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Failure to develop HIV infection after receipt of HIV-contaminated blood and postexposure prophylaxis
THE JOURNAL CLUB For first-time donors, the prevalence of HIV decreased from 0.030% in 1991-1992 to 0.015% in 1996, and the prevalence of HCV decreased from 0.63% in 1992 to 0.40% in 1996; these differences were statistically significant. The prevalence of HIV in the general US population was estimated as 0.3% in 1992, whereas the prevalence of HCV was estimated as 1.8%. There were no significant changes in the prevalence of hepatitis B surface antigen (HBsAg) (0.2%) or HTLV (0.04% overall) in first-time donors. Incidence rates in repeat donors per 100,00 person-years were 2.92 for HIV, 3.25 for HCV, 10.4 for HBV, and 1.59 for HTLV, and did not change significantly over the observation period. The authors conclude that deferral of donors for behavioral risk is effective, because the prevalence of markers in first-time donors is significantly lower than that of the generaI population. The decrease in HIV and HCV prevalence in first-time donors may result in a lower number of windowperiod donations. The relatively high prevalence of HBsAg supports the utility of a universal HBV vaccination program.
(M.G.) Transfusions of polymerized bovine hemoglobin in a patient with severe autoimmune hemolytic anemia. J. Mullon, G. Giacoppe, C, Clagett, et al. N Engl J Med 342:1638-1643, 2000. In this remarkable case, the authors report the use of HBOC201, a polymerized bovine hemoglobin solution, in a 21-yearold woman with life-threatening autoimmune hemolytic anemia. The patient initially presented with isolated thrombocytopenia, and after investigation, oral steroids were started for a presumptive diagnosis of idiopathic thrombocytopenic purpura (ITP). Twelve days later, she developed fever, dyspnea, and cardiac ischemia. Laboratoz7 investigations showed a hematocrit of 7.5%, a positive direct antiglobulin test (DAT) with immunoglobulin G (IgG) alone, and indirect antiglobulin test (IAT) reactivity with all panel cells. High-dose steroids and intravenous immunoglobulin (IVIG) therapy were instituted, with no improvement. Plasmapheresis, splenectomy, and cyclophosphamide therapy similarly resulted in no improvement. Up to 8 red cell transfusions were required daily to maintain a hematocrit of 12% and avoid cardiac ischemic changes on electrocardiogram (ECG). Transfusions were accompanied by fever, nausea, and back pain, attributed to hemolysis. Because of accelerated hemolysis and the ineffectiveness of transfusion therapy, HBOC-201 (Hemopure, Biopure, Cambridge, MA) was administered at day 75. HBOC-201 is a gluteraldehydepolymerized bovine hemoglobin solution with a P50 close to that of human red cells. It has a dose-dependent half-life of 8 to 23 hours and is undergoing phase 2 trials in elective surgery and sickle cell anemia patients. Hypertensive effects have been mixed in mlimal and human studies. The patient received a total of 11 units of HBOC-201 (330 g hemoglobin, equivalent to approximately 5.5 red cell units) over a 7-day period. During this time, her course was complicated by neutropenic septic shock. Administration of HBOC-201 resulted in improvement in arterial blood gases, aud was estimated to contribute up to 60% of the total average hemoglobin concentration of 5.5 g/dL. Hematocrit concentration, which does not measure the acellular HBOC-201, was as low as 4.4%. No toxicity was attributable to HBOC-201 administration, although a vasopressor effect may have been masked by concurrent sepsis. Eventually, cycIo-
89 sporin therapy was initiated and resulted in a sustained response, and the patient left the hospital with no sequelae. This case illustrates that ceil-free oxygen carriers may be life-saving in severe cases of autoimmune hemolysis. (M.G.)
Failure of routine HIV-1 tests in a case involving transmission with preseroconversion blood components during the infectious window period. A.E. Ling, K.E. Robbins, T.M. Brown, et al. J A M A 284:210-214, 2000. This case report from Singapore describes human immunodeficiency virus (HIV) transmission attributable to a windowperiod donation. The donor was found to be anti-HIV positive in October 1997. Recipients of the platelet concentrate and red cell unit produced fl'om his earlier donation, made 4 months previously in June 1997, also were found to be anti-HIV positive. Testing of the untransfused plasma from the earlier donation was again anti-HIV and p24 antigen negative, but polymerase chain reaction (PCR) positive. DNA sequencing confirmed identity of the HIV viral sequences in the donor and 2 infected recipients. The viral load in the preseroconversion plasma was thought to be very low (5 to 39 copies of HIV/mL), because quantitative assays with a limit of detection of 40 copies/mL were negative, whereas qualitative assays with a limit of detection of 5 copies /mL were positive. Undiluted samples of the preseroconversion plasma were consistently positive using fire 2 HIV NAT tests currently in clinical trials for screening blood donors in the United States (Chiron NAT Assay and Roche AmpliScreen NAT Assay). However, inconsistent results were obtained on samples diluted 1 in 8 or greater, to simulate minipool testing. The Food and Drug Administration (FDA) has proposed that minipool assays should be abte to detect a minimum of 5,000 viral copies/mL per single donation. This case illustrates that current protocols that meet this standard may not be sufficiently sensitive to detect early window period infectious donations. No information is provided on the prevalence of HIV in the general population or the blood donor population in Singapore. In an accompanying editorial entitled "Will Blood Transfusion Ever be Safe Enough," Dr Harvey Klein from the National Institutes of Health (NIH) comments on the high level of safety achieved in blood transfusion in developed countries today, as demon strated by the article by Glynn et al. (JAMA 284:238-240, 2000). Nevertheless, rare cases of disease transmission continue to occur, as demonstrated in the article by Lynn et al. Public perception of risk, and the expectation of a zero-risk blood supply, will ultimately lead to single-unit testing, even if the estimated marginal incremental improvement in safety comes at a very high cost. (M.G.)
Failure to develop HIV infection after receipt of HIVcontaminated blood and postexposure prophylaxis. T.L. Katzenstein E. Dickmeiss, H. Aladdin, et aL Ann Intern Med 133:31-33, 2000. The authors report a case of transfusion of human immunodeficiency virus (HIV)-contaminated blood that did not lead to infection in the recipient because of prompt receipt of postdonation information of donor infection and institution of postexposure antiretroviral therapy. The donor developed fever and a rash 1 week after blood donation and was diagnosed as having primary HIV infection with a high HIV RNA load (2 • 106
90 copies/mL). The donor denied usual risk factors for HIV, but had been involved in an incident of head butting in a gay bar involving substantial bleeding, 18 days before blood donation. The donor informed medical staff that he had donated blood 1 week earlier. The fresh frozen plasma was still in inventory and was found to be negative for anti-HIV antibodies and p24 antigen, but positive for HIV RNA at 11,000 copies/mL. The recipient of the red cell unit was a 13-year-old who had received 5 units of red cells, 3 units of fresh frozen plasma, and 1 unit of platelets during corrective orthopedic surgery. HIV antibody, p24 antigen, HIV DNA (Amplicor HIV-1 test, Roche Diagnostic Systems) HIV RNA (Amplicor HIV-1 Monitor, Roche Diagnostic Systems), as well as cultures for HIV using peripheral blood mononuclear cells were all negative. However, an optimized HIV RNA method with a lower limit of detection of 3 copies/mL was positive. The author suggested caution in interpreting this result because the quantity was at the detection limit, and all later samples tested negative. The recipient was immediately started on postexposure prophylaxis with zidovudine, lamivudine, and indinavir. Some drug substutions were necessary because of extensive side effects. The postexposure prophylaxis was eventually stopped after 9 months because of intolerable side effects. HIV testing has remained negative over 6 mohths after discontinuation of prophylactic therapy. This case illustrates the importance of advising donors to contact the Blood Center should they develop symptoms of infection in the postdonation period. In addition, it is possible that HIV polymerase chain reaction mini-pool testing would have been positive in this donor. (M.G.)
Acute severe isovolemic anemia impairs cognitive function and memory in humans. R.B. Weiskepf, J.H. Kramer, M. Vie~e, et al. Anesthesiology 92:1646-1652, 2000. Although there has been a movement away from the use of a fixed transfusion trigger for all surgical or medical patients, few data are available on the precise benefits of transfusion in acute anemia. Biologic markers such as measurements of total oxygen consumption, blood lactate concentration, and cardiac output, as well as clinical indices such as multi-organ dysfunction scores, have been used to try and determine when tissue hypoxia and the negative effects of lack of transfusion occur. The authors hypothesize that although these measurements may not
THE JOURNAL CLUB show evidence of inadequate systematic oxygen delivery, they may not be sensitive enough to detect inadequate regional perfusion. Neuronal tissue is sensitive to hypoxemia, and cognitive dysfunction has been demonstrated in mountain climbers at high altitude. In this study, the authors measured cognitive function in 9 healthy young (mean age, 29 years) volunteers at their baseline hemoglobin concentration of 14 g/dL, after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dL, and again after return to a hemoglobin concentration of 7 and 14 g/dL. Isovolemic anemia was achieved by phlebotomy and replacement of blood loss with 5% albumin and autologous platelet-rich plasma, and increase in hemoglobin was achieved by autologous red cell transfusion. Cognitive function was determined by using standardized neuropsychological testing systems such as speed and accuracy in addition and immediate and delayed recall of word lists. The volunteers were administered the tests several times before the day of phlebotomy to minimize enhanced performance attributable to practice. The tests were then administered at baseline hemoglobin concentration after the insertion of 2 peripheral venous cannulas, and 15 minutes after producing the desired hemoglobin concentration, as well as the next morning, when all the red cell units had been retransfused. A control study was conducted at least 1 week later, with placement of the intravenous cannulas and testing at similar times, but without phlebotomy. No changes occurred at hemoglobin concentrations of 7 g/dL. However, at lower levels of hemoglobin, reaction times (at 6g/dL) and then immediate and delayed memory (at 5g/dL) were impaired. Test results improved or reverted to baseline when a hemoglobin level of 7 g/dL was restored, and all tests were similar to baseline when the starting hemoglobin concentration was achieved. There was no change from baseline in the control study. Study limitations include the small number of subjects; although a larger study was planned, the trial was stopped because of the differences noted. The study subjects were not blinded because the authors thought that the changes associated with severe anemia would be easily recognized in any case. In addition, the authors point out that it is difficult to extrapolate their results obtained in a group of healthy volunteers with a relatively brief period of anemia, to patients with a more prolonged period of anemia. Nevertheless, this model provides an interesting approach to test the efficacy of red cell transfusion or alternate therapies in the setting of acute anemia. (M.G.)
(M.G.) Transfusions of polymerized bovine hemoglobin in a patient with severe autoimmune hemolytic anemia. J. Mullon, G. Giacoppe, C, Clagett, et al. N Engl J Med 342:1638-1643, 2000. In this remarkable case, the authors report the use of HBOC201, a polymerized bovine hemoglobin solution, in a 21-yearold woman with life-threatening autoimmune hemolytic anemia. The patient initially presented with isolated thrombocytopenia, and after investigation, oral steroids were started for a presumptive diagnosis of idiopathic thrombocytopenic purpura (ITP). Twelve days later, she developed fever, dyspnea, and cardiac ischemia. Laboratoz7 investigations showed a hematocrit of 7.5%, a positive direct antiglobulin test (DAT) with immunoglobulin G (IgG) alone, and indirect antiglobulin test (IAT) reactivity with all panel cells. High-dose steroids and intravenous immunoglobulin (IVIG) therapy were instituted, with no improvement. Plasmapheresis, splenectomy, and cyclophosphamide therapy similarly resulted in no improvement. Up to 8 red cell transfusions were required daily to maintain a hematocrit of 12% and avoid cardiac ischemic changes on electrocardiogram (ECG). Transfusions were accompanied by fever, nausea, and back pain, attributed to hemolysis. Because of accelerated hemolysis and the ineffectiveness of transfusion therapy, HBOC-201 (Hemopure, Biopure, Cambridge, MA) was administered at day 75. HBOC-201 is a gluteraldehydepolymerized bovine hemoglobin solution with a P50 close to that of human red cells. It has a dose-dependent half-life of 8 to 23 hours and is undergoing phase 2 trials in elective surgery and sickle cell anemia patients. Hypertensive effects have been mixed in mlimal and human studies. The patient received a total of 11 units of HBOC-201 (330 g hemoglobin, equivalent to approximately 5.5 red cell units) over a 7-day period. During this time, her course was complicated by neutropenic septic shock. Administration of HBOC-201 resulted in improvement in arterial blood gases, aud was estimated to contribute up to 60% of the total average hemoglobin concentration of 5.5 g/dL. Hematocrit concentration, which does not measure the acellular HBOC-201, was as low as 4.4%. No toxicity was attributable to HBOC-201 administration, although a vasopressor effect may have been masked by concurrent sepsis. Eventually, cycIo-
89 sporin therapy was initiated and resulted in a sustained response, and the patient left the hospital with no sequelae. This case illustrates that ceil-free oxygen carriers may be life-saving in severe cases of autoimmune hemolysis. (M.G.)
Failure of routine HIV-1 tests in a case involving transmission with preseroconversion blood components during the infectious window period. A.E. Ling, K.E. Robbins, T.M. Brown, et al. J A M A 284:210-214, 2000. This case report from Singapore describes human immunodeficiency virus (HIV) transmission attributable to a windowperiod donation. The donor was found to be anti-HIV positive in October 1997. Recipients of the platelet concentrate and red cell unit produced fl'om his earlier donation, made 4 months previously in June 1997, also were found to be anti-HIV positive. Testing of the untransfused plasma from the earlier donation was again anti-HIV and p24 antigen negative, but polymerase chain reaction (PCR) positive. DNA sequencing confirmed identity of the HIV viral sequences in the donor and 2 infected recipients. The viral load in the preseroconversion plasma was thought to be very low (5 to 39 copies of HIV/mL), because quantitative assays with a limit of detection of 40 copies/mL were negative, whereas qualitative assays with a limit of detection of 5 copies /mL were positive. Undiluted samples of the preseroconversion plasma were consistently positive using fire 2 HIV NAT tests currently in clinical trials for screening blood donors in the United States (Chiron NAT Assay and Roche AmpliScreen NAT Assay). However, inconsistent results were obtained on samples diluted 1 in 8 or greater, to simulate minipool testing. The Food and Drug Administration (FDA) has proposed that minipool assays should be abte to detect a minimum of 5,000 viral copies/mL per single donation. This case illustrates that current protocols that meet this standard may not be sufficiently sensitive to detect early window period infectious donations. No information is provided on the prevalence of HIV in the general population or the blood donor population in Singapore. In an accompanying editorial entitled "Will Blood Transfusion Ever be Safe Enough," Dr Harvey Klein from the National Institutes of Health (NIH) comments on the high level of safety achieved in blood transfusion in developed countries today, as demon strated by the article by Glynn et al. (JAMA 284:238-240, 2000). Nevertheless, rare cases of disease transmission continue to occur, as demonstrated in the article by Lynn et al. Public perception of risk, and the expectation of a zero-risk blood supply, will ultimately lead to single-unit testing, even if the estimated marginal incremental improvement in safety comes at a very high cost. (M.G.)
Failure to develop HIV infection after receipt of HIVcontaminated blood and postexposure prophylaxis. T.L. Katzenstein E. Dickmeiss, H. Aladdin, et aL Ann Intern Med 133:31-33, 2000. The authors report a case of transfusion of human immunodeficiency virus (HIV)-contaminated blood that did not lead to infection in the recipient because of prompt receipt of postdonation information of donor infection and institution of postexposure antiretroviral therapy. The donor developed fever and a rash 1 week after blood donation and was diagnosed as having primary HIV infection with a high HIV RNA load (2 • 106
90 copies/mL). The donor denied usual risk factors for HIV, but had been involved in an incident of head butting in a gay bar involving substantial bleeding, 18 days before blood donation. The donor informed medical staff that he had donated blood 1 week earlier. The fresh frozen plasma was still in inventory and was found to be negative for anti-HIV antibodies and p24 antigen, but positive for HIV RNA at 11,000 copies/mL. The recipient of the red cell unit was a 13-year-old who had received 5 units of red cells, 3 units of fresh frozen plasma, and 1 unit of platelets during corrective orthopedic surgery. HIV antibody, p24 antigen, HIV DNA (Amplicor HIV-1 test, Roche Diagnostic Systems) HIV RNA (Amplicor HIV-1 Monitor, Roche Diagnostic Systems), as well as cultures for HIV using peripheral blood mononuclear cells were all negative. However, an optimized HIV RNA method with a lower limit of detection of 3 copies/mL was positive. The author suggested caution in interpreting this result because the quantity was at the detection limit, and all later samples tested negative. The recipient was immediately started on postexposure prophylaxis with zidovudine, lamivudine, and indinavir. Some drug substutions were necessary because of extensive side effects. The postexposure prophylaxis was eventually stopped after 9 months because of intolerable side effects. HIV testing has remained negative over 6 mohths after discontinuation of prophylactic therapy. This case illustrates the importance of advising donors to contact the Blood Center should they develop symptoms of infection in the postdonation period. In addition, it is possible that HIV polymerase chain reaction mini-pool testing would have been positive in this donor. (M.G.)
Acute severe isovolemic anemia impairs cognitive function and memory in humans. R.B. Weiskepf, J.H. Kramer, M. Vie~e, et al. Anesthesiology 92:1646-1652, 2000. Although there has been a movement away from the use of a fixed transfusion trigger for all surgical or medical patients, few data are available on the precise benefits of transfusion in acute anemia. Biologic markers such as measurements of total oxygen consumption, blood lactate concentration, and cardiac output, as well as clinical indices such as multi-organ dysfunction scores, have been used to try and determine when tissue hypoxia and the negative effects of lack of transfusion occur. The authors hypothesize that although these measurements may not
THE JOURNAL CLUB show evidence of inadequate systematic oxygen delivery, they may not be sensitive enough to detect inadequate regional perfusion. Neuronal tissue is sensitive to hypoxemia, and cognitive dysfunction has been demonstrated in mountain climbers at high altitude. In this study, the authors measured cognitive function in 9 healthy young (mean age, 29 years) volunteers at their baseline hemoglobin concentration of 14 g/dL, after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dL, and again after return to a hemoglobin concentration of 7 and 14 g/dL. Isovolemic anemia was achieved by phlebotomy and replacement of blood loss with 5% albumin and autologous platelet-rich plasma, and increase in hemoglobin was achieved by autologous red cell transfusion. Cognitive function was determined by using standardized neuropsychological testing systems such as speed and accuracy in addition and immediate and delayed recall of word lists. The volunteers were administered the tests several times before the day of phlebotomy to minimize enhanced performance attributable to practice. The tests were then administered at baseline hemoglobin concentration after the insertion of 2 peripheral venous cannulas, and 15 minutes after producing the desired hemoglobin concentration, as well as the next morning, when all the red cell units had been retransfused. A control study was conducted at least 1 week later, with placement of the intravenous cannulas and testing at similar times, but without phlebotomy. No changes occurred at hemoglobin concentrations of 7 g/dL. However, at lower levels of hemoglobin, reaction times (at 6g/dL) and then immediate and delayed memory (at 5g/dL) were impaired. Test results improved or reverted to baseline when a hemoglobin level of 7 g/dL was restored, and all tests were similar to baseline when the starting hemoglobin concentration was achieved. There was no change from baseline in the control study. Study limitations include the small number of subjects; although a larger study was planned, the trial was stopped because of the differences noted. The study subjects were not blinded because the authors thought that the changes associated with severe anemia would be easily recognized in any case. In addition, the authors point out that it is difficult to extrapolate their results obtained in a group of healthy volunteers with a relatively brief period of anemia, to patients with a more prolonged period of anemia. Nevertheless, this model provides an interesting approach to test the efficacy of red cell transfusion or alternate therapies in the setting of acute anemia. (M.G.)