Joel D. Meyers

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

Early Treatment with Ganciclovir to Prevent Cytomegalovirus Disease after Allogeneic Bone Marrow Transplantation

BACKGROUND Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir for the early treatment of CMV infection in asymptomatic recipients of bone marrow transplants whose surveillance cultures for CMV became positive. METHODS Bone marrow--allograft recipients who were seropositive for CMV antibodies or who received seropositive marrow were screened for CMV excretion by culture of throat swabs, blood, urine, or bronchoalveolar-lavage fluid. In this double-blind trial, 72 patients who had marrow engraftment and were excreting virus were randomly assigned to receive either placebo or ganciclovir (5 mg per kilogram of body weight twice a day for one week, followed by 5 mg per kilogram per day) for the first 100 days after transplantation. Patients were followed for the development of biopsy-confirmed CMV disease, ganciclovir-related toxicity, and survival. RESULTS Between assignment to the study drug and day 100 after transplantation, CMV disease developed in only 1 of the 37 patients assigned to receive ganciclovir (3 percent), but in 15 of the 35 patients assigned to receive placebo (43 percent, P less than 0.00001). The ganciclovir recipients had rapid suppression of virus excretion; 85 percent had negative cultures after one week of treatment, as compared with 44 percent of the placebo group (P = 0.001). The principal toxic reaction was neutropenia; 11 ganciclovir recipients had an absolute neutrophil count below 0.75 x 10(9) per liter, as compared with 3 placebo recipients (P = 0.052). Treatment was discontinued in 11 ganciclovir recipients and 1 placebo recipient because of neutropenia (P = 0.003). After treatment was stopped, the neutrophil count recovered in all patients. Overall survival was significantly greater in the ganciclovir group than in the placebo group both 100 days and 180 days after transplantation (P = 0.041 and 0.027, respectively). CONCLUSIONS Early treatment with ganciclovir in patients with positive surveillance cultures reduces the incidence of CMV disease and improves survival after allogeneic bone marrow transplantation.

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.

Acyclovir for Prevention of Cytomegalovirus Infection and Disease after Allogeneic Marrow Transplantation

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting). The probability that cytomegalovirus infection would develop within the first 100 days after transplantation was 0.70 among acyclovir recipients and 0.87 among control patients at medians of 62 and 40 days after transplantation, respectively (P = 0.0001 by log-rank test). Invasive cytomegalovirus disease developed in 19 acyclovir recipients (22 percent) and 25 control patients (38 percent) (P = 0.008). Survival within the first 100 days after transplantation was better among acyclovir recipients (P = 0.002). Acyclovir prophylaxis was associated with a relative risk of 0.5 or less for the development of cytomegalovirus infection or disease or for death within the first 100 days after transplantation (P less than or equal to 0.04), in proportional-hazards regression analysis. We conclude that prophylaxis with intravenous acyclovir significantly reduced the risk of both cytomegalovirus infection and cytomegalovirus disease in seropositive patients after allogeneic bone marrow transplantation and that it was also associated with significantly improved survival.

Adenovirus Infections in Patients Undergoing Bone-Marrow Transplantation

Viral infection is commonly observed after bone-marrow transplantation. We isolated adenovirus from 51 of 1051 patients undergoing marrow transplantation between 1976 and 1982. Of the 46 isolates available for typing, 13 (27.7 per cent) were of the closely related species 11, 34, or 35 (subgenus B). All 13 of the patients with these species had positive urine cultures. The species have previously been associated with the acquired immunodeficiency syndrome or with renal transplantation but are not commonly found in community surveys. Invasive infection was confirmed by biopsy or autopsy in 10 of 51 patients. Seven of the 10 had virus isolated from lung, and 4 died from pneumonia attributed to adenovirus. Two of the five patients with renal isolates had evidence of virally induced renal impairment, and both patients with liver isolates had adenovirus hepatitis. There was no common source that accounted for these adenovirus infections, and the most likely source of infection appeared to be endogenous viral reactivation. The only identifiable risk factor for the development of infection and for severe disease was the presence of moderate to severe graft versus host disease.

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.

Activity of 9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine in the Treatment of Cytomegalovirus Pneumonia

Ten marrow transplant recipients with biopsy-proven cytomegalovirus pneumonia were treated with the acyclic nucleoside analog 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (BW B759U). Viruria and viremia ceased after 4 days of treatment in all patients with cultures initially positive from these sites. Cytomegalovirus was eliminated from respiratory secretions after a median of 8 days. Despite this antiviral effect, only one patient survived the pneumonia. Quantitative cultures of lung tissue before and after treatment confirmed that therapy with BW B759U was associated with substantial antiviral activity, with a mean decrease in viral titers of more than 99.99% after treatment. Neutropenia developed in three patients when mean peak and trough plasma levels exceeded 50 and 10 mu mol/L, respectively, but no other toxicity was seen. BW B759U is the first antiviral agent showing consistent activity against cytomegalovirus in vivo, and it should be evaluated in the earlier management of cytomegalovirus infections after marrow transplantation and in serious cytomegalovirus infections in other immunocompromised patients.

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

BACKGROUND Human herpesvirus 6 (HHV-6) is a recently described herpesvirus that is epidemiologically and biologically similar to cytomegalovirus. It is the cause of exanthem subitum (roseola) in children. METHODS To evaluate the possible role of HHV-6 infection in pneumonitis in immunocompromised patients, we used quantitative HHV-6 polymerase chain reactions to study lung-biopsy specimens from 15 patients with pneumonitis after bone marrow transplantation and lung tissue from 15 immunocompetent subjects without pneumonitis and 6 fetuses. RESULTS HHV-6 DNA was detected in lung tissue from all 15 patients, from 14 seropositive control subjects, and from none of the 7 seronegative control subjects. Six patients had levels of HHV-6 DNA in lung tissue that were 10 to 500 times higher than those in any of the other patients or control subjects. Increased levels of HHV-6 DNA correlated with a decreased risk of death from pneumonitis (P = 0.015), an increased severity of graft-versus-host disease (P = 0.023), and the presence of idiopathic pneumonitis (P = 0.037). Levels of HHV-6 DNA correlated directly with the changes in HHV-6 antibody titers in the interval between the pretransplantation period and the open-lung biopsy (P = 0.002). Low levels of HHV-6 antibody at the time of the open-lung biopsy were also associated with the diagnosis of idiopathic pneumonitis (P = 0.002). CONCLUSIONS The concentrations of HHV-6 genome in lung tissue and their relation to changes in serologic titers support an association between HHV-6 infection and idiopathic pneumonitis in immunocompromised hosts.

Intravenous Acyclovir to Treat Mucocutaneous Herpes Simplex Virus Infection After Marrow Transplantation: A Double-Blind Trial

Acyclovir, a new antiviral agent, was compared to a placebo in a randomized double-blind trial of treatment for culture-proven herpes simplex virus infection after marrow transplantation. Patients received either intravenous acyclovir at 750 mg/m2 body surface area per day or a placebo for 7 days. Thirteen of 17 patients given acyclovir had a beneficial response as compared with two of 17 given the placebo (p less than 0.01). The duration of positive cultures was shorter among acyclovir recipients (3 versus 17 days, p less than 0.00005). Also shorter were the median days to resolution of pain (10 versus 16 days, p = 0.03), to crusting of lesions (7 versus 14 days, p = 0.01), and to total healing (14 versus 28 days, p = 0.03). No acyclovir toxicity was observed. Recurrent infection was common. Acyclovir provided significant antiviral and clinical efficacy without toxicity in highly immunosuppressed patients but had no effect on virus latency.

Herpes Simplex Virus Pneumonia: Clinical, Virologic, and Pathologic Features in 20 Patients

Herpes simplex virus (herpesvirus) was isolated from autopsy lung specimens of 20 patients with clinical, roentgenographic, and histologic evidence of pneumonia. Mucocutaneous herpesvirus infection preceded the onset of pneumonia in 17. Twelve patients had focal pneumonia, 10 of whom had concomitant herpetic tracheitis, esophagitis, or both. Eight patients had diffuse interstitial pneumonia, six of whom had dissemination of herpesvirus to the other organs. Of the eight lung isolates available for typing, seven were herpesvirus-1 and one, herpesvirus-2. A high prevalence of herpesvirus antibody in serum samples obtained before pneumonia and identical restriction endonuclease patterns between mucosal and lung isolates in individual patients indicated that, in most cases, herpesvirus pneumonia was due to endogenous reactivation of virus. Focal herpesvirus pneumonia appeared to result from contiguous spread of herpesvirus to lung parenchyma, whereas diffuse interstitial pneumonia appeared to be a manifestation of hematogenous dissemination of virus.