Raleigh A. Bowden

Epidemiology of Aspergillus Infections in a Large Cohort of Patients Undergoing Bone Marrow Transplantation

To investigate the incidence, risk factors, and outcome of Aspergillus infections among marrow transplant recipients, records from 2496 patients were reviewed, and 214 patients had Aspergillus organisms identified. Of these, 158 had invasive aspergillosis, 44 were colonized, and 12 had contaminated cultures. The incidence of invasive aspergillosis increased from 5.7% to 11.2% during the study. The onset of infection was bimodal, peaking 16 and 96 days after transplant. For patients within 40 days after transplant, underlying disease, donor type, season, and transplant outside of laminar air flow rooms were associated with significant risk for invasive aspergillosis. For patients >40 days after transplant, age, underlying disease, donor type, graft-versus-host disease, neutropenia, and corticosteroid use were associated with increased risk of aspergillosis. Only 31% of infected patients were neutropenic at the time of diagnosis. The risk factors for aspergillosis depend on the time after marrow transplant and include both host and environmental characteristics.

Ganciclovir Prophylaxis To Prevent Cytomegalovirus Disease after Allogeneic Marrow Transplant

Cytomegalovirus (CMV) disease has been an important source of morbidity and mortality during allogeneic marrow transplant [1, 2]. Patients who are CMV seropositive, regardless of the donor status, have an incidence of 69% infection with CMV [2]. Despite recent advances in antiviral therapy, established CMV disease is difficult to treat. Cytomegalovirus interstitial pneumonia remains a disease with a mortality rate of between 30% and 55% [3-5]. Adequate therapy for CMV gastrointestinal disease in patients with marrow transplant has not been well defined [6]. Ganciclovir, an acyclic nucleoside analog, has been shown to have activity against CMV in the treatment of CMV infection in immunocompromised hosts [7-9]. In a recent attempt to prevent CMV disease, ganciclovir was given to marrow transplant recipients excreting CMV after transplant but before CMV disease was diagnosed [10, 11]. Both early treatment studies showed a significant clinical and statistical reduction in CMV pneumonia, gastrointestinal disease, and death after marrow transplantation but failed to identify patients diagnosed with CMV disease without previous positive surveillance cultures. An alternative approach to early treatment strategies is to give ganciclovir at the time of engraftment to all patients who are CMV seropositive. The advantage of this prophylaxis strategy, compared with early treatment strategies, is the inclusion of all patients at risk for developing CMV disease. The concern with ganciclovir prophylaxis is myelosuppression. Therefore, we have performed a randomized placebo-controlled trial of ganciclovir given to CMV-seropositive allogeneic marrow transplant recipients at the time of engraftment and before CMV excretion or disease. Methods Patients Patients who were CMV seropositive before transplant and were to receive an allogeneic marrow transplant for hematologic malignancy requiring total body irradiation or busulfan-cyclophosphamide at the Fred Hutchinson Cancer Research Center were eligible for study entry. Signed informed consent was obtained according to Food and Drug Administration and institutional guidelines. Protocol Design Patients were entered into this double-blind study before transplant and were followed with weekly viral cultures. Patients were assigned randomly to receive ganciclovir or placebo at the time of engraftment, which was defined as an absolute neutrophil count of 0.750 109/L or greater for 2 consecutive days. Ganciclovir was given at a dose of 5 mg/kg body weight, administered intravenously twice daily for 5 days and then once daily until day 100 after transplant. Patients were excluded from the study if they received a T-cell-depleted transplant, were younger than 2 years of age, had a serum creatinine level greater than 220 mol/L, were allergic to acyclovir or ganciclovir, had received a marrow transplant in the previous 6 months, or had documented CMV excretion before randomization. Patients received high-dose acyclovir prophylaxis from the time of conditioning until engraftment [12]. Virus cultures were obtained from urine, blood, and throat on a weekly basis through day 100 or until leaving Seattle, whichever was longer. All patients who began to excrete virus were removed from the study and treated with ganciclovir [11]. Viral infection was defined as recovery of virus from the throat, urine, or blood. Disease caused by CMV was defined as recovery of virus from a visceral site (lung, gastrointestinal tissue) or by bronchoalveolar lavage in patients who had associated signs (pulmonary infiltrate) and symptoms consistent with CMV infection. Marrow toxicity was defined as an absolute neutrophil count of less than 0.750 109/L for 2 consecutive days. Bacterial or fungal infection was defined as the recovery of the organism from a blood culture or other normally sterile site. Laboratory Procedures Virus cultures included both centrifugation culture [13] and conventional culture. Conventional cultures were maintained for 5 weeks. Statistical Design Study end points were the development of CMV infection and marrow toxicity. Development of CMV disease and death were secondary end points. The analysis of infection, disease, toxicity, and mortality was evaluated from start of the study drug to day 100 after transplant. Mortality and disease were analyzed at 180 days after transplant. Comparison of time to specific events was done according to the method of Kaplan-Meier [14] with analysis by log-rank test [15]. Other comparisons were done using the chi-square test, Fisher exact test, Student t-test, or the Wilcoxon test, as appropriate. Fifty patients were entered into the study at which point a scheduled interim analysis was performed. A difference in the incidence of CMV infection between study arms at P = 0.005 was required to stop the study. At the completion of the interim analysis, a statistically significant difference between the study arms for CMV infection was found at the P = 0.005 level, and the study was terminated. Seventy patients had been enrolled in the study by the time the interim analysis had been completed. Sixty-four patients were included in the final analysis. Results From November 1990 to August 1991, 114 consecutive CMV-seropositive patients were eligible for the study. Twenty-one patients were not enrolled, with three refusing study entry and three receiving T-cell-depleted marrow transplants. The other 15 patients were enrolled in protocols that precluded ganciclovir administration or conflicted with the blinded design of our study. Ninety-three patients were entered into the study before transplant. Between transplant and engraftment, 23 patients became ineligible for study before randomization with acute renal failure (eight patients), hematologic relapse (eight patients), refusal (three patients), failure to engraft (two patients), and positive culture for CMV (two patients). Seventy patients were randomized at engraftment and received the study drug. When the interim analysis showed a difference between the ganciclovir and placebo arms, the study was stopped. Five of the 70 patients had not reached an end point when the result of the interim analysis became available. All five of these patients had been enrolled in the study less than 2 weeks and are not included in the final analysis but were treated with ganciclovir during the remainder of their transplant course. None of these five patients developed CMV excretion or disease during the first 100 days after transplant. One additional patient was excreting CMV the day before study entry and received two doses of study drug before culture results became available. This patient was withdrawn from the study and was treated with ganciclovir. This left 64 evaluable patients with 33 receiving ganciclovir and 31 receiving placebo (Table 1). There were no statistical differences between groups except for the day after transplant for study withdrawal and for total days on study. The median day for study withdrawal in the ganciclovir group was 88 days (range, 44 to 114 days after transplant) compared with a median of 59 days (range, 24 to 100 days after transplant) in the placebo group (P = 0.001). This difference was reflected in the total number of days on study with a difference in medians of 25 days between the two groups (P < 0.001). Table 1. Characteristics of Study Groups Effect of Prophylactic Ganciclovir on Cytomegalovirus and Other Herpesvirus Infection Ganciclovir prophylaxis resulted in a marked reduction in CMV infection (Figure 1). Fourteen of 31 (45%) patients on placebo excreted CMV from the start of the study drug to day 100 after transplant compared with 1 of 33 (3%) ganciclovir recipients (P < 0.001). Cytomegalovirus was recovered from urine in eight patients, blood in four patients, and throat cultures in two patients. Four of the 14 patients on placebo who excreted virus at some time after the start of study drug to day 100 after transplant developed CMV gastrointestinal disease. One patient developed CMV interstitial pneumonia 9 days after gastrointestinal disease was diagnosed. Five patients on placebo who developed CMV disease did not have detectable virus excretion before the onset of disease. None of the patients on ganciclovir excreted virus while on the study drug. One ganciclovir recipient who received 4 days of drug had virus isolated from the blood 36 days after stopping drug secondary to neutropenia. Another ganciclovir recipient had virus isolated from the blood on day 104, 40 days after termination from the study for neutropenia. Neither patient developed CMV disease. Figure 1. Cytomegalovirus infection after allogeneic marrow transplant. P Ganciclovir prophylaxis was also effective in suppressing herpes simplex virus excretion. Fourteen of 31 placebo recipients excreted herpes simplex virus while on study, compared with zero of 33 ganciclovir recipients. One placebo recipient had a case of varicella-zoster infection while on study. Effect of Prophylactic Ganciclovir on Cytomegalovirus Disease Ganciclovir prophylaxis was effective in eliminating CMV disease during the first 100 days after marrow transplant. Nine (29%) placebo recipients developed CMV disease from the start of study drug to day 100 after transplant, compared with no cases of disease in the ganciclovir group (P < 0.001). Three patients had CMV interstitial pneumonia, five had gastrointestinal disease, and one patient had pneumonia and gastrointestinal disease (Table 2). The median day to onset of CMV disease was 47 days after transplant (range, 43 to 74 days). Cytomegalovirus interstitial pneumonia was diagnosed earlier than gastrointestinal disease, with medians of 44 (range, 43 to 47 days) and 60 days (range, 45 to 74 days), respectively, consistent with previously published data [1]. Two of the nine patients died of CMV interstitial pneumonia. Table 2. Occurrence of Cytomegalovirus Disease* When analyzed at 180 days after tran

Treatment of Cytomegalovirus Pneumonia with Ganciclovir and Intravenous Cytomegalovirus Immunoglobulin in Patients with Bone Marrow Transplants

STUDY OBJECTIVE To determine if the combination of ganciclovir and intravenous cytomegalovirus immunoglobulin is effective in patients with cytomegalovirus pneumonia after bone marrow transplant. DESIGN Consecutive entry trial with treatment for a minimum of 14 days. PATIENTS Consecutive sample of 25 patients with bone marrow transplants and cytomegalovirus pneumonia after transplant proven by open lung biopsy or bronchoalveolar lavage. Patients with abnormal renal function or concomitant infectious causes of pneumonia, or who were respirator-dependent at diagnosis, were not eligible. INTERVENTIONS Induction treatment consisted of ganciclovir, 2.5 mg/kg body weight every 8 hours for 14 days, and cytomegalovirus immunoglobulin, 400 mg/kg on days 1, 2, and 7 and 200 mg/kg on day 14. Ganciclovir dosage was adjusted for renal function. Patients who were improved but still symptomatic after 14 days were given maintenance treatment consisting of ganciclovir, 5 mg/kg once daily for an additional 14 days, and immunoglobulin, 200 mg/kg on day 21. Patients with clinical deterioration continued to receive induction doses. Ganciclovir therapy was discontinued if the neutrophil count fell below 500 X 10(6)/L for 2 consecutive days. MEASUREMENT AND MAIN RESULTS Serial tests of renal and liver function, blood counts, and viral cultures of blood, throat, and urine were obtained 3 times a week. Thirteen of twenty-five (52%) patients (95% CI, 31 to 72) survived the initial episode of pneumonia. Viral excretion ceased in 17 of 23 (74%) patients treated more than 96 hours. Proven recurrences of pneumonia occurred in 3 patients and possible recurrences in 2 after treatment was stopped. Three patients developed neutropenia during induction therapy and 6 patients during maintenance therapy. CONCLUSIONS Survival of 13 (52%) of 25 patients from the initial episode of cytomegalovirus pneumonia with the regimen of ganciclovir and cytomegalovirus immunoglobulin is significantly better (P less than 0.001) than the survival of 13 of 89 (15%) patients using previous antiviral regimens.

Candidemia in Allogeneic Blood and Marrow Transplant Recipients: Evolution of Risk Factors after the Adoption of Prophylactic Fluconazole

The prophylactic use of fluconazole is common in blood and marrow transplant (BMT) recipients. To evaluate how fluconazole has influenced the development of azole resistance and candidemia, weekly mouthwashings were done, and fluconazole susceptibility was determined for 1475 colonizing and invasive isolates obtained from patients undergoing BMT. Of 585 patients, 256 (44%) were colonized with Candida species during the course of BMT. Of these, 136 patients (53%) had at least 1 mouthwashing sample that yielded Candida species other than C. albicans on culture. Only 4.6% of patients developed candidemia. Overall, C. albicans was the most common colonizing isolate, but it caused only 7% of cases of candidemia. About 5% of colonizing C. albicans strains and 100% (2 of 2) invasive C. albicans strains were fluconazole-resistant. Colonization, cytomegalovirus disease, and bacteremia are risk factors for the development of candidemia. The use of prophylactic fluconazole is associated with a low incidence of candidemia and attributable mortality, despite colonization with azole-resistant Candida species in BMT recipients.

Cytomegalovirus Immune Globulin and Seronegative Blood Products to Prevent Primary Cytomegalovirus Infection after Marrow Transplantation

In an attempt to prevent primary cytomegalovirus infection after marrow transplantation, we randomly assigned 97 patients who were seronegative for antibody to cytomegalovirus before transplantation to receive one of the following: (1) both intravenous cytomegalovirus immune globulin and seronegative blood products (23 patients); (2) seronegative blood products alone (28 patients); (3) globulin alone (22 patients); or (4) neither treatment (24 patients). Patients not assigned to receive seronegative blood products received unscreened blood products from random donors. The incidence of cytomegalovirus infection according to study group among patients in the study for at least 62 days was 5 percent, 13 percent, 24 percent, and 40 percent, respectively. Among 57 patients with seronegative marrow donors, those who received seronegative blood products had significantly less infection (1 of 32) than those who received standard blood products (8 of 25, P less than 0.007). In contrast, the use of seronegative blood products did not appear to prevent cytomegalovirus infection among patients with seropositive marrow donors. The possibility that cytomegalovirus immune globulin as used in this study can prevent cytomegalovirus infection or ameliorate cytomegalovirus disease was not confirmed, and it cannot be recommended for routine use without additional study.

Immunomodulatory and Antimicrobial Efficacy of Intravenous Immunoglobulin in Bone Marrow Transplantation

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.

Clinical Significance of Nephrotoxicity in Patients Treated with Amphotericin B for Suspected or Proven Aspergillosis

The records of 239 immunosuppressed patients receiving amphotericin B for suspected or proven aspergillosis were reviewed to determine rates of nephrotoxicity, dialysis, and fatality. The mean and median durations of treatment were 20.4 and 15.0 days, respectively. The creatinine level doubled in 53% of patients and exceeded 2.5 mg/dL in 29%; 14.5% underwent dialysis; and 60% died. A multivariate Cox proportional hazards analysis showed that patients whose creatinine level exceeded 2.5 mg/dL (hazard ratio [HR], 42.02; P<.001), allogeneic bone marrow transplantation (BMT) patients (HR, 6.34; P<. 001), and autologous BMT patients (HR, 5.06; P=.024) were at greatest risk for requiring hemodialysis. Use of hemodialysis (HR, 3. 089; P<.001), duration of amphotericin B use (HR, 1.03 per day; P=. 015), and use of nephrotoxic agents (HR, 1.96; P=.017) were associated with greater risk of death, whereas patients undergoing solid organ transplantation were at lowest risk (HR, 0.46; P=.002). These data indicate that elevated creatinine levels during amphotericin B treatment are associated with a substantial risk for hemodialysis and a higher mortality rate, but the risks vary in different patient groups.

The Impact of Candidemia on Length of Hospital Stay, Outcome, and Overall Cost of Illness

Although numerous studies have examined trends in nosocomial fungal infections, few have specifically addressed the cost of care associated with candidemia. This study analyzes the direct medical costs associated with treating candidemia in the United States. The study design was a cost-of-illness analysis estimating the average cost of candidemia for a single episode of care. Data were obtained from three sources: the 1993 Healthcare Cost and Utilization Project of the Agency for Health Care Policy and Research, the relevant literature, and a clinical expert in systemic fungal infections. The estimated cost (1997 U.S.

Human Herpesvirus 6 in Lung Tissue from Patients with Pneumonitis after Bone Marrow Transplantation

) of an episode of care for candidemia is

A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients.

34,123 per Medicare patient and