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Broadening the spectrum of patient groups at risk for transfusion-associated GVHD: implications for universal irradiation of cellular blood components

2003; Wiley; Volume: 43; Issue: 12 Linguagem: Inglês

10.1111/j.0041-1132.2003.00631.x

1537-2995

Kenneth C. Anderson,

Advanced Radiotherapy Techniques

In this issue of TRANSFUSION, Leitman and colleagues1 report a case of fatal transfusion-associated GVHD (TA-GVHD) in a patient with systemic lupus erythematosus receiving fludarabine. Although TA-GVHD has been previously reported in patients receiving fludarabine therapy for hematologic malignancies, most commonly chronic lymphocytic leukemia,2 the current report extends those at risk to individuals receiving fludarabine treatment for nonmalignant conditions. An accompanying article, also in this issue of TRANSFUSION, describes a retrospective record review of transfusions over a 10-year period at The American University of Beirut-Medical Center.3 Ten cases of fatal TA-GVHD were identified in immunocompetent hosts who received fresh nonleukoreduced, nonirradiated blood, again because they were not recognized at the time of transfusion to be at risk for this complication. The case report by Leitman and coworkers1 is particularly instructive and highlights the characteristics of TA-GVHD, as well as the importance of clinical acumen in suspecting and confirming the diagnosis. Two weeks after her third monthly treatment with 30 mg per g2 fludarabine subcutaneously on Days 1 to 3, 500 mg/m2 cyclophosphamide orally on Day 1, and prednisone orally on a tapering schedule, the patient developed leukopenia treated with G–CSF, as well as anemia and thrombocytopenia requiring transfusion. She developed clinical features including fever, diffuse rash, aminotransferase elevations, elevated bilirubin, and pancytopenia 10 days after transfusion, characteristic of TA-GVHD.4-6 These manifestations can be attributed to drug reactions, infection, or underlying disease, leading to underreporting of the incidence of TA-GVHD, unless the index of suspicion is high, as in this case. Once TA-GVHD is suspected, it can readily be confirmed. As in this case, characteristic but not pathognomonic histopathologic skin changes, along with marrow aplasia, support the diagnosis. TA-GVHD can readily be confirmed by demonstrating the presence of donor cells in the affected recipient on the basis of sex typing, ABO typing, cytogenetics, and/or DNA polymorphism studies.7, 8 As was true in this case, an implicated donor can often be identified. In this case, a fresh nonirradiated PLT concentrate transfused 90 days after fludarabine therapy was implicated based on circulating lymphocytes expressing foreign HLA alleles. The likelihood of developing TA-GVHD is related to the number and viability of transfused lymphocytes in the cellular component, the extent of immunosuppression in the recipient, and/or the degree of HLA antigen sharing between the donor and recipient. Even at present we do not know how these three variables interact to predispose to TA-GVHD, and risk groups for TA-GVHD are therefore unfortunately newly identified, as in this case, owing to the occurrence of this fatal complication in patients not previously recognized to be at risk. In this case, this PLT concentrate likely contained 108 lymphocytes; although leukoreduction can now reduce that level of residual contaminating lymphocytes to less than 106, even leukoreduced components have mediated TA-GVHD9, 10 and therefore must be gamma irradiated. This PLT concentrate was only 3 days old, and fresh products have higher lymphocyte viability and risk of transmitting TA-GVHD than stored components; although use of stored products may decrease risk of TA-GVHD, such products must be irradiated. Finally, HLA typing of the donor of the implicated PLT concentrate and of the recipient revealed the presence of circulating lymphocytes with donor alleles, confirming the diagnosis. Donor lymphocytes can also be identified in other recipient tissues, that is, skin, in the context of clinical TA-GVHD. The well-recognized setting predisposing to TA-GVHD in immunocompetent patients is when the cellular component donor is homozygous for a haplotype shared by the recipient,11-13 a setting in which donor lymphocytes are not recognized as foreign and rejected by the recipient. In the present case, this was not the case and the recipient shared only HLA DRβ1 and DQβ1 epitope with this donor, highlighting our inability at present to define the extent of HLA antigen sharing necessary to predispose to GVHD as it relates both to lymphocyte content and to viability in the component on the one hand, as well as extent of immunosuppression in the recipient on the other. The importance of identifying patients at risk for TA-GVHD is also unfortunately illustrated by this case, because this complication is nearly uniformly fatal. Attempted immunosuppressive therapies with glucocorticoids, antithymocyte globulin, cyclosporine, cyclophosphamide, and anti-T cell MoAbs, as well as PBPC transplantation, as was planned for this patient, have tragically only rarely been effective.14 Therefore, the major emphasis has been on identification of those at risk and its prevention. Fortunately TA-GVHD is preventable using gamma irradiation of cellular components, and both the FDA and the AABB recommend doses of irradiation to be 25 Gy (2500 cGy) to the central midplane with a minimum dose at any point of 15 Gy (1500 cGy), along with provisions to verify that irradiation at the appropriate dose has been performed.15 Irradiation is recommended in these clinical settings: cellular components given to a patient identified as being at risk for TA-GVHD, cellular components used for intrauterine transfusion, cellular components from a blood relative, and cellular components from donors selected for HLA compatibility, by typing or crossmatching.16 The current case expands the first category of individuals identified to be at risk for TA-GVHD to include not only patients receiving fludarabine for hematologic malignancies, but also to include all patients receiving fludarabine. Moreover, a case of TA-GVHD in a patient with non-Hodgkin's lymphoma who received cladarabine has recently been reported,15 and extension of those at risk for TA-GVHD to all patients receiving nucleoside analog therapy should be considered. What have we learned from this case report? This host was not previously recognized as being at risk for TA-GVHD, highlighting the fact that we cannot yet precisely define the extent of immunosuppression or HLA sharing which predisposes to this complication. Sadly, this case further confirms that TA-GVHD remains virtually untreatable and fatal once it has developed. In the transfusion community we go to great lengths using donor screening and associated testing to successfully minimize infectious complications of transfusion. What can be done to assure that all patients at risk for TA-GVHD receive irradiated components? This case extends the spectrum of patients at risk who should receive irradiated cellular components to the subgroup of similar patients. More importantly, however, this case further strengthens the argument and highlights the urgent need for universal provision of gamma irradiated cellular components to avoid this fatal immunohematologic complication of transfusion. As pointed out recently by Ness and Lipton,17 there are numerous examples besides this case in the medical literature, suggesting that the selective application of a transfusion protocol can lead to an adverse event, at least for some of the selected recipients. They cite the case of child with pneumonia, thought to be secondary to HIV infection, who had congenital immunodeficiency that had not previously been diagnosed. By the time the treating clinicians recognized the correct diagnosis, unirradiated blood had been administered, resulting in TA-GVHD and the death of the patient. Therefore, even patients in groups who qualify for selective transfusion protocols are not likely to receive these necessary blood components without a community standard that all patients receive irradiated cellular components. Indeed, surveys have revealed marked heterogeneity in practices regarding cellular blood component irradiation.6 Because irradiation is readily achievable and free of side effects, the only reason not to adopt universal irradiation of cellular components is cost. In the future technologies which inactivate lymphocytes within cellular components, such as viral inactivation,18 may offer a potential alternative to avoid TA-GVHD. At present, however, this tragic case highlights the urgent need to consider universal irradiation of cellular components in transfusion medicine practice.