A 36-year-old man is involved in a head-on motor vehicle accident, sustaining multiple blunt-force injuries. He is unconscious upon arrival at the ED and in hemorrhagic shock. He is given multiple transfusions with emergency-released packed red blood cell and plasma units to stabilize his condition before transfer to higher-level care. Upon arrival at a higher-level care facility, he undergoes surgical repair of his injuries and appears to be recovering. When the patient's history is taken, it reveals that he has been diagnosed with stage II classic Hodgkin lymphoma and has been treated so far with one round of doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) chemotherapy without any serious complications.
On day 8 of his hospitalization, he begins to develop new-onset fevers, diffuse coalescing erythematous skin lesions, diarrhea, and jaundice. Laboratory testing confirms new-onset liver dysfunction, mild anemia, new-onset neutropenia, and thrombocytopenia. A skin biopsy and colonoscopy are performed, as are radiographic and laboratory tests for evidence of a new infection. His current medications are also reviewed to investigate a possible new drug reaction.
Transfusion-associated graft-versus-host disease
Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare, usually fatal complication of blood product transfusion. It occurs when viable donor lymphocytes from a transfused blood product are not destroyed by the transfusion recipient's immune system and instead begin to proliferate in vivo. These donor lymphocytes recognize the recipient's human leukocyte antigen (HLA) proteins as foreign and trigger an immune response. As a part of this immune response, these proliferating donor lymphocytes begin to destroy cells within the recipient's skin, gastrointestinal tract, and liver, similar to GVHD that can occur after allogeneic stem-cell transplant. Uniquely in TA-GVHD, these proliferating donor lymphocytes also begin to attack the hematopoietic cells within the recipient's bone marrow.
As the donor lymphocytes mount an immune response against the foreign recipient, patients often develop fever, coalescing macular or bullous skin rashes, acute liver injury with intrahepatic cholestasis, and aplastic anemia due to bone marrow failure. Almost all patients with TA-GVHD die of overwhelming infection or bleeding complications. Treatment with various immunosuppressant regimens has been attempted but proven almost universally unsuccessful in stopping TA-GVHD. Hence, the best option available to clinicians is to try to prevent its occurrence in the first place, particularly in patients at increased risk.
Normally, viable donor lymphocytes within a blood product are destroyed by the recipient's cellular immune system after transfusion. This process of destroying transfused donor lymphocytes can fail, though, for two reasons: 1) HLA protein similarity between the donor and recipient, allowing donor lymphocytes to evade the recipient's immune system (e.g., directed donations between biologic relatives) (11. Thaler M, Shamiss A, Orgad S, et al. The role of blood from HLA-homozygous donors in fatal transfusion-associated graft-versus-host disease after open-heart surgery. N Engl J Med. 1989;321:25-8. [PMID: 2786605]) and 2) impaired cellular immunity in the recipient, hindering destruction of transfused donor lymphocytes.
Cases of TA-GVHD have been reported in several patient groups with potentially impaired cellular immunity. Reported risk factors include: congenital cellular immunodeficiencies (e.g., severe combined immunodeficiency, Wiskott-Aldrich syndrome, DiGeorge syndrome) (22. Sebnem Kilic S, Kavurt S, Balaban Adim S. Transfusion-associated graft-versus-host disease in severe combined immunodeficiency. J Investig Allergol Clin Immunol. 2010;20:153-6. [PMID: 20461970]), bone marrow or stem-cell transplant (including before harvest or transplantation) (33. Postmus PE, Mulder NH, Elema JD. Graft versus host disease after transfusions of non-irradiated blood cells in patients having received autologous bone marrow. A report of 4 cases following ablative chemotherapy for solid tumors. Eur J Cancer Clin Oncol. 1988;24:889-94. [PMID: 2844543]), Hodgkin lymphoma (44. Decoste SD, Boudreaux C, Dover JS. Transfusion-associated graft-vs-host disease in patients with malignancies. Report of two cases and review of the literature. Arch Dermatol. 1990;126:1324-9. [PMID: 2221937]), receipt of purine analogue drugs (azathioprine, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine, vidarabine) (55. Boldt DH, Von Hoff DD, Kuhn JG, et al. Effects on human peripheral lymphocytes of in vivo administration of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5’-monophosphate (NSC 312887), a new purine antimetabolite. Cancer Res. 1984;44:4661-6. [PMID: 6205751], 66. Leitman SF, Tisdale JF, Bolan CD, et al. Transfusion-associated GVHD after fludarabine therapy in a patient with systemic lupus erythematosus. Transfusion. 2003;43:1667-71. [PMID: 14641861]) or antilymphocyte agents (alemtuzumab, antithymocyte or antilymphocyte globulin, basiliximab) (77. Marsh J, Socie G, Tichelli A, et al; European Group for Blood and Marrow Transplantation (EBMT) Severe Aplastic Anaemia Working Party. Should irradiated blood products be given routinely to all patients with aplastic anaemia undergoing immunosuppressive therapy with antithymocyte globulin (ATG)? A survey from the European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party [Letter]. Br J Haematol. 2010;150:377-9. [PMID: 20528874]), and solid organ malignancies usually undergoing intensive chemotherapy regimens (88. Labotka RJ, Radvany R. Graft-versus-host disease in rhabdomyosarcoma following transfusion with nonirradiated blood products. Med Pediatr Oncol. 1985;13:101-4. [PMID: 3856732]).
It should be noted that a subset of patients acquiring TA-GVHD have no such risk factors for impaired cellular immunity and their predisposing factor for TA-GVHD remains unknown (99. Kopolovic I, Ostro J, Tsubota H, et al. A systematic review of transfusion-associated graft-versus-host disease. Blood. 2015;126:406-14. [PMID: 25931584]).
Viable donor lymphocytes are present in any blood product that has not been previously frozen. Hence, any blood product except frozen plasma, cryoprecipitate, or deglycerolized red blood cells can cause TA-GVHD. To help mitigate the risk of TA-GVHD, cellular blood products can either be irradiated or, if platelets, undergo pathogen reduction. Either of these blood product modifications cause DNA damage to the donor lymphocytes within the blood product, preventing those donor lymphocytes from proliferating later within the recipient.
The approach to cellular blood product irradiation varies across institutions. Some institutions universally irradiate all cellular blood products, while others only irradiate cellular blood products at the request of the ordering clinician. We perform a hybrid approach at our institution: Irradiate whole blood or packed red blood cells products at the request of the ordering clinician and universally irradiate or pathogen-reduce all platelet products. We recommend that hospitalists contact their local blood bank or transfusion lab to learn what their approach is to cellular blood product irradiation and develop a mitigation strategy for TA-GVHD.
Irradiation of whole blood or packed red blood cell products causes immediate damage to red blood cell membranes. This leads potassium levels to rise within the blood product during storage as intracellular potassium leaks out (1010. Janatpour K, Denning L, Nelson K, et al. Comparison of X-ray vs. gamma irradiation of CPDA-1 red cells. Vox Sang. 2005;89:215-9. [PMID: 16262754], 1111. Weiskopf RB, Schnapp S, Rouine-Rapp K, et al. Extracellular potassium concentrations in red blood cell suspensions after irradiation and washing. Transfusion. 2005;45:1295-301. [PMID: 16078915]). For transfusion recipients with pre-existing potassium issues, irradiated whole blood or packed red blood cells that have been stored for extended periods in inventory may cause issues. One can minimize this adverse effect by irradiating whole blood or packed red blood cells at or near the time of issuance (on demand).
Irradiation of platelet products, on the other hand, does not cause any clinically significant changes during subsequent storage. Irradiated platelet products have similar in vitro responses and in vivo recovery as nonirradiated platelet products (1212. Rock G, Adams GA, Labow RS. The effects of irradiation on platelet function. Transfusion. 1988 Sep-Oct;28:451-5. [PMID: 3420673], 1313. Sweeney JD, Holme S, Moroff G. Storage of apheresis platelets after gamma radiation. Transfusion. 1994;34:779-83. [PMID: 8091467], 1414. Van der Meer PF, Pietersz RN. Gamma irradiation does not affect 7-day storage of platelet concentrates. Vox Sang. 2005;89:97-9. [PMID: 16101691]).
Back to the patient
The patient's blood cultures and imaging are negative for infection. Skin biopsy reveals histologic features compatible with GVHD, and there is no pronounced eosinophilic infiltrate that would suggest a drug reaction. Colon biopsies also reveal histologic features compatible with GVHD, while special stains for cytomegalovirus or cryptosporidium infection are negative.
The patient does not have the expected history of allogeneic stem-cell transplant for a classic diagnosis of GVHD. His Hodgkin lymphoma is a risk factor for developing TA-GVHD, which occurred after receipt of non-irradiated cellular blood products.
His fevers, skin lesions, liver dysfunction, diarrhea, and cytopenias continue to worsen despite various medical interventions, including multiple immunosuppressant agents. Eventually, he acquires a bacterial infection due to extensive skin breakdown, gastrointestinal damage, and critical neutropenia and becomes septic. He dies days later despite aggressive and maximal antimicrobial therapy and vasopressor support.