frac- Red cells can be stored at 4 C for 21 42 days according tion inspired oxygen concentration; PAOP, pulmonary artery to preservative solution. This allowable duration of occlusion pressure; CVP, central venous pressure. storage is based on FDA-defined criteria for red cell

© 2014 The Association of Anaesthetists of Great Britain and Ireland 43 Anaesthesia 2015, 70 (Suppl. 1), 38–45 Hart et al. | Immunological consequences of transfusion integrity, i.e. free hemoglobin < 1% and 75% Æ 9% of Infectious complications re-transfused red cells recoverable 24 hours later in Postoperative infections are a major burden to the healthy volunteer blood donors [101]. The storage lesion healthcare system and patient recovery. Reducing the reflects changes that occur during refrigeration with bio- risk of hospital-acquired infections is considered very mechanical membrane changes (i.e. phospholipids, pro- important today, with measures including appropriate teins and lipid peroxidation), and increased red cell antibiotic prophylaxis, hand-washing, and minimising fragility, as well as biochemical changes within the red use of urinary catheters and drains. Such efforts are cell rendering it less capable of its own maintenance (e.g. included in programs dedicated to enhancing surgical 2,3 DPG depletion, ATP depletion, loss of nitric oxide). recovery [123, 124]. Early retrospective evidence showed Additionally, free iron and leukocyte-derived inflamma- a strong association between infectious complications tory cytokines accumulate (e.g. IL-6 and TNF) [99]. and red cell transfusion [125]. One explanation for such Older red cells may be less effective at oxygen findings is confounding by the indication for transfu- delivery, while introducing immunological stress. Evi- sion, e.g. anaemia in a patient with tachycardia and pre- dence for detrimental outcomes with older blood existing infection. The most compelling evidence for an include observational data in critical care [102], association derives from a meta-analysis of restrictive vs trauma [103], liver transplantation [104, 105], breast liberal transfusion strategies that included 18 rando- reconstruction [106], cardiac surgery [107, 108] and mised trials with 7593 patients [100]. Restrictive proto- À cardiology [102, 109]. However, there is evidence chal- cols usually withhold transfusion until Hb < 70 g.l 1 À lenging this association [110–112] and other data while liberal ones maintain Hb > 100 g.l 1. With seri- showing that fresh red cell-associated harm [113]. The ous infection, the risk ratio for association between temporal relationship between transfusion and morbid- restrictive protocols and severe infection was 0.82 (95% ity is complicated and storage effects are best resolved CI 0.72–0.95). The number needed to treat as such to by randomised trials. Ongoing studies include those on avoid a serious complication was 38 [100]. Interestingly, inpatients [114], cardiac surgery (www.clinicaltrials.gov the benefit of restrictive transfusion practice was not lost NCT00458783, NCT00991341, and NCT00458783), by leukoreduction, suggesting that it is either ineffective abdominal surgery (NCT01914328), paediatric or that leukocyte-independent mechanisms of immuno- intensive care (NTC01977547 and NCT01586923), and modulation also play a role. adult intensive care (NCT01638416 and NCT01638416). Cancer recurrence It is difficult from retrospective surgical populations to Prestorage leukoreduction determine how red cell transfusion affects cancer Prestorage leukoreduction leaves a leukocyte count of recurrence because of confounding factors related to < 5 9 106 per unit (99.9%, or a 3 log, reduction). resection and transfusion need [126]. The more This nearly eliminates the risk of leukotropic virus difficult the resection, the greater the need for red cells transmission such as cytomegalovirus [115] or and the greater the odds of an extensive or residual Epstein-Barr virus [116], while reducing HLA allo-im- cancer. A Cochrane review found a pooled estimate of munisation [117]), and bacterial or parasitic contami- cancer recurrence at 1.42 (95% CI 1.20–1.67), although nation [118, 119]. Some evidence suggests a decrease whether transfusions suppress anti-cancer immune- in the risk of TRALI and transfusion-related acute cir- surveillance remains speculative [127]. culatory overload [95]. It may also reduce TRIM, although the association with postoperative infections, Solid organ transplantation multi-organ dysfunction and death is less clear [120, Human leukocyte antigens (HLA) allo-immunisation 121]. Whilst prestorage leukoreduction is mandatory with red cells in those awaiting transplantation is an in Canada and most of Europe, it is only recom- important concern. However, red cells are inconsistently mended by the FDA in the USA, reflecting the lack of immunogenic with 10–30% developing HLA antibodies definitive risk-cost benefit evidence [122]. with ≤ 20 transfusions [128]. In contrast, the rate is

< 2% in male donors regardless of transfusion history donor T-cells recognise the recipient’s tissues as [129, 130]. Despite low seroconversion risk with red foreign and mount an attack on the recipient. This cells, once present, HLA antibodies call for complex and may be seen with directed donation between relatives, cumbersome desensitisation to minimise allograft rejec- with HLA-matched platelets, or in populations with tion. reduced genetic diversity where a close HLA match is more likely between a recipient and a random donor, Transfusion-associated graft vs host disease e.g. in Japan [133]. The incidence is unknown, espe- Transfusion-associated graft vs host disease is a rare, cially in the immunocompetent, but is estimated to be but usually fatal complication of blood transfusion. between 0.1% and 1% in susceptible individuals [132– Three factors are important in its pathogenesis: 134]. Transfusion-associated graft vs host disease is immune integrity of recipient; degree of HLA similar- probably under-recognised and misdiagnosed as sepsis ity between donor and recipient; and number of active or a drug reaction [135, 136]). The UK SHOT report T-cells introduced – it is higher with fresh and/or reported 13 cases between 1996 and 2001, with no fur- non-leukoreduced blood [131]. Donor T-cells are usu- ther cases until 2009 [34]. Virtually no cases were ally destroyed by host defense mechanisms and cleared reported since pre-storage leukoreduction was intro- within days [132]. However, destruction of donor duced in the UK in 1999, despite mitigation failures T-cells may not occur if the recipient is immunocom- such as missed irradiation [34, 84]. Clinical manifesta- promised or if the donor T-cells are not recognised as tions include fever, rash, hepatitis, and diarrhea 1– foreign because of their similarity with recipient epi- 2 weeks after transfusion, although onset may be topes. In either case, failure to recognise identifiably delayed by as much as three months [137]. Pancytope- foreign epitopes, as in the case of HLA homozygous nia follows, and mortality is high (> 90%), due to haplosimilar donors in relation to heterozygous overwhelming sepsis. Management options are few and recipients, permits donor lymphocyte escape. The successful treatment is rare [138]. The emphasis is therefore on prevention by avoidance or irradiation of Table 3 Risk factors for transfusion-associated graft vs cellular products in at-risk patients (Table 3) [134]. host disease. Increasing regulation regarding caesium source irradia- tors because of concern over terrorist activity has led Significantly increased risk to a search for alternative strategies, such as pathogen Congenital immunodeficiency syndromes Bone marrow transplantation reduction [139]. (allogeneic and autologous) Transfusions from blood relatives Conclusion (directed donations) Intra-uterine transfusions Immunological consequences of blood transfusion may HLA-matched platelet transfusions not be trivial. The risk of harm and inventory steward- Hodgkins disease Patients treated with purine analogues ship compel increasingly conservative practices. Mea- Minimally increased risk sures to reduce transfusion include pre-operative Acute leukaemia optimisation, intra-operative blood conservation, and Non-Hodgkin’s lymphoma Solid tumour treated with intensive postoperative considerations. Immunological conse- chemotherapy or radiotherapy quences of transfusion should be factored into all Exchange transfusions Preterm infants transfusion decisions and subsequent review of any Solid organ transplant recipients post-transfusion sequelae. No perceived increased risk Healthy newborns Patients with AIDS Competing interests HLA, human leukocyte antigen; AIDS, acquired immunodefi- No external funding or competing interests declared. ciency syndrome.

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