Intravenous immunoglobulin and the risk of hepatic veno-occlusive disease after bone marrow transplantation
Sullivan KM, Kansu E, Storer B, Jocom J, Emerson G, Reagan T, Emerson V, Siadak MF, Davis C, Appelbaum FR, et al
Biology of Blood & Marrow Transplantation. 1998;4((1):):20-6.
Recent reports using historical controls or registry cohorts suggest, respectively, either an increase in the mortality or a decrease in the incidence of hepatic veno-occlusive disease (VOD) with the administration of intravenous immunoglobulin (i.v.Ig) after bone marrow transplantation. These divergent results prompted us to conduct a retrospective analysis of two randomized clinical trials conducted at our center to determine the effect of i.v.Ig infusions on the development and severity of VOD. Patients were randomized to receive (n=318) or not to receive (n=315) i.v.Ig prophylaxis after human leukocyte antigen-identical sibling (n=414), mismatched or unrelated (n=178), or autologous or syngeneic (n=41) marrow transplantation. To determine the relationship of i.v.Ig to the development and severity of VOD, a single observer reviewed data displays created for each patient for grading VOD without knowledge of patient i.v.Ig use. In this analysis, VOD was defined as hyperbilirubinemia > or =2.0 mg/dL before day 20 and abrupt weight gain > or =2% before day 14 posttransplant in the absence of other causes of liver disease. Hepatic VOD developed in 235 (37%) of the 633 randomized patients. No evidence for VOD was found in 230 (36%) patients. The remaining 168 (27%) patients were classified as having liver disease of uncertain etiology. Hepatic VOD was judged to be severe in 63 (10%) and mild or moderate in 172 (27%) patients. The number of patients developing any VOD or severe VOD was similar between those randomized to i.v.Ig prophylaxis and untreated controls (115 vs. 120 and 32 vs. 31, respectively). Logistic regression models identified several covariates as significant (p < 0.01) factors associated with the development of severe VOD. Increased risk occurred with elevated pretransplant serum aspartate aminotransferase (odds ratio [OR] = 2.64) and earlier year of transplant (OR = 3.73); decreased risk occurred with autologous or twin donors (OR = 0.09) and acute myeloid leukemia (OR = 0.39). The development of any VOD was associated with an elevated pretransplant alkaline phosphatase (OR = 4.1), pretransplant use of vancomycin (OR = 1.6) or amphotericin (OR = 3.0), posttransplant use of cyclosporine (OR = 2.5), older patient age (OR = 1.03), and obesity (OR = 0.78). We concluded from the controlled trials of 633 patients that the administration of i.v.Ig did not influence the development or severity of VOD after bone marrow transplantation.
A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery
Sullivan KM, Storek J, Kopecky KJ, Jocom J, Longton G, Flowers M, Siadak M, Nims J, Witherspoon RP, Anasetti C, et al
Biology of Blood & Marrow Transplantation. 1996;2((1):):44-53.
To determine whether intravenous immunoglobulin (IVIg) given monthly from day 90 to day 360 posttransplantation decreased the incidence of late infection, chronic graft-vs.-host disease (GVHD), and obliterative bronchiolitis after marrow transplantation, patients were assigned randomly to receive either IVIg (500 mg/kg/month) or no IVIg prophylaxis. Participants were registered before transplantation, and 250 patients (123 IVIg and 127 control) were evaluable for events after day 100. The two groups were balanced for age, marrow source, cytomegalovirus (CMV) seropositivity, pretransplantation conditioning, and prophylaxis for infection and GVHD. Between days 100 and 365 posttransplantation, the incidence of bacteremia or septicemia per 100 patient-days of risk was 0.10 in the IVIg group and 0.12 in the controls (p = not significant). During the same period, the incidence of localized infection was marginally higher in control patients than in IVIg recipients (0.44 vs. 0.24, respectively; relative risk [RR] 1.46, p < 0.07). Administration of IVIg prophylaxis had no effect on survival, the incidence of obliterative bronchiolitis, severity of airflow obstruction, or the incidence or mortality of chronic GVHD. After discontinuing IVIg prophylaxis at day 360, subsequent recovery of endogeneous humoral immunity was impaired (serum IgG1 and IgA levels were significantly lower than controls at day 730), and total infections were less common in the second year in control patients than in former IVIg recipients (0.12 vs 0.19, respectively; RR 0.61, p = 0.03). We conclude that in the absence of hypogammaglobulinemia, monthly administration of IVIg given from day 90 to 360 does not reduce late complications and may impair long-term humoral immune recovery after marrow transplantation.
Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation
Sullivan KM, Kopecky KJ, Jocom J, Fisher L, Buckner CD, Meyers JD, Counts GW, Bowden RA, Peterson FB, Witherspoon RP,, et al
New England Journal of Medicine. 1990;323((11):):705-12.
BACKGROUND Graft-versus-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Since intravenous immunoglobulin has shown benefit in several immunodeficiency and autoimmune disorders, we studied its antimicrobial and immunomodulatory role after marrow transplantation. METHODS In a randomized trial of 382 patients, transplant recipients given immunoglobulin (500 mg per kilogram of body weight weekly to day 90, then monthly to day 360 after transplantation) were compared with controls not given immunoglobulin. By chance, the immunoglobulin group included more patients with advanced-stage neoplasms; otherwise, the study groups were balanced for prognostic factors. RESULTS Control patients seronegative for cytomegalovirus who received seronegative blood products remained seronegative, but seronegative patients who received immunoglobulin and screened blood had a passive transfer of cytomegalovirus antibody (median titer, 1:64). Among the 61 seronegative patients who could be evaluated, none contracted interstitial pneumonia; among the 308 seropositive patients evaluated, 22 percent of control patients and 13 percent of immunoglobulin recipients had this complication (P = 0.021). Control patients had an increased risk of gram-negative septicemia (relative risk = 2.65, P = 0.0039) and local infection (relative risk = 1.36, P = 0.029) and received 51 more units of platelets than did immunoglobulin recipients. Neither survival nor the risk of relapse was altered by immunoglobulin. However, among patients greater than or equal to 20 years old, there was a reduction in the incidence of acute GVHD (51 percent in controls vs. 34 percent in immunoglobulin recipients; P = 0.0051) and a decrease in deaths due to transplant-related causes after transplantation of HLA-identical marrow (46 percent vs. 30 percent; P = 0.023). CONCLUSIONS Passive immunotherapy with intravenous immunoglobulin decreases the risk of acute GVHD, associated interstitial pneumonia, and infections after bone marrow transplantation.
Antimicrobial and immunomodulatory effects of intravenous immunoglobulin in bone marrow transplantation
Sullivan KM, Kopecky K, Jocom J, Buckner CD, Counts G, Meyers JD,, et al.,
Blood. 1988;72((5, Suppl 1):):410a.. Abstract No. 1550.
The effect of prophylactic intravenous immune globulin on the incidence of septicemia in marrow transplant recipients
Petersen FB, Bowden RA, Thornquist M, Meyers JD, Buckner CD, Counts GW, Nelson N, Newton BA, Sullivan KM, McIver J,, et al
Bone Marrow Transplantation. 1987;2((2):):141-7.
Ninety-seven patients randomized to receive (45 patients) or not to receive (52 patients) intravenous cytomegalovirus immune globulin before and after allogeneic marrow transplantation were evaluated retrospectively for the occurrence of bacterial and fungal septicemia in the first 100 days post-transplant. In a proportional hazards regression test, infection prevention regimens, immunoglobulin administration, age and occurrence of acute graft-versus-host disease were tested simultaneously for the occurrence of septicemia in the pre- and post-engraftment period. Of these factors, only patients receiving immunoglobulin had significantly fewer episodes of septicemia following engraftment with 11 (26%) patients in the globulin group having 14 episodes compared to 22 (42%) patients in the control group having 27 episodes (p = 0.039). None of the patients experienced complications with the immunoglobulin infusions. These results suggest that the administration of intravenous immunoglobulin may be a practical and effective method to decrease the incidence of septicemia following marrow transplantation.
Prevention of nosocomial infections in marrow transplant patients: a prospective randomized comparison of systemic antibiotics versus granulocyte transfusions
Petersen FB, Buckner CD, Clift RA, Nelson N, Counts GW, Meyers JD, Thomas ED
Infection Control. 1986;7((12):):586-92.
One hundred twelve patients with hematologic malignancies underwent marrow transplantation from HLA-matched sibling donors and were randomized to receive either prophylactic granulocyte transfusions (PG, 67 patients) or prophylactic systemic antibiotics (PSA, 45 patients) as prophylaxis against nosocomial infections. Patients were treated in conventional hospital rooms and studied until day 100 post-transplant. For the entire study period, 26 patients (39%) in the PG group developed septicemia compared to 15 patients (33%) in the PSA group. Twenty-eight patients (42%) in the PG group developed local major infections compared to 19 patients (42%) in the PSA group. Ten patients (15%) in the PG group developed viral interstitial pneumonitis compared to 6 patients (13%) in the PSA group. None of these differences were statistically significant. There was no difference in the incidence of bacterial or fungal infections or viral interstitial pneumonitis between the two groups during the granulocytopenic or post-engraftment period. There was no difference in the incidence and severity of graft-versus-host-disease (GVHD). Inability to carry out the prophylaxis was frequent in the PG group, with complications necessitating discontinuance of transfusion in 24% of the recipients and 13% of the donors. The use of PG as an infection prophylaxis modality in marrow transplantation is not supported by this study, as it is difficult to carry out and because PG did not show any advantage over the use of PSA in preventing nosocomial infections.
Early infectious complications in allogeneic marrow transplant recipients with acute leukemia: effects of prophylactic measures
Buckner CD, Clift RA, Thomas ED, Hersman J, Sanders JE, Stewart PS, Wade JC, Murphy M, Counts G, Meyers JD
One hundred eighty-two patients with acute leukemia underwent allogeneic marrow transplantation and received one of two forms of infection prophylaxis: isolation and decontamination procedures in laminar air flow rooms (90 patients) or prophylactic granulocyte transfusion from a single family member (92 patients). Infection acquisition and survival were analyzed from the time of admission to 100 days posttransplant. There were 20 major local infections in the laminar air flow group and 16 in the prophylactic granulocyte group. Of the patients in the laminar air flow group, 24 (27%) had 27 episodes of bacteremia, while 23 (25%) of the prophylactic granulocyte group had 25 episodes of bacteremia. There were no significant differences in infection acquisition between the two groups during the period of granulocytopenia or after engraftment. The mortality during the first 100 days was 28% for the laminar air flow group and 35% for the prophylactic granulocyte group. Thirteen patients (14%) in the laminar air flow group and five (5%) in the prophylactic granulocyte group died with bacterial or fungal infections. There were no statistically significant differences between the two groups in overall incidence of or mortality from interstitial pneumonitis which was the predominant cause of death. However, the subset of patients who were seronegative for cytomegalovirus antibody at the time of transplant and received granulocytes from seropositive donors had a significantly higher incidence of and mortality from cytomegalovirus interstitial pneumonitis.
Granulocyte transfusions for the prevention of infection in patients receiving bone-marrow transplants
Clift RA, Sanders JE, Thomas ED, Williams B, Buckner CD
New England Journal of Medicine. 1978;298((19):):1052-7.
Prophylaxis by granulocyte transfusions against infection associated with granulocytopenia was studied in 69 patients receiving bone-marrow transplants for the therapy of hematologic neoplasia or aplastic anemia. Patients were randomized to receive or not to receive granulocyte transfusions when their circulating granulocyte levels fell to less than 200 per cubic millimeter during the period between transplantation and the development of graft function. During the first 21 posttransplant days, there were two local infections and no septicemias in 29 transfused patients. Seven local infections and 10 septicemias developed among the 40 controls. This protection was afforded by granulocytes collected by reversible leukoadhesion as well as by cells collected by continuous-flow centrifugation.