Original Article
Immunomodulatory and Antimicrobial Efficacy of Intravenous Immunoglobulin in Bone Marrow Transplantation
N Engl J Med 1990; 323:705-712September 13, 1990
- Abstract
- Abstract
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 imunoglobulin recipients. Neither survival nor the risk of relapse was altered by immunoglobulin. However, among patients ≥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. (N Engl J Med 1990; 323: 705–12.)
Media in This Article
Figure 1
Serum Levels of Immunoglobulins and Immunoglobulin Subclasses in Patients Given Intravenous Immunoglobulin (Solid Circles) and Control Patients Not Given Immunoglobulin (Open Circles).Figure 2
Cumulative Incidence of Interstitial Pneumonia in the Immunoglobulin and Control Groups, According to Serologic Status for Cytomegalovirus (CMV) before Transplantation.Article Activity
- Article
IMMUNODEFICIENCY following myeloablative chemoradiotherapy can foster a variety of opportunistic infections after bone marrow transplantation.1 2 3 4 Cytomegalovirus is the most frequent fatal infection and is especially common among patients seropositive for this organism and patients in whom acute graft-versus-host disease (GVHD) develops.5 , 6 Supportive care includes the use of laminar-airflow isolation,7 antibiotic and antiviral prophylaxis,8 , 9 transfusions of cytomegalovirus-seronegative blood products,10 and treatments to hasten immune recovery11 and ameliorate GVHD.12 Nevertheless, transplantation-related complications remain a major cause of morbidity and mortality, especially among older patients and those with cytomegalovirus seropositivity, HLA-mismatched donors, or advanced-stage neoplasms.13 14 15
Immunoglobulin administration is effective therapy for hypogammaglobulinemia and associated immunodeficiency disorders.16 17 18 Current techniques allow the manufacture of intravenous immunoglobulin that fully retains its antibody content and function.19 Recently, an immunomodulatory role of immunoglobulin has been suggested by reports of successful treatment of autoimmune disorders with this agent.20 , 21 In previous studies of marrow transplantation, the use of immunoglobulin has been limited predominantly to patients seronegative for cytomegalovirus in an attempt to prevent infection with this virus. However, techniques of supportive care have varied widely, and results have conflicted in regard to the prevention of infection and interstitial pneumonia.10 , 22 23 24 25 26 27 28 The following controlled trial was designed to test immunoglobulin as an antimicrobial agent and an immunomodulator of GVHD in a broad range of marrow-graft recipients, including older patients and patients with advanced cancers, patients with cytomegalovirus seropositivity, and HLA-nonidentical donors.
Methods
Study Design
The trial was a stratified, randomized comparison of patients who received immunoglobulin prophylaxis and control patients who did not. The study end points were acute GVHD, infection, interstitial pneumonia, and death. The stratification factors for randomization were age (<20 vs. ≥20 years), serologic status for cytomegalovirus before transplantation (negative vs. positive), type of transplant (HLA-identical, HLA-nonidentical, autologous or twin, or T-cell depleted), and protective isolation (standard room vs. room with laminar airflow).
Within each stratum, randomization was conducted in blocks of two patients to ensure that the study groups were balanced. Patients were eligible for study if they were seropositive for cytomegalovirus before transplantation or if they were seronegative, had seronegative marrow donors, and were undergoing allogeneic transplantation for hematologic neoplasms.
Treatment Protocol
Consent forms were approved by the institutional review board. Patients assigned to immunoglobulin treatment received 500 mg per kilogram of body weight (10 ml per kilogram) in each of 15 weekly infusions from day 7 before transplantation to day 90 after transplantation. Thereafter, the same dose was given in each of nine monthly infusions until day 360. The initial rate of infusion was 0.02 ml per kilogram per minute for 30 minutes. The rate was increased to 0.04 ml per kilogram per minute for 30 minutes, then to a final maximum of 0.08 ml per kilogram per minute.
Ten unselected lots of commercially available intravenous immunoglobulin (Gamimune N [Cutter Biological, Berkeley, Calif.], pH 4.25) were used. Unmodified human immunoglobulin was prepared by cold alcohol fractionation of pooled plasma from at least 1000 donors, according to the Cohn—Oncley technique. Ethanol was removed from the third supernatant by diafiltration with water at pH 4. Native immunoglobulin was concentrated by ultrafiltration, incubated at 27°C for 24 days, and infused as a 5 percent (50 mg per milliliter) sterile solution (pH 4.25±0.25) in 10 percent maltose. Details of the biochemistry, monomeric content, IgG-subclass distribution, stability, safety, and specific antibacterial, antiviral, and antifungal antibody titers of immunoglobulin have been previously reported.19
Transplantation Regimen
Patients with aplastic anemia were prepared for transplantation with cyclophosphamide (200 mg per kilogram). Patients with malignant diseases received cyclophosphamide (120 mg per kilogram); most then received total-body irradiation in fractionated doses for a total of 12 to 15.75 Gy. The day of marrow infusion was designated as day 0. Immunosuppression was induced with methotrexate and cyclosporine after allogeneic transplantation.12 The assessment and grading of acute and chronic GVHD have been previously described.29 , 30 Acute GVHD of grades II through IV was treated with methylprednisolone (2 mg per kilogram per day), antithymocyte globulin (15 mg per kilogram, given six times), cyclosporine (3 mg per kilogram per day intravenously or 12.5 mg per kilogram per day orally), or a combination of these agents.31 Chronic GVHD was treated with prednisone alone (1 mg per kilogram every other day) or in combination with azathioprine (1.5 mg per kilogram per day) or cyclosporine (12.0 mg per kilogram every other day).32 , 33
Supportive Care
The following care was routinely given to both the immunoglobulin recipients and control patients. To prevent Pneumocystis carinii infection, trimethoprim–sulfamethoxazole was given until day 120. To prevent exogenous acquisition of primary cytomegalovirus infection, all seronegative patients with hematologic neoplasms who had seronegative marrow donors received red-cell and platelet transfusions exclusively from seronegative blood donors.10 Seropositive patients did not receive screened blood. To prevent endogenous reactivation of cytomegalovirus, seropositive patients received prophylactic intravenous acyclovir (500 mg per square meter of body-surface area every eight hours) from day −5 to day 30.9
All patients in laminar-airflow isolation received the same regimen of enteric decontamination.7 , 8 No patient received prophylactic systemic antibiotics except the initial six patients enrolled, in whom these drugs were used inadvertently.8 Leukocyte-poor transfusions and oral immunoglobulin were not administered. Immunoglobulin could be given according to schedules other than that described above under only two conditions: patients in the immunoglobulin group could receive both ganciclovir and immunoglobulin if cytomegalovirus pneumonia confirmed by tissue examination developed34; and patients in the control group could receive immunoglobulin as necessary at the discretion of the attending physician if severe hypogammaglobulinemia (IgG level, <4.00 g per liter on two determinations) and recurrent bacterial infection developed. Only two control patients received immunoglobulin during the first 100 days under the latter condition, and they have not been excluded from analysis.
Definition and Evaluation of Infection
The following definitions were established before the study began. Bacteremia was indicated by one or more positive blood cultures associated with fever as the only sign of infection, or by more than one positive blood culture with the same organism regardless of any sign of infection. Septicemia was indicated by one or more positive blood cultures for any organism, associated with either hypotension or documented local infection caused by the same organism recovered from the blood. Local infection was demonstrated by isolation of organisms from a site associated with signs or symptoms of infection, if the organisms recovered were capable of causing the clinical findings. "Clinical" local infection was denoted by the presence of signs and symptoms at an infected site in the absence of microbiologic confirmation. Infections of the oral cavity or upper respiratory tract or infections with herpes simplex were not recorded. Seronegativity for cytomegalovirus was indicated by a negative result (titer, <1:8) on antibody testing by both latex agglutination and complement fixation. Cytomegalovirus infection was demonstrated by isolation of the virus from any site in previously uninfected patients. Cytomegalovirus disease was indicated by tissue evidence of virus with associated signs and symptoms of infection. Interstitial pneumonia was indicated by the presence of nonbacterial, nonfungal pneumonitis with hypoxia and interstitial infiltrates on chest radiography. "Clinical" interstitial pneumonia was defined by clinical and radiologic features when tissue confirmation was not obtained.
Viral cultures were performed as previously described.10 Viral, fungal, and bacterial cultures were routinely obtained from biopsy and autopsy specimens and during diagnostic evaluations of fever. Surveillance chest radiographs were obtained at least weekly until discharge from the transplantation center in Seattle. Patients were examined for infection daily in the hospital and at least weekly in the clinic until discharge from the Seattle center, which occurred a median of 99 days after transplantation.
Patients
Between May 1986 and November 1987, 383 patients were registered for the study. One patient for whom only bone marrow storage was intended was ineligible, leaving 382 eligible patients. Five controls and five immunoglobulin recipients did not undergo transplantation, one control and one patient assigned to immunoglobulin treatment received the wrong therapy, and one patient assigned to immunoglobulin treatment refused it. The remaining 369 patients (97 percent) were able to be fully evaluated. Table 1Table 1
Characteristics of the Study Groups. shows the characteristics of the study groups before transplantation. The groups differed significantly only in their disease status (P = 0.05 by Pearson's chi-square test). Among patients with acute leukemia, 78 in the immunoglobulin group and 47 in the control group had advanced disease in relapse.Statistical Analyses
Analyses of survival (censored at last contact) and mortality without relapse (also censored at relapse) included all 382 eligible patients. Analyses of relapse (censored with respect to death without relapse) were limited to 355 patients with cancer who could be evaluated. Analyses of interstitial pneumonia and infection included the 369 patients who could be fully evaluated, except for the analysis of cytomegalovirus infection, which included 299 patients from whom no virus was isolated within 24 days of transplantation. Analyses of GVHD were restricted to the 325 patients with allografts that could be evaluated. Data on patients were censored with respect to the risk of infection, interstitial pneumonia, and acute GVHD at day 100, early discharge, graft rejection, relapse of cancer, or death.
Results were based on the data available on May 1, 1989. Logrank tests with two-sided significance levels were used to compare the times to death, relapse, acute GVHD, and interstitial pneumonia.35 All analyses were stratified according to age, assignment to standard or laminar-airflow isolation, serologic status for cytomegalovirus, and type of transplant. To allow for multiple infections, relative risks were estimated from proportional-hazards regression models that were stratified additionally according to the number of previous infections.36 Regression models were also used to adjust for imbalances in covariates not used in stratification. Cumulative-incidence curves were calculated to identify differences between treatment groups and strata.37
Results
Side Effects, Antibody Titers, and Engraftment
The mean (±SD) volume of immunoglobulin given was 604±245 ml, infused over 3.4±1.1 hours. Adverse reactions were noted during 14 of 2226 weekly infusions (0.6 percent): chills (10 infusions), fever (1), headache (1), pruritus (1), and flushing (1). There was no apparent hepatotoxicity. As shown in Table 2Table 2
Post-transplantation Course of the Study Groups.*, liver enzyme levels in the immunoglobulin recipients were slightly lower after transplantation than those in the controls (P<0.003 by two-sample t-test of log-transformed median bilirubin values).Immunoglobulin recipients had significantly higher serum levels of IgG and its subclasses (Fig. 1Figure 1
Serum Levels of Immunoglobulins and Immunoglobulin Subclasses in Patients Given Intravenous Immunoglobulin (Solid Circles) and Control Patients Not Given Immunoglobulin (Open Circles).), and their specific antibody titers were higher by two to four dilutions (Table 2). Among patients with hematologic neoplasms who were seronegative for cytomegalovirus and had seronegative bone marrow donors, 21 of 22 control patients alive at day 90 remained seronegative after receiving transfusions from seronegative blood donors. In contrast, all 16 seronegative patients receiving immunoglobulin and screened blood became seropositive (median cytomegalovirus titer on day 90, 1:64; range, 1:8 to 1:512).Recovery of the white-cell count was similar in the two study groups (Table 2). Actuarial estimates showed that among patients surviving until day 90, 31 percent of controls and 20 percent of immunoglobulin recipients still required platelet transfusions (P = 0.055). The median number of units of platelets given daily during the period of transfusion (2.6 vs. 2.7) or until censoring (1.3 vs. 1.1) did not differ significantly. However, control patients required on average 51 more units of platelets. They received platelet transfusions a median of 21 days longer than immunoglobulin recipients (P = 0.055).
Infection
Of 58 seronegative patients given screened blood products, only 1 had cytomegalovirus isolated from any culture after day 24. In contrast, half of 241 seropositive patients had cytomegalovirus infection; however, the incidence did not differ between the two study groups.
Table 3Table 3
Post-transplantation Infections in the Study Groups.* summarizes additional data on infection. Septicemia and local infection were significantly reduced in the immunoglobulin group. Thirty-three episodes of gram-negative septicemia developed in controls, as compared with 11 episodes in immunoglobulin recipients (relative risk = 2.65 among controls, P = 0.0039). The genus of the gram-negative organisms included pseudomonas species (control vs. immunoglobulin group, 17 vs. 8 episodes), klebsiella species (5 vs. 1), enterobacter species (5 vs. 0), acinetobacter species (3 vs. 0), bacteroides species (2 vs. 1), Escherichia coli (1 vs. 0), and citrobacter species (0 vs. 1). A total of 144 episodes of local infection developed in controls, as compared with 94 episodes in immunoglobulin recipients (relative risk = 1.36 among controls, P = 0.029). Local fungal infections were due predominantly to candida (12 vs. 5 episodes) and aspergillus (9 vs. 2). There was no significant difference in the number of episodes of cytomegalovirus enteritis (18 vs. 16).The observation that episodes of infection were reduced in association with immunoglobulin prophylaxis was made both before and after recovery of the neutrophil count. Time-dependent proportional-hazards regression analyses found no significant difference in the protective effect before or after the neutrophil count returned to 1.0×109 per liter. Specifically, the relative risk of gram-negative septicemia in control patients as compared with immunoglobulin recipients was 5.12 before neutrophil recovery and 1.92 after recovery (P = 0.091). The risk of any local infection during the two periods also did not differ (relative risk =1.41 and 1.40, respectively).
Interstitial Pneumonia
Figure 2Figure 2
Cumulative Incidence of Interstitial Pneumonia in the Immunoglobulin and Control Groups, According to Serologic Status for Cytomegalovirus (CMV) before Transplantation. shows that the cumulative incidence of interstitial pneumonia among 308 cytomegalovirus-seropositive patients was 22 percent in controls and 13 percent in immunoglobulin recipients (P = 0.021). In contrast, interstitial pneumonia did not develop in any of 61 seronegative patients given screened blood. Among patients less than 20 years old, 7 of 57 controls and 8 of 65 immunoglobulin recipients had interstitial pneumonia. In contrast, among patients ≥20 years old, 27 of 128 controls and 11 of 119 immunoglobulin recipients had pneumonia (P = 0.0032).The effect of acute GVHD and immunoglobulin prophylaxis on the development of interstitial pneumonia was analyzed by proportional-hazards regression after adjustment for age, serologic status for cytomegalovirus, type of transplant, and type of protective isolation. The risk of interstitial pneumonia was increased among the controls as compared with immunoglobulin recipients (relative risk = 1.70, P = 0.064). The risk was also increased among patients with Grade II to IV acute GVHD as compared with those without GVHD (relative risk = 3.05, P = 0.0009). Analogous comparisons of the risk of cytomegalovirus pneumonia showed that the relative risk was 1.34 in control patients (P = 0.38) and 3.77 in patients with acute GVHD (P = 0.0016).
Acute GVHD
Table 2 lists the frequency and severity of GVHD in 220 patients who received HLA-identical transplants and 105 who received HLA-nonidentical transplants. Acute GVHD was more frequent among control patients, in terms of both the overall number of patients (Table 2) and the percentage of patients with specific organ involvement (skin, 62 percent in controls vs. 52 percent in immunoglobulin recipients; liver, 33 percent vs. 20 percent; and gut, 33 percent vs. 25 percent). Among patients less than 20 years old, the incidence of Grade II to IV acute GVHD was similar in the two study groups; among patients 20 or older, acute GVHD was significantly increased in the control group (Fig. 3Figure 3
Cumulative Incidence of Acute GVHD Grades II through IV in Patients ≥20 Years Old.). This effect was observed in both the patients given HLA-identical marrow (43 percent of controls vs. 28 percent of immunoglobulin recipients; P = 0.029) and those given HLA-nonidentical marrow (71 percent vs. 49 percent; P = 0.078). Multivariate analysis of the 325 allograft recipients confirmed that the risk of acute GVHD was increased among control patients as compared with immunoglobulin recipients (relative risk = 1.63, P = 0.0056).Survival, Relapse, and Mortality
To date, the median duration of follow-up since randomization is 2.0 years in the 69 surviving control patients and 1.9 years in the 66 surviving immunoglobulin recipients. The actuarial survival after two years is 35±4 percent and 33±4 percent, respectively (P = 0.79).
Relapse of cancer was the leading cause of death. Among patients ≥20 years of age, the cumulative incidence of relapse was similar (43 percent of controls vs. 44 percent of immunoglobulin recipients). However, relapse rates differed significantly among patients less than 20 years of age (47 percent of controls vs. 78 percent of immunoglobulin recipients; P = 0.0074). This difference appeared to be due to the larger number of patients with advanced-stage neoplasms in the immunoglobulin group. Proportional-hazards analysis of the recurrence of neoplasms confirmed that the presence of advanced-stage disease was associated with an increased risk of relapse (P<0.0001) but failed to show that immunoglobulin administration had an independent influence on the recurrence of cancer (P = 0.26).
Among patients less than 20 years old, the cumulative incidence of mortality not due to relapse was similar in the two study groups. Among patients ≥20 years old, the incidence was 48 percent in the control group and 36 percent in the immunoglobulin group (P = 0.083). Although there was no difference in transplantation-related mortality among patients ≥20 years old who were given HLA-nonidentical marrow, mortality not due to relapse was significantly reduced in patients in this age group who were given HLA-identical marrow (Fig. 4Figure 4
Cumulative Incidence of Mortality without Relapse in Patients ≥20 Years Old Who Received HLA-identical Transplants.).Discussion
The aim of our study was to reduce the morbidity of transplantation. We found that patients who received immunoglobulin had a significant reduction in acute GVHD and associated interstitial pneumonia, septicemia, and local infection, as compared with patients who did not receive immunoglobulin. Associated with this protective effect was a reduction in the mortality not due to relapse among patients ≥20 years of age. Moreover, such benefit was observed although the immunoglobulin group had a higher proportion of patients with neoplasms in advanced stages, in whom transplantation-related morbidity would be more likely.15 These findings are especially encouraging for the treatment of adult transplant recipients, since previous studies have demonstrated a significant risk of transplant-related mortality among older patients, even after adjustment for GVHD in time-dependent analyses.38
We advise caution in interpreting these results since overall survival was not improved. It is also of concern that immunoglobulin has the potential to attenuate a graft-versus-leukemia effect associated with GVHD.38 , 39 We found, however, no evidence of such an adverse interaction. When the imbalance between the study groups in disease stage and acute GVHD was controlled for in the multivariate analysis, no association could be demonstrated between immune prophylaxis and relapse. The increase in relapse was limited to patients less than 20 years of age and appeared to be due to advanced-stage disease. It is noteworthy that immunoglobulin had no apparent effect on GVHD in these patients. Conversely, in patients ≥20 years old, immunoglobulin was associated with a reduction in the incidence of GVHD, without a change in the incidence of recurrent leukemia.
As shown by other investigators,17 , 19 the toxicity of immunoglobulin was minimal. It is noteworthy that platelet recovery improved, and the period during which platelet transfusions were needed was decreased by 21 days. Our study differed from others reporting decreased alloimmunization and improved platelet responsiveness, in that platelets from multiple donors and lower doses of immunoglobulin were used.40 In our study the recovery of myeloid function was unaffected. Thus, differences in the rates of septicemia and infection with candida or aspergillus were not due to differences in the rates of neutrophil recovery.
Previous studies of immunoglobulin have focused on patients seronegative for cytomegalovirus.10 , 22 , 26 The current trial confirms that these patients are now protected by the use of seronegative blood products.10 In seropositive patients, reactivation of endogenous virus remains a serious threat to a successful outcome.5 , 13 In a controlled study of seropositive patients, Ringdén et al. reported that cytomegalovirus infection or pneumonia was not prevented by the administration of immune plasma.24 However, the number of patients they studied (27 controls and 27 plasma recipients) could have been insufficient to allow a difference to be detected. Our finding of a reduced incidence of interstitial pneumonia in seropositive patients who received immunoglobulin prophylaxis requires confirmation, but it is an encouraging observation in patients at high risk.
Antimicrobial efficacy is probably due to several factors. Antibody replacement, enhanced neutralization, and augmented opsonocytophagic function could improve the defenses of the immunocompromised host. In several aspects, the ontogeny of immune reconstitution in bone marrow recipients recapitulates the immune development of newborns.2 This clinical parallel is reinforced by demonstration of an antimicrobial benefit of immunoglobulin in high-risk infants.41 Restoration of immunocompetence would facilitate a regulated inflammatory response to infection. Several investigators have suggested that the pathogenesis of cytomegalovirus pneumonia involves an immune response to virus.34 , 42 Although our study showed no influence of immunoglobulin on the acquisition of microbial pathogens (as evidenced by the lack of an effect on cytomegalovirus infection or bacteremia), the expression of disease was modified by prophylaxis (as evidenced by the reduced incidence of interstitial pneumonia and septicemia). This salutary effect has been observed in studies of animals given immunoglobulin, in which hypotension, organ damage, and mortality due to gram-negative bacteremia were reduced.43 Similarly, studies of immunoglobulin prophylaxis in renal-transplant recipients also report a reduction in symptomatic cytomegalovirus disease without any change in the rates of viral isolation or seroconversion.44
An immunomodulatory effect is further suggested by the reduction in the incidence of acute GVHD. Immunoglobulin treatment has been effective in several autoimmune disorders, including idiopathic thrombocytopenic purpura, Kawasaki disease, and Guillain—Barré syndrome.20 , 21 , 45 , 46 Our findings confirm a previous report by Winston et al. on 75 recipients of HLA-identical marrow grafts: the rate of Grade I to IV acute GVHD was reduced in patients given immunoglobulin (1000 mg per kilogram per week, for a total of 19 infusions) as compared with control patients (13 of 38 immunoglobulin recipients with GVHD [34 percent] vs. 24 of 37 controls [65 percent]; P = 0.01).26 Possible mechanisms of immune modulation by immunoglobulin include inhibition of cellular immune function (T-cell activation, cell-mediated lympholysis, mixed-lymphocyte-culture reactivity, and antibody-dependent cellular cytotoxicity),47 , 48 restriction of B-cell differentiation,49 and enhancement of suppressor-T-cell activity.50 , 51 In addition, immunoglobulin might inhibit the synthesis of cytokines mediating GVHD and inflammatory responses.52 , 53 This hypothesis is supported by experiments in mice given semiallogeneic transplants, in which GVHD was prevented by the administration of antimouse recombinant tumor necrosis factor.54 Alternatively, antibodies contained in immunoglobulin might modify the expression of GVHD, perhaps by antiidiotypic regulation.55 , 56 Serum levels of antibody to the core glycolipid of E. coli J5 ("anti-endotoxin") were found to be significantly higher in healthy marrow recipients than in those in whom GVHD developed.57 This protection by antibody to gut-derived endotoxin suggests that bacterial flora may have a role in the development of GVHD.
Microbial influence on the pathogenesis of GVHD is further suggested by gnotobiotic studies demonstrating that GVHD was reduced by germ-free isolation and enteric decontamination.58 , 59 In the present study, however, laminar-airflow isolation had no apparent influence on GVHD. This may have been due to the reduced success of decontamination in patients receiving irradiation.8 At present, the relation of infection to GVHD remains poorly understood. Some studies suggest that viral infection facilitates the development of GVHD,60 , 61 whereas others report that GVHD activates latent cytomegalovirus infection.5 , 6 Since a reactivation of virus could induce the expression of HLA molecules and stimulate the production of lymphokines mediating GVHD, the prevention of infection might decrease GVHD. The data from the present trial, however, suggest the reverse; that is, the prevention of GVHD reduces the rate of infection and interstitial pneumonia.
Although immunoglobulin significantly reduced early complications of bone marrow transplantation, the long-term effectiveness of passive immunotherapy requires further study. An analysis of the rates of late infection, obliterative bronchiolitis, and chronic GVHD, especially among recipients of HLA-nonidentical marrow, would be useful.62 63 64 Reductions in late morbidity and mortality, the use of resources, and the cost of care should be considered in relation to the expense of treatment.65 Further study is also required to determine the optimal dose, route, and schedule for immunoglobulin prophylaxis.
Supported in part by grants (CA-18221, CA-18029, CA-15704, CA-47748, CA-09515, and HL-36444) from the National Institutes of Health and by Cutter Biological, Miles Incorporated. Dr. Thomas is the recipient of a Research Career Award (AI-02425) from the National Institute of Allergy and Infectious Diseases.
We are indebted to the nurses and support staff of the Fred Hutchinson Cancer Research Center and Swedish Hospital Medical Center for conduct of this study, and to James Pennington, M.D., Meera Banaji, M.B., B.S., Cheryl Cox, R.N., M.S.N., Patrick Pallansch, R.N., Bonnie McGregor, David Anderson, and David BogdanofF, Ph.D.
Source Information
From the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, and Cutter Biological, Miles Incorporated, Berkeley, Calif. (M.D.B., R.S.S.). Address reprint requests to Dr. Sullivan at the Fred Hutchinson Cancer Research Center, 1124 Columbia St., Seattle, WA 98104.
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