Transfusion-associated GVHD after fludarabine therapy in a patient with systemic lupus erythematosus

BACKGROUND: Fludarabine, a purine antimetabolite with potent immunosuppressive properties, has previously been associated with the development of transfusion-associated GVHD (TA-GVHD) in patients with hematologic malignancies. Its role as a risk factor for TA-GVHD in patients without underlying leukemia or lymphoma is uncertain. STUDY DESIGN AND METHODS: A 42-year-old female with refractory lupus nephritis received three monthly cycles of fludarabine (30 mg/m2/day on Days 1-3) and cyclophosphamide (500 mg/m2 on Day 1). Three months after the last dose of fludarabine, she received 2 units of packed RBCs and 6 units of pooled random platelets, none of which were irradiated. Two weeks later, fever, rash, aminotransferase elevations, hyperbilirubinemia, and pancytopenia developed. RESULTS: Marrow biopsy showed severe aplasia and skin biopsy was consistent with GVHD. Allele-level HLA typing on circulating lymphocytes revealed extra HLA alleles not present in her pretreatment sample, but identical to the HLA haplotypes of an unrelated platelet donor. Treatment with antithymocyte globulin, cyclosporine, and prednisone was followed by preparatory conditioning for a PBPC transplant from an HLA-identical sibling, but the patient died of disseminated candidiasis before transplant. CONCLUSIONS: Fludarabine and other purine analogs are increasingly used in the treatment of disorders other than hematologic malignancy, such as autoimmune disease. The occurence of TA-GVHD after fludarabine therapy in a patient with lupus strongly suggests that this drug is sufficiently immunoablative to be an independent risk factor for TA-GVHD. Irradiation of blood components should be considered in all patients who receive fludarabine therapy.     

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.     

Spontaneous resolution of transfusion-associated graft-versus-host disease

BACKGROUND: Transfusion-associated graft-versus-host disease (TA-GVHD) is a serious complication of blood transfusion that is characterized by high fever, a scaly maculopapular erythematous rash, diarrhea, hepatocellular damage with marked elevation of liver function test values, and pancytopenia. It can occur in immunocompetent as well as immunocompromised recipients. The existence of atypical TA-GVHD that resolves spontaneously and does not exhibit all of the manifestations has been suggested, but there has been to date no documented diagnosis of GVHD supported by evidence of engraftment. CASE REPORT: A female patient presented and was diagnosed with acute myelogenous leukemia (AML:M4), and, after unsuccessful combination chemotherapy, she received a transfusion and developed manifestation of TA-GVHD as well as evidence of chimerism. TA-GVHD was proved by demonstrating Y chromosome-specific genes in the skin by polymerase chain reaction. The manifestations of clinical GVHD abated within 4 months. CONCLUSION: Polymerase chain reaction analysis of Y chromosomes in specimens from female patients is useful in the diagnosis of suspected cases of spontaneously resolving TA-GVHD.     

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.     

Transfusion-associated graft-versus-host disease in patients with Hodgkin''s disease and T cell lymphoma

Two patients, one with Hodgkin's disease and one with peripheral T cell lymphoma, developed transfusion-associated graft-versus-host disease 16 and 8 days after transfusion of red cell and platelet concentrates. Fever and skin rash were followed rapidly by an elevation of liver enzymes and the onset of diarrhoea and pancytopenia. Despite treatment with high-dose methylprednisolone and anti-lymphocyte globulin, commenced within 7 and 2 days of the onset of rash, grade IV GvHD persisted and both patients died with severe pancytopenia. HLA types of peripheral lymphocytes of the patient with Hodgkin's disease were inconsistent with those of her parents and siblings, but HLA typing of her fibroblasts revealed that her true type was consistent with those of her parents and that her circulating lymphocytes were not genetically her own. The HLA types of the patient with T-cell lymphoma were inconsistent with those of her siblings which suggests, but, in the absence of other evidence, does not prove, chimaerism.     

Transfusion-associated graft-versus-host disease in a presumably immunocompetent patient after transfusion of stored packed red cells

A 54-year-old woman developed transfusion-associated graft-versus-host disease (TA-GVHD) after the transfusion of stored packed red cells obtained from unrelated donors. The patient was presumed to be immunocompetent. A diagnosis of TA-GVHD was made by clinical features and postmortem pathologic findings. Sex chromatin analysis of the patient's lymphocytes demonstrated chimerism. HLA typing of the blood donors revealed one to be HLA-homozygous for one of the patient's HLA haplotypes (A33-B44-Cblank). This case illustrates the risk in the general patient population of TA-GVHD after routine blood transfusion therapy. Workers should be aware of this possibility and should continue searching for an efficient way to prevent it.     

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。     

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 graft-versus-host disease associated with transfusions of HLA- matched, HLA-homozygous platelets from unrelated donors

BACKGROUND : Transfusion-associated graft-versus-host disease (TA-GVHD) due to blood from HLA-homozygous related and unrelated blood donors has been described. CASE REPORT: Fatal TA-GVHD due to the transfusion of HLA-matched platelets from an unrelated HLA-homozygous donor is reported. A 61-year-old man with a history of diabetes mellitus and myelodysplastic syndrome was diagnosed with acute myelogenous leukemia in November 1991. Induction chemotherapy resulted in aplasia, which was followed by a normocellular marrow with mild dysplasia and continued karyotypic abnormalities. High-dose chemotherapy was given in a second attempt to achieve complete remission. HLA-matched platelets were ordered when platelet refractoriness developed. The patient was HLA- heterozygous for HLA-A and -B antigens (A2, 29; B37, 44). Over the next 7 days, four unirradiated HLA-matched plateletpheresis units were transfused; one was probably homozygous for both HLA-A and -B antigens (A2, -; B44, -) and was transfused first, and three were probably homozygous for an HLA-B antigen (A2, 29; B44, -) and were white cell reduced. No blood relatives served as donors. Seven days after the first HLA-matched platelet transfusion, fever, chills, and diarrhea developed; 2 days later, a rash was present. Liver enzymes increased markedly. Renal and respiratory failure ensured. A skin biopsy was consistent with GVHD. Despite immunosuppressive therapy, the patient died 19 days after the first HLA-matched platelet transfusion. CONCLUSION : TA-GVHD has been recognized in immunocompromised, HLA- heterozygous patients receiving blood from blood relatives who are HLA- homozygous. patients receiving blood from either blood relatives or non- blood relatives who are HLA-homozygous. This HLA-heterozygous patient received transfusions of unirradiated, class I HLA-homozygous platelets, which were specifically ordered as HLA-matched, and his death was attributed to TA-GVHD. Consideration should always be given to providing irradiated blood for immunosuppressed patients, especially when HLA-matched platelets are used, to prevent TA-GVHD.     

A case of transfusion-associated graft-versus-host disease not prevented by white cell-reduction filters

A case of transfusion-associated graft-versus-host disease (TA-GVHD) in a patient with non-Hodgkin's lymphoma is reported. The patient, a 67-year-old woman, was diagnosed as having diffuse, mixed type non-Hodgkin's lymphoma, at clinical stage IIIA. She was treated with combination chemotherapy and received multiple blood transfusions for anemia and thrombocytopenia. Although white cells (WBCs) were reduced in the transfused components by WBC-reduction filters, the patient developed TA-GVHD that was confirmed by skin biopsy. It is suggested that the WBC reduction attained with these filters does not prevent TA-GVHD in immunocompromised patients. It is recommended that all blood components should be irradiated before transfusion to such patients.     

Microchimerism, GVHD, and tolerance in solid organ transplantation

The phenomenon of microchimerism and its relationship to long-term graft tolerance is an area of active study. The ability to establish a tolerant state has been enhanced with current immunosuppressive drugs and emerging therapies such as donor HPC infusions. An undesirable outcome of host-donor WBC interaction is GVHD. GVHD is a rare complication reported most frequently in liver transplantation. Two cases of GVHD reported in recipients of organs from donors homozygous for a shared HLA haplotype would support a policy of avoiding the use of these donors. TA-GVHD is very rare in solid organ transplant recipients, with only four published cases; only two had convincing supportive evidence and one of these had an underlying hematologic abnormality. These few cases do not support a policy of routine irradiation of cellular blood components for all solid organ transplant recipients. The use of donor HPC infusions to enhance chimerism and graft tolerance has increased the number of GVHD cases observed (usually mild) and decreased the severity and number of rejection episodes. The long-term effects of donor HPC infusions on graft survival is under investigation.     

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 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.     

How is transfusion-associated graft-versus-host disease similar to,yet different from,organ transplantation-associated graft-versus-host disease?

Graft-versus-host disease (GVHD) is a rare, usually fatal complication following blood transfusion or organ transplantation, namely transfusion-associated GVHD (TA-GVHD) and organ transplantation-associated GVHD (OA-GVHD). The dominant mechanism of GVHD is exposure to viable donor lymphocytes that are not recognized as foreign by, but able to respond to, the recipient. The clinical features and relative risk factors of either TA-GVHD or OA-GVHD are yet to be fully understood. The current review article aims to discuss and summarize the similarities and differences between TA-GVHD and OA-GVHD to gain a deeper understanding of the pathogenesis.It is evident that the shared human leukocyte antigens (HLA) between donor and recipient and immunocompromised status of the recipient are the two main risk factors for the development of both TA-GVHD and OA-GVHD. In particular, the homozygous donor with donor-dominant one-way matching at the three loci HLA-A, -B, and -DR has a high risk of developing GVHD following liver transplantation, and such donors should be excluded to prevent it. However, the development of GVHD is thought to be related to a combination of several risk factors, and the contribution of each risk factor remains unknown. Further studies are warranted to determine the important contributing factors that lead to an accurate prediction of GVHD development.     

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.     

HLA—Cw配型与异基因造血干细胞移植后GVHD关系的临床初探

目的探讨HLA-Cw配型在异基因造血干细胞移植中与GVHD的发生和复发的关系。方法对HLA6个位点（A、B、DR／DQ）全相合的同胞供者9例异基因外周血干细胞移植和10例脐带血移植进一步进行HLA-Cw配型,分析HLA-Cw配型与GVHD发生的关系。结果16例HLA-Cw相合者,共植入15例（94％）,其中Ⅰ-Ⅱ度急性GVHD发生11例（69％）,Ⅲ度急性GVHD2例（12．5％）,慢性GVHD15例（94％）,无复发病例。在HLA—Cw不相合3例中,2例发生Ⅲ度GVHD并且早期死亡,1例早期复发。在HLA—Cw配型相合与不相合两组间,急性Ⅰ～Ⅱ度及Ⅲ度GVHD的发生其差异均具有统计学意义（P〈0．05）。结论HLA—Cw配型相合供体造血干细胞移植有利于减少植入后急性GVHD发生及复发,提示HLA-Cw位点配型在造血干细胞移植,尤其是异基因移植中具有重要意义。     

A rapid molecular diagnosis of posttransfusion graft-versus-host disease by polymerase chain reaction

A woman with recurrent Paget's disease of the vulva developed acute graft-versus-host disease (GVHD) 12 days after radical surgery and massive blood transfusion. Molecular diagnosis of lymphocyte chimerism in the peripheral blood was made by polymerase chain reaction (PCR) directed against a Y chromosome-specific sex-determining region Y (SRY) gene. PCR with skin biopsy after onset of GVHD also revealed infiltration of SRY-positive donor lymphocytes. The diagnosis was confirmed by HLA-DNA typing with PCR-sequence-specific oligonucleotide that revealed the presence of complex HLA-DR chimerism in the peripheral lymphocytes collected after onset of GVHD. The use of SRY- directed PCR is a rapid technique for the early diagnosis of acute posttransfusion GVHD in female patients.     

单倍体相合骨髓移植白血病患者造血重建的临床研究

为研究未去除T细胞的单倍体骨髓移植后造血重建的特点 ,对 15例HLA 2 - 3个位点不匹配骨髓移植亲属供者使用G CSF 3- 4 μg/ (kg·d) ,连续 7天后采髓。预处理方案采用大剂量阿糖胞苷联合环磷酰胺和全身照射。应用环孢菌素A和氨甲喋呤、抗胸腺细胞球蛋白及霉酚酸酯 (MMF)预防移植物抗宿主病。移植后观察血像、骨髓像、行染色体分析及HLA位点鉴定。移植后分别于 3,6和 12个月及 2年追踪鉴定植入状态。结果发现 ,15例患者全部移植物植入 ,移植后中性粒细胞 >0 .5× 10 9/L和血小板 >2 0× 10 9/L的时间分别为 18(13- 2 3)天及 2 2 (16- 32 )天。骨髓像显示各系造血均恢复。 7例应用染色体检查 ,8例应用HLA位点 ,4例应用血型 ,1例应用DNA指纹检测 ,植入鉴定结果除 1例复发患者于移植后 2个月骨髓复发植入鉴定为供、受者嵌合外 ,其他患者均呈持续全部稳定植入。移植后发生I度急性GVHD 8例 ,II-IV度GVHD 5例 ,可评价的慢性GVHD共 8例。结论 :供者应用G CSF后采髓 ,加大预处理剂量 ,联合应用作用机理不同的多种免疫抑制剂进行HLA单倍体的骨髓移植 ,可跨越人类HLA多样性屏障。     

Universal or selective irradiation: a comparison of approaches

Pathological mechanisms proposed for transfusion-associated graft-versus-host diseases (TA-GVHD) include HLA homozygosity in donor cells of the transfusion unit that is shared by the recipient (one-way HLA match) and immunosuppression in the transfusion recipient. Which of these factors is indispensable or to what degree each factor contributes to the development of TA-GVHD has been the issue of debate. In countries like Japan with higher HLA homogeneity, TA-GVHD occurrence was thought to be primarily dependent on the one-way HLA match mechanism regardless of immunosuppression. Accordingly, universal irradiation of blood components has been conducted with no further TA-GVHD cases. In other developed countries, in contrast, TA-GVHD was thought to be a sort of extrapolation of GVHD observed among heavily immunosuppressed patients. Guidelines with the detailed list of diseases with the indication for irradiated components have been established in those countries. Although TA-GVHD occurrence decreased markedly after the introduction of universal leukoreduction, a considerable number of TA-GVHD cases have occurred among immunocompetent patients mostly by the one-way HLA match mechanism. Because one-way HLA matching with donor homozygosity is thought to be a ubiquitous and independent mechanism for TA-GVHD, it could occur in any transfusion setting regardless of immunosuppression. It would be thoughtful to select an area-specific strategy considering the drawbacks of irradiation and the frequency of TA-GVHD in that area. However, if complete abolition of TA-GVHD is required from the perspective of the high fatality of the disorder, universal irradiation of cellular components will be necessary.     

Guest Editorial: Two hits and four factors affecting the development of,or resistance to,transfusion-associated graft-versus-host disease

Transfusion-associated graft-versus-host disease (TA-GVHD), a rare but usually fatal adverse effect of transfusion, is hypothesized here as a two-hit phenomenon: 1) predisposing “cytokine weather” irrespective of immunocompetence, plus 2) consequence of a (partial or total) one-way (donor to recipient) HLA match of viable donor T lymphocytes with proliferation potential. Since the introduction of irradiation, universal leukoreduction with third or later generation filters, and avoidance of transfusion from blood relatives, TA-GVHD has been successfully prevented in developed countries. However, potassium release from stored red blood cells is accelerated after irradiation, increasing the likelihood of hyperkalemia-associated mortality during rapid, and/or high-volume RBC transfusions, including exchange transfusions and extracorporeal circuit priming. Pathogen inactivation technologies may effectively prevent T lymphocyte replication, but have not yet been perfected for whole blood or red cell components. Protection against organ transplantation-associated GVHD (mainly from liver transplants) would likewise be improved by knowing and avoiding HLA one-way matched organ donors.