The role of transfusion-transmitted virus in patients undergoing hemodialysis

JOURNAL CLUB

Questionable efficacy of plasma exchange for thrombotic thrombocytopenic purpura after bone marrow transplantation. J. Teruya, lid. Styler, S. Verde, ot al. J Clin Apheresis 16:169-174, 2001. Thrombotic thrombocytopenic purpttra (TTP) occurring after bone marrow transplant (BMT) is a rare complication that carries with it a very poor prognosis. As in primary TTP, the clinical and laboratory findings of thrombocytopenia, microangiopathic hemolytic anemia, increased lactic dehydrogenase, renal failure, fever, and central nervous system symptoms are all needed to make this diagnosis. However, BMT-related complications with similar signs and symptoms, such as bone marrow suppression, graft-versus-host disease, and systemic infection, often make the diagnosis of TTP in post-BMT patients difficult. It has been speculated that TTP in the post-BMT patient is associated with endothelium damaged by cyclosporine, total body irradiation, or other drugs, whereas in other types of acquired TTP, the likely causative factor is an antibody targeted against the protease that normally cleaves large von Willebrand factor multimers. Given these confounding complications, as well as the likelihood that the causative agents in each setting are different, the efficacy of therapeutic plasma exchange (TPE) in this setting is not well recognized. To further clarify the role of TPE, Teruya et al retrospectively evaluated 307 patients who were referred for TPE with a diagnosis of TTP after BMT at Hahnemann University Hospital between 1989 and 1999. Seven out of 307 post-BMT patients met these investigators' inclusionary criteria for post-BMT TTP, which included thrombocytopenia, schistocytes with anemia, elevated lactic dehydrogenase, and exclusion of DIC by negative D-dimers. Central nervous system symptoms and renal failure were not included in the diagnostic criteria, reportedly because the investigators believed that these symptoms could have arisen from other, unrelated factors. The time between BMT and diagnosis of TTP in these 7 patients averaged 4.5 months (range, 19 days-13 months). Six of these 7 patients were taking cyclosporine A at the time of diagnosis, 1 was taking tacrolimus, and 2 had had total body irradiation. Five patients had developed grade II-IV graft-versus-host disease. Five of these 7 patients underwent daily TPEs, with the total number of procedures ranging from 2 to 35, of 1.0 to 1.3 plasma volumes, using fresh-frozen or cryoprecipitate-reduced plasma as replacement fluid. One of the 7 was treated with a protein A column. The final patient diagnosed with post-BMT TTP died before initiation of TPE. All patients received platelet transfusions for severe bleeding episodes because of the fact that the thrombocytopenia in post-BMT patients can be caused by decreased production as well as increased consumption of platelets. Of the 6 patients who underwent TPE, 4 did not show any sustained clinical or laboratory response, and 2 developed systemic infection with multiorgan failure, requiring cessation of TPE. Ultimately, all patients died within 58 days of diagnosis of TTP of causes including infection with multiorgan failure, cerebral hemorrhagic infarction, or unknown (including sudden death). The complicated clinical scenarios of these patients, the variability of clinical presentation, the lack of strict inchisionary criteria, and the variability of treatment regimens make the findings difficult to evaluate in this retrospective analysis. In

327 addition, several inconsistencies between the text, abstract, tables and figures make these complicated facts even more challenging for the reader to interpret. However, it does appear that TPE had little positive effect on short- or long-term mortality in this patient group. Given this somewhat confusing data combined with other reports of TPE's seeming lack of efficacy in the post-BMT setting, it is not clear that TPE has a role in the post-BMT patient with a diagnosis of TTP. Further investigation, best performed as a multicenter prospective analysis, is clearly needed before clear recommendations regarding the role of TPE in the post-BMT patient with TTP can be made. (C.H.)

The role of transfusion-transmitted virus in patients undergoing hemodialysis. R. Va/tuil/e, F. Frankel, F. Gomez, H. et a/. J Clin Gastroenterol 34:86-88, 2002. This article presents a clinical study conducted to establish the prevalence of transfusion-transmitted virus (TTV) infection in a patient group undergoing hemodialysis. Other studies have reported TTV prevalence in hemodialysis populations, but the investigators of this study focused on the presence of the virus in relation to the following factors: age, sex, duration of dialysis, transfusion history, and chronic elevation of alanine transferase levels. The investigators studied a patient group on maintenance hemodialysis in Buenos Aires. The study group consisted of 75 patients, 29 of whom were women and 46 of whom were men who underwent dialysis 3 times per week. Total DNA was extracted from serum sanaples, and polymerase chain reaction was performed using primers to the open reading frame I region of the TTV genome. The product from the polymerase chain reaction amplification was analyzed by electrophoresis. Additionally, TTV genotyping was performed on the samples by restriction fragment length polymorphism. The results were classified into 6 major genotypes. Information regarding epidemiologic factors such as age, sex, and dialysis and transfusion history were also collected from the patients. Results of the data analysis showed that 32 patients (42.7%) were infected with TTV. Sixteen (50%) of these infected patients were found to have TTV type 1. The differences between the TTV-infected and noninfected patient groups were not statistically significant with regard to age, sex, or dialysis duration. However, there was a statistically significant difference shown when comparing the TTV-infected and noninfected groups and their history of transfusion. Eighty-four percent of the TTV-infected individuals reported a history of transfusion, whereas only 63% of the non-TTV infected group reported a history of transfusion (P = .04). Hepatitis C infection was reported in 10 patients (4 of whom had TTV infection) and chronic alanine transferase elevation (defined as a 1.5-fold or more elevation over normal levels in peaks or sustained for at least 6 months) was reported in 9 patients (5 of whom were TTV infected). The results of this study showed a TTV infection prevalence rate similar to rates reported in other studies. Additionally, this study found TTV genotype 1 to be the most prevalent genotype, which concurs with other currently available reports. It was concluded that in the studied patient population, the TTV infection rate was not influenced by age, sex, or mean duration of dialysis but did correlate with a positive transfusion history. The epidemiologic role of the TTV virus has yet to be

328 elucidated. Previous studies have shown the virus to have a high prevalence rate in populations susceptible to parenteral infections such as intravenous drug abusers, hemophilia patients, and hemodialysis patients. The virus has also been found in factor concentrate products, which use human albumin as a stabilizer. Despite these findings, there remains no clearly defined association between TTV and hepatitis. This study is Valuable because the invesngators have contributed to the knowledge base concerning the relationship of transfusion and TTV. (C.H.)

Adoptive transfer of simian immunodeficiency virus (SIV) naive autologous CD4+ cells to macaques chronically infected with SIV is sufficient to induce long-term nonprogressor status, F. Villinger, G.T. Brice, A.E. Mayne, et a/. Blood 99:590-99, 2002. Adoptive transfer has been performed in HIV-infected patients in an attempt to fully reconstitute the immune system. This involves collecting blood as early as possible from the patient, isolating the lymphocyte population, expanding and activating the CD4 + ceils with anti-CD3/CD28, and cryopreserving the cells until the patient is ready for transfusion. Adoptive transfer of allogeneic bone marrow transplant patients with vtremia using donor-derived, virus-specific cytotoxic T lymphocytes (CTLs) for Epstein-Barr virus or cytomegalovirus showed significant lowering of the patients' viral load and extended autiviral activity. This was not seen in the HIVinfected patients after adoptive transfer and may be because of an intrinsic defect in the transferred T cells or an abnormal microenvironment for homing, survival, and executing immune function. Villinger et al collected peripheral blood mononuclear cells (PBMCs) for adoptive transfer from rhesus macaques before infection with simian immunodeficiencv virus (SIV) to determine whether the microenvironmem is defective in infected animals. The monkeys were first immunized with influenza virus to boost their immune system. The PBMCs were either cryopreserved as collected or the CD4 +cells were isolated and activated/expanded before cryopreservation. Two monkeys were infected with the virus and received no treatment (group 1). The other 9 monkeys (groups 2 and 3) received the antiretroviral drug 9-R-[2-phosphonylmethoxypropyl] adenine for 4 weeks after the plasma viral load set point was reached after SIV infection. Group 2 monkeys got no additional treatment; Group 3 monkeys received 2.5 • 108 autologous, unfractionated PBMCs intravenous weekly for 6 weeks, whereas group 4 monkeys received 2.5 • 108 autologous, activated/expanded CD4 +ceils intravenous weekly for 6 weeks. Sequential studies of plasma RNA viral loads, PBMC and lymph node proviral DNA loads, CTL precursors against SIV env and SIV gag/pol, virus-neutralizing antibodies, CD4/CD8 counts, and immune responses against influenza were performed. 9-R-[2-phosphonylmethoxypropyl] adenine therapy alone provided 7 to 10 weeks of viral replication control, with decreased plasma RNA and cellular proviral DNA loads and rescue of gag/pol and env CTL precursors, but the SIV infection resumed its clinical course after cessation of therapy. Adoptive transfer of either autologous pre-SIV infection-collected PBMCs or activated CD4 +cells after short-term antiretroviral therapy provided extended control of viral loads, despite the fact that the transfused cells were not primed against SIV.

JOURNAL CLUB Therefore. it was concluded that lack of a profound effect after adoptive transfer in HIV-infected patients is most likely because of an intrinsic defect in the T ceils ~which are collected after the patient is infected) rather than a defect in the microenvironment. Qualitative differences were seen in the antiviral defenses induced by the unmampulated PBMCs versus the activated CD4 *cells. PBMCs predominantly enhanced serum neutralization antibody titers, production of soluble viral replication suppressor factors, and' development of SIV env CTI_ precursors. Activated CD4 +ceils promoted CTL responses to both SIV gag/pol and SIV envelope and generally provided more potent antiviral control than unfractionated PBMCs. Acti,tated CD4 +cells. containing influenza-primed memory CD4 *cells. were markedly more efficient than PBMCs containing both CD4 and CD8 influenza specific memory cells at enhancing influenza-specific CTL responses after adoptive transfer. Adoptive immunotherapy with autologous SIV nave CD4 +cells was sufficient to induce antiviral control via induction of anti-SIV immune responses in the absence of continued antiviral chemotherapy. This study supports additional trials with allogenetc lymphocytes in subjects with SIV infection receiving high-dose antiretroviral therapy. (C.H.)

Quality indicators of blood utilization: Three College of American Pathologists Q-Probes studies of 12 288 404 red blood cell units in 1639 hospitals. D.A. Novis, S. Rennet, R. Friedberg, et al. Arch Pathol Lab Med 126:150-156, 2002. The College of American Pathologists conducts multi-institutional surveys, known as Q-Probes. which may assist hospitals in setting performance goals for quality indicators for their institution. This article summarizes results of 3 Q-Probes about cross-match to transfusion ratios (C:T ratiok red cell expiration rates, and red cell discard rates before expiration date (wastage). In the first study, hospitals of all sizes retrospectively tallied 12 months of blood bank data on the number of red cell units collected, received, transfused, wasted, or outdated, as well as the number of cross-matches performed at their institution. In the second study, similar data were collected for an additional 24 months, with the addition of the number of units shipped to other facilities. The third investigation focussed on hospitals with 200 or fewer beds; in addition to the above data collected for a 12-month period, participants answered an expanded questionnaire. In all, 1639 institutions tracked the history o f 12,288,404 red cell units. Over a 3-year period, the C:T ratio decreased from 2.46 to 1.99; in the third stud~,2-,it'declined further to 1.67. Expiration rates for nondirec~ed allogeneic red cell units decreased from 2.3% to 2.0%. Wastage rates were 1.0% in the first 2 studies and 0.6% in the third study, performed in smaller hospitals. The top-performing 10% of participants had C:T ratios of 1.5 or less and minimal expiration and wastage rates of less than 0.1%. Thehottom--iogrforming 10% of participants had C:T ratios of 2.4 to 2.5, expiration rates of 3.5 to 5.1%, and unit wastage rates of 0.7 to 3.0%, depending on the study. Monitoring of requests for blood components by transfusion indication criteria and monitoring of categories of health care workers associated with blood wastage were associated with small decreases in expiration rates in some of the studies. Teaching hospitals had higher C:T ratios, expiration