Transfusion-associated graft-versus-host disease in immunocompetent patients: report of a fatal case associated with transfusion of blood from a second-degree relative, and a survey of predisposing factors

A patient without evident immune deficiency who received a transfusion of blood from a second-degree family member developed fatal transfusion- associated graft-versus-host disease (TA-GVHD). The donor was homozygous for an HLA haplotype for which the recipient was heterozygous (one-way HLA match). All 39 reported cases of TA-GVHD in immunocompetent patients were reviewed to ascertain the predisposing factors and to define the indications for irradiating blood for this population. HLA typing was described in 15 cases; in 13, including seven related and six unrelated donors, a one-way HLA match was present. Thirty-one (79%) of the 39 cases were reported from Japan (and 196 other cases are cited in the Japanese literature), but a one-way HLA match among unrelated donors at HLA-A, -B, -DR loci is only approximately two to four times more likely in Japanese persons than in whites. Fresh blood (< 96 hours old) was used in 29 (94%) of the 31 cases reported from Japan and in 33 (87%) of 38 cases overall (in one case, the age of the blood used was not reported). Thus, factors that appear to predispose to TA-GVHD in immunocompetent patients are a one- way HLA match, fresh blood, and, possibly, Japanese ancestry. Irradiating cellular blood components from all blood relatives of transfusion recipients will not completely eliminate the risk of TA- GVHD.     

Fatal erythroderma (suspected graft-versus-host disease) after cholecystectomy. Retrospective analysis

Fatal postoperative erythroderma (POE) developed in a 52-year-old woman with gallstones who underwent elective cholecystectomy. During surgery, she was transfused with 3 units of unirradiated packed red cells stored in the liquid state for at least 4 days after collection. The POE is believed to have been the result of transfusion-associated graft-versus-host disease (TA-GVHD). The diagnosis of GVHD was based upon the characteristic clinical picture and retrospective HLA typing. The implicated donor was homozygous for an HLA haplotype that appeared to be shared with the recipient: A24-CBL-Bw52-DR2-DRw52-DQw1, the most common haplotype in the Japanese population. This case raises the possibility that a transfusion of relatively fresh blood from a donor who has no HLA antigens incompatible with the recipient may result in GVHD in patients with no apparent immunoincompetence who are undergoing relatively minor surgery with no chemotherapy or radiation therapy.     

Transfusion-associated GVHD: 10 years' experience at the American University of Beirut-Medical Center

BACKGROUND: Although rare, transfusion-associated GVHD (TA-GVHD) is a fatal complication of blood transfusion in which active lymphocytes from the donor attack and destroy recipient organs and tissues. STUDY DESIGN AND METHODS: A search of patient records was carried out at the American University of Beirut-Medical Center, looking for patients who developed TA-GVHD over a 10-year period extending from 1991 to 2001. Relevant information was collected and analyzed. RESULTS: A total of 10 records were found as a result of this search. All were immunocompetent and received fresh nonleukoreduced, nonirradiated blood. The majority received the transfusion at outside periphery hospitals. They received different treatment modalities. The mortality rate was 100 percent. CONCLUSION: TA-GVHD is a serious complication with very high mortality. Effective prevention guidelines should be established in Lebanon including irradiation and the creation of a central blood bank.     

Potential for transfusion-associated graft-versus-host disease due to apheresis platelets matched for HLA class I antigens

Transfusion-associated graft-versus-host disease (TA-GVHD) has been reported in immunocompetent recipients of nonirradiated cellular blood components from donors who are homozygous for an HLA haplotype shared with the patient. In these cases, donor lymphocytes have no antigens foreign to the recipient, and this similarity in HLA antigens appears important for the development of TA-GVHD. Experience with 65 patients receiving apheresis platelets matched for class I HLA antigens was reviewed to determine the incidence of such a transfusion among HLA- matched, unrelated donor-recipient pairs. In 5 percent of transfusions (31/673), the patient received lymphocytes from a donor exhibiting no antigens foreign to the recipient, but the patient had additional HLA-A or -B antigens not present on donor lymphocytes. Twenty-three percent (n = 15) of patients received at least one such transfusion. In addition, most patients were immunosuppressed as a result of their underlying disease or therapy, which may decrease the degree of antigen matching required to initiate TA-GVHD. Until the pathogenesis of this disease is better understood, it is recommended that the transfusion of an HLA-matched cellular blood component be considered a risk factor for the development of TA-GVHD regardless of the patient's immune status, and that all such blood components be irradiated.     

Transfusion‐associated graft‐versus‐host disease in a liver transplant recipient: an unusual presentation and review of the literature

BACKGROUND: Transfusion‐associated graft‐versus‐host disease (TA‐GVHD) is a rare, nearly universally fatal complication from transfusion of nonirradiated cellular blood components, occurring when a recipient's immune system is unable to recognize and destroy transfused T lymphocytes. Irradiation of cellular components eliminates this risk. We present an unusual case of a liver transplant recipient developing TA‐GVHD 13 weeks after transfusion of a random unit of nonirradiated red blood cells (RBCs) that happened to be from a donor homozygous for an HLA haplotype shared by the patient. STUDY DESIGN AND METHODS: This study was a single case review of a liver transplant recipient who developed skin GVHD and marrow aplasia. Clinical course and the chimerism studies involving the patient, the liver donor, and the blood donor are detailed. RESULTS: The patient presented 3 months posttransplant with GVHD of his skin and marrow aplasia. In addition to standard antigraft immunosuppression, this patient had started the interleukin‐1 receptor antagonist anakinra on Posttransplant Day 13 for an acute gout flare. Chimerism studies on the patient's peripheral blood identified a population of CD3 cells that did not originate with either the patient or his liver donor. HLA studies and microsatellite profiling of the unknown CD3 population identified the source of the patient's TA‐GVHD, a unit of nonirradiated, nonleukoreduced apheresis RBCs. CONCLUSION: Use of an immunomodulating agent may have contributed to the development of TA‐GVHD in a liver transplant patient who received a random unit of nonirradiated RBCs by chance from an unrelated haploidentical donor.     

Fatal transfusion-associated graft-versus-host disease in an immunocompetent recipient of a volunteer unit of red cells

BACKGROUND:  Transfusion-associated graft-versus-host disease (TAGVHD) is a lethal complication of transfusion of nonirradiated cellular blood components to a susceptible recipient.
CASE REPORT:  An 82-year-old man underwent cardiac surgery during which he received 6 units of red cells (RBCs) and a 6-unit pool of platelets (PLTs). He was discharged with a normal white blood cell (WBC) count and hemoglobin (Hb) level and a PLT count of 104 × 10⁹ per L. He was readmitted 2 weeks later with a diffuse erythematous rash, a sore throat, and difficulty swallowing. His WBC count was 2.1 × 10⁹ per L, his Hb level was 12.0 g per dL, and his PLT count was 131 × 10⁹ per L. The next day he had worsening cytopenias: WBC count, 1 × 10⁹ per L; Hb level, 10.9 g per dL; PLT count, 104 × 10⁹ per L. He also had diarrhea. A marrow biopsy showed a severe hypoplasia without evidence of malignancy. A skin biopsy showed Grade II GVHD. The patient worsened and despite aggressive therapy he expired on Postoperative Day 42. DNA-based HLA testing of the 12 blood donors was performed. One of the RBC donors was found to be homozygous for an HLA Class I and Class II haplotype in the patient.
CONCLUSION:  This is the first reported case in the United States of fatal TAGVHD from RBCs in an immunocompetent patient who received a randomly selected unit of RBCs from a donor who was homozygous for a shared HLA haplotype. The policy of selective irradiation should be reexamined.     

Fatal transfusion-associated graft-versus-host disease with concomitant immune hemolysis in a group A combat trauma patient resuscitated with group O fresh whole blood

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but well-established fatal complication of blood transfusion. It can occur in immunocompetent patients when they receive transfusions from human leukocyte antigen-haploidentical donors who have lymphocytes with antigens that are not recognized as foreign by the host, but that recognize the host's tissues as foreign. It is generally viewed as a T-cell-mediated process. Graft-induced immune hemolysis or passenger lymphocyte syndrome is a well-described complication of marrow or solid organ transplantation in which immune competent donor B cells produce alloantibodies to recipient red blood cell (RBC) antigens and cause hemolysis of the recipient's RBCs. It is generally considered as a separate process from GVHD, although it could be considered a type of GVHD. Despite the theoretical possibility of both a B-cell and T-cell component to TA-GVHD, detection of a humoral antibody in cases of acute TA-GVHD has not been described. We describe the clinical course and laboratory evaluation of a group A combat trauma patient who was acutely resuscitated with group O fresh whole blood and RBCs and group AB fresh-frozen plasma who experienced the onset of the clinical symptoms of TA-GVHD as well as the onset of hemolysis due to donor-derived anti-A in his plasma 11 days after transfusion.     

Transfusion-associated graft-versus-host disease in immunocompetent patients: case series and review of the literature

BACKGROUND: Transfusion-associated graft-versus-host disease (TA-GVHD) is a fatal complication of transfusion of blood products that usually affects immunocompromised patients. Articles reporting this condition in immunocompetent recipients are usually from countries that still have problems in irradiation of blood products. CASE REPORTS: This report presents fatal TA-GVHD in four immunocompetent patients referred from rural areas where blood irradiation is still not the routine procedure to our tertiary-care center between July 2004 and July 2005. A similar history and chronological order of events were observed: fresh whole-blood transfusion from relatives, fever, rash, liver dysfunction, diarrhea, and pancytopenia. Skin biopsies demonstrated Grade II to III GVHD involvement. Marrow biopsies showed hypoplasia. In two cases, HLA typing studies were performed. Donors were homozygous for a shared HLA haplotype in the patients. All cases were admitted to the intensive care unit within 3 weeks after transfusions with the diagnosis of sepsis, which rapidly progressed to septic shock and multiorgan failure. Another common observation was Candida albicans growth in blood cultures. Unfortunately, all died despite prompt and appropriate sepsis treatment, along with immunomodulatory therapy. CONCLUSION: TA-GVHD is probably more prevalent than reported in the literature. It must be considered in the differential diagnosis, if the patient with a recent transfusion history admits with fever, skin rash, abnormal liver function tests, and pancytopenia associated with hypoplastic marrow. In rural areas where gamma irradiation is not possible, the overall policy of transfusion (e.g., restriction of transfusion indications and alternative methods for pathogen inactivation) should be reassessed.     

Diagnosis of transfusion-associated graft-vs.-host disease: the importance of short tandem repeat analysis

Transfusion-associated graft-vs.-host disease (TA-GvHD) can occur following transfusion of blood products containing immunocompetent lymphocytes, usually from HLA homozygous donors, into immunocompromised patients sharing one HLA haplotype with the donor. The diagnosis of TA-GvHD may be delayed due to the initial nonspecific clinical features involved. Investigations to detect the presence of donor-derived cells in the blood and/or affected tissues of the recipient are essential to confirm the diagnosis. We report the investigation of suspected TA-GvHD using short tandem repeat (STR) analysis, to detect the presence of donor cells (chimerism), in an immunocompetent patient admitted for coronary artery bypass surgery. Peripheral blood and skin biopsies (from affected and nonaffected sites) from the patient and peripheral blood samples from the implicated donors were taken for HLA typing and STR analysis. STR analysis revealed the presence of donor material in the patient's peripheral blood sample and in DNA extracted from the affected skin biopsy but not the unaffected biopsy, suggesting lymphocytes from this donor were responsible for the development of TA-GvHD. Furthermore, HLA typing results supported the diagnosis of TA-GvHD. These data demonstrate the use of STR and HLA analysis as effective tools in the diagnosis of TA-GvHD.     

The impact of universal leukodepletion of the blood supply on hemovigilance reports of posttransfusion purpura and transfusion-associated graft-versus-host disease

BACKGROUND: The pathogenesis of posttransfusion purpura (PTP) and transfusion-associated graft-versus-host disease (TA-GVHD) involves patient exposure to donor platelets (PLTs) and T lymphocytes, respectively, which are removed during blood component leukodepletion (LD). STUDY DESIGN AND METHODS: Reports of PTP and TA-GVHD to the UK hemovigilance scheme Serious Hazards of Transfusion (SHOT) from 1996 to 2005 were compared before and after implementation of universal LD during 1999. RESULTS: There were 45 reports of PTP, with a mean of 10.3 per year before universal LD and 2.3 per year afterward (p < 0.001). All patients had received red cells, but before universal LD, only 1 of 31 (3%) cases had also received PLTs, compared to 8 of 14 (57%) afterward (p < 0.001). Thirty-four cases (76%) had human platelet antigen (HPA)-1a antibodies, whereas 11 had antibodies to other HPA specificities, only 1 of which occurred after LD. Two cases reported before LD also had heparin-dependent PLT antibodies. There were 13 reports of TA-GVHD, all fatal, of which only 2 cases of undiagnosed immunodeficiency met current UK criteria for irradiated components. Eight others had one or more risk factors: B-cell malignancy (6), steroids (1), fresh blood (1), and donor-recipient HLA haplotype share (4). Eleven cases were due to non-LD and 2 to LD components (p < 0.001). No cases have been reported since 2001. In an additional 405 cases, nonirradiated components were transfused in error to high-risk recipients, mainly on fludarabine, but none developed TA-GVHD. CONCLUSIONS: These findings suggest that universal LD has further reduced the already low risk of TA-GVHD in immunocompetent recipients and has altered the profile of PTP cases.     

Renal transplantation: HLA-linked, non-cytotoxic antibodies develop after blood transfusion

1. A previously untransfused dialysis patient was given blood from a single donor on three occasions and sera were obtained from the recipient before and after transfusion. 2. The sera were tested against B-lymphocytes from the blood donor and his family in the erythrocyte-antibody rosette inhibition assay to determine whether any Fc-receptor-blocking activity which developed was HLA linked. 3. Antibody activity was noted after the second transfusion and was directed toward B-lymphocytes from the blood donor and his family members sharing the haplotype HLA A11, B12 with him. 4. These antibodies were removed by the absorption of active sera with lymphocytes from the blood donor but not from (a) his sibling who shared no HLA antigens with him or (b) the transfusion recipient. Absorption of the active sera with platelets from the blood donor did not remove activity. 5. These results indicate that Fc-receptor-blocking antibodies developing after blood transfusion are directed to HLA-linked antigens on donor lymphocytes.     

Experimental allergic encephalomyelitis in the absence of a classical delayed-type hypersensitivity reaction. Severe paralytic disease correlates with the presence of interleukin 2 receptor-positive cells infiltrating the central nervous system

One characteristic of experimental allergic encephalomyelitis (EAE) in all species is the presence of a considerable leukocyte infiltrate in the central nervous system (CNS). By adoptive transfer of EAE into irradiated or nonirradiated Lewis strain rats we now show that the bulk (greater than 90%) of infiltrating cells in the CNS are superfluous to the induction of disease, as lethally irradiated recipients, despite having very few infiltrating cells in the CNS, acquire severe paralytic EAE. The reduction in the level of infiltration in irradiated recipients is selective, however, as both irradiated and nonirradiated diseased animals have very similar numbers of cells expressing IL-2-R. Disease in irradiated recipient animals is associated with substantial submeningeal hemorrhage in the spinal cord and brain stem and similar hemorrhages are found in recipients rendered leukopenic with cytotoxic drugs. Clinical signs of disease and hemorrhage are preventable, however, by administration to the recipient rats of mAbs specific for the CD4 antigen. Classic delayed-type hypersensitivity (DTH) reactions are transferable with the same cells that produce EAE in both irradiated and nonirradiated recipient rats, but such transfer of DTH is observed only in nonirradiated recipient animals and not in irradiated rats. Collectively, the findings reported herein support the conclusion that the paralysis characteristic of acute EAE is mediated by the direct action of very small numbers of activated CD4+ lymphocytes that infiltrate the CNS and produce their effects by inducing vascular damage. The findings are not consistent with reports that the lesions in EAE are produced by a classic DTH reaction.     

A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria

We investigated the molecular defect of the ferrochelatase gene in a Japanese patient with erythropoietic protoporphyria (EPP), and identified a novel 16 base pair (574-589) deletion within exon 5. This deletion resulted in a frame-shift mutation and created a premature stop codon at amino acid position 198. The same molecular defect was also identified in his mother and a brother who had symptomatic EPP, but not in his father who was asymptomatic. The subjects with EPP were homozygous for the low expression haplotype, while his father was heterozygous for this haplotype. These results indicate that the combination of a 16 base pair deletion and low expression of the wild-type allelic variant is responsible for EPP in this pedigree.     

The irradiation of blood and blood components to prevent graft-versus-host disease: Technical issues and guidelines

In recent years, there have been several advances in blood irradiation practice. These include a better definition of the most appropriate dose level that should be used when irradiating blood components. Commercial innovation has provided the tools for a quality assurance program to assess the dose that is delivered throughout the canister in a free-standing irradiator, and, through the use of radiationsensitive indicator labels, to confirm that the irradiation process has taken place. With the apparent increased use of linear-accelerators to irradiate blood components, appropriate quality assurance measures need to be developed. The maximum storage period for irradiated red cells should be shorter than for nonirradiated red cells if the treatment is performed early during the storage period because irradiation reduces the in vivo 24-hour red cell recovery parameter. The storage period for irradiated platelets does not need to be modified. Some questions are being raised regarding whether fresh-frozen plasma should be irradiated to inactivate a small number of immunocompetent progenitor cells that may be present.Table 4 summarizes the practices that should be followed in connection with the technical issues that have been addressed in this article. These guidelines follow the recommendations issued in July 1993 by the FDA in the United States. This article and Tables 1 and 2 contain additional guidelines.     

Transfusion induced Graft versus host disease - Case report in a 2 year child

Graft-versus-host disease (GVHD) is a rare, almost always fatal complication of a blood transfusion. It occurs much more commonly after bone marrow transplantation, a setting in which it is less severe-mortality rate of 20-25% following transplantation versus 80-90% when associated with a transfusion. Transfusion associated GVHD occurs in two settings: when the recipient is immunodeficient; and when there is a specific type of partial HLA matching between the donor and recipient. Here we present a case of transfusion associated GVHD which developed when a 2 year old immunocompetent girl was given whole blood which was taken by his father. Inspite of very intense therapy with parental steroids and oral cyclosporine the child succumbed to death.     

Origins of circulating endothelial cells and endothelial outgrowth from blood

Normal adults have a small number of circulating endothelial cells (CEC) in peripheral blood, and endothelial outgrowth has been observed from cultures of blood. In this study we seek insight into the origins of CEC and endothelial outgrowth from cultures of blood. Fluorescence in situ hybridization analysis of blood samples from bone marrow transplant recipients who had received gender-mismatched transplants 5-20 months earlier showed that most CEC in fresh blood had recipient genotype. Endothelial outgrowth from the same blood samples after 9 days in culture (5-fold expansion) was still predominantly of the recipient genotype. In contrast, endothelial outgrowth after approximately 1 month (102-fold expansion) was mostly of donor genotype. Thus, recipient-genotype endothelial cells expanded only approximately 20-fold over this period, whereas donor-genotype endothelial cells expanded approximately 1000-fold. These data suggest that most CEC in fresh blood originate from vessel walls and have limited growth capability. Conversely, the data indicate that outgrowth of endothelial cells from cultures of blood is mostly derived from transplantable marrow-derived cells. Because these cells have more delayed outgrowth but a greater proliferative rate, our data suggest that they are derived from circulating angioblasts.     

输血相关性移植物抗宿主病的研究进展

输血相关性移植物抗宿主病 (TA GVHD)的发生需具备输入一定数量的免疫活性的淋巴细胞、供体与受体之间存在组织相容性及受者的免疫功能低下。供、受体淋巴细胞相互作用 ,激活并使供者的T细胞克隆性扩增 ,导致细胞因子释放 ,继而损伤受者的细胞和组织 ,典型的临床表现有发热、皮疹、肝炎、腹泻和全血细胞减少。本病虽少见但其病死率高达 90 %以上。输注前 ,将血液或血细胞进行γ 射线或紫外线照射 ,可预防TA GVHD的发生。     

Massive haemolysis in a group A recipient of a group O peripheral blood stem cell allogeneic transplant

A 28-year-old man with lymphoblastic lymphoma received G-CSF mobilized stem cells from his HLA identical sister, who had been taking methotrexate for psoriasis until 1 month prior to harvest. The recipient's blood group was A Rh D positive and donor's group O Rh D positive. Engraftment and major haemolysis were evident by day 9. From day 9 to day 13 he received 17 units of blood (approximately 3 L of red cells) at a time when his calculated red cell volume was 1 L. This massive transfusion requirement was not explained by his clinical condition and led us to consider factors that may have influenced the degree of haemolysis. The stem cell graft contained 2.85 x 10(6) CD34+ cells kg(-1) and we speculate there was B cell hyperactivity following the withdrawal of methotrexate in the donor and this went unchecked by the omission of methotrexate in the GVHD prophylaxis of the recipient. We have also considered the phenomenon of bystander haemolysis, previously unreported in this situation, as haemolysis of transfused group O blood must have also occurred. The case also illustrates the importance of transfusing donor type red cells and recipient type fresh frozen plasma (FFP) and platelets into minor mismatched transplant patients. The decision to revert to donor type FFP and platelets should only be made when the direct antiglobulin test is negative and the appropriate isohaemagglutinins are no longer demonstrable.     

Effects of 4000 rad irradiation on the in vitro storage properties of packed red cells

Immunosuppressed patients who require red cell transfusions receive irradiated (1500-3000 rad) packed red cells. These cells are irradiated immediately before infusion. If a large group of patients become immunosuppressed due to exposure to radiation or chemicals, the ability to supply large volumes of irradiated blood at the time of use might not be possible. An alternate solution to providing quantities of irradiated blood is to irradiate the units prior to storage. This study presents in vitro data comparing storage of paired packed red cell units either irradiated or not irradiated. Five units of fresh blood drawn into citrate-phosphate-dextrose-adenine (CPDA-1) were packed to a hematocrit of 75 +/- 1 percent, and then each unit was divided in two equal parts. One of each pair was irradiated (4000 rads), and both parts of each unit were stored for 35 days at 4 degrees C. Samples were analyzed every 7 days. Irradiation caused a slight drop in red cell adenosine triphosphate and 2,3 diphosphoglycerate and a slight increase in plasma hemoglobin compared to controls. Methemoglobin, pH, and glucose consumption were identical to the controls. The evidence indicates that irradiation did not cause biochemical or metabolic changes in the red cells that would lead us to suspect a difference between irradiated and nonirradiated stored red cells in function or viability. These negative findings require in vivo confirmation.     

Early diagnosis and successful treatment of a patient with transfusion-associated GVHD with autologous peripheral blood progenitor cell transplantation

BACKGROUND: Transfusion-associated GVHD (TA-GVHD) is an uncommon complication of blood transfusion. Diagnosis of TA-GVHD is difficult, and it is usually rapidly fatal. There are few documented sur- vivors of TA-GVHD. CASE REPORT: A 61-year-old woman with chronic lymphocytic leukemia (CLL) was treated with fludarabine followed by combination chemotherapy and high-dose radioimmunotherapy and peripheral blood progenitor cell (PBPC) rescue. She was transfused with nonirradiated blood components at an outside hospital and presented 10 days later with rash, elevated liver enzymes, and progressive pancytopenia. Skin biopsy was consistent with GVHD, and HLA typing of lymphocytes from the patient demonstrated mixed chimerism. The patient was treated with solumedrol and cyclosporin A, followed by high-dose cyclophosphamide and antithymocyte globulin and autologous PBPC infusion. She had rapid engraftment, resolution of skin rash, and normalization of liver function abnormalities. She is in good health with normal blood counts and no evidence of CLL 34 months after transplantation. CONCLUSION: TA-GVHD occurs in the setting of an immunocompromised recipient receiving nonirradiated blood components. A typical presentation includes skin rash, liver function abnormalities, and pancytopenia. Demonstration of mixed chimerism by HLA typing facilitated diagnosis in this patient. High-dose immunosuppression, facilitated by the availability of autologous PBPCs, resulted in a successful outcome.