Original Article
A Randomized, Controlled Trial of Prophylactic Ganciclovir for Cytomegalovirus Pulmonary Infection in Recipients of Allogeneic Bone Marrow Transplants
N Engl J Med 1991; 324:1005-1011April 11, 1991
- Abstract
- Abstract
Background.
Cytomegalovirus (CMV)-associated interstitial pneumonia is a major cause of death after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir in recipients of bone marrow transplants who had asymptomatic pulmonary CMV infection. We also sought to identify risk factors for the development of CMV interstitial pneumonia.
Methods.
After bone marrow transplantation, 104 patients who had no evidence of respiratory disease underwent routine bronchoalveolar lavage on day 35. The 40 patients who had positive cultures for CMV were randomly assigned to either prophylactic ganciclovir or observation alone. Ganciclovir (5 mg per kilogram of body weight intravenously) was given twice daily for two weeks and then five times per week until day 120.
Results.
Of the 20 culture-positive patients who received prophylactic ganciclovir, 5 (25 percent) died or had CMV pneumonia before day 120, as compared with 14 of the 20 culture-positive control patients (70 percent) who were not treated prophylactically (relative risk, 0.36; P = 0.01). No patient who received the full course of ganciclovir prophylaxis went on to have CMV interstitial pneumonia. Four patients treated with ganciclovir had maximal serum creatinine levels ≥221 μmol per liter (2.5 mg per deciliter), as compared with none of the controls (P = 0.029). Of the 55 CMV-negative patients who could be evaluated, 12 (22 percent) had CMV pneumonia — a significantly lower rate than in the untreated CMV-positive control patients (relative risk, 0.33; P = 0.003). The strongest predictors of CMV pneumonia were a lavage-fluid culture that was positive for CMV and a CMV-positive blood culture, both from specimens obtained on day 35.
Conclusions.
In recipients of allogeneic bone marrow, asymptomatic CMV infection of the lung is a major risk factor for subsequent CMV interstitial pneumonia. Prophylactic ganciclovir is effective in preventing the development of CMV interstitial pneumonia in patients with asymptomatic infection. (N Engl J Med 1991; 324: 1005–11.)
Article Activity
- Article
CYTOMEGALOVIRUS (CMV)-associated interstitial pneumonia is the most common infectious cause of death after allogeneic bone marrow transplantation and thus is an important factor in limiting the success of this procedure.1 2 3 4 In a series of 525 recipients of allogeneic bone marrow transplants studied over a 10-year period, the incidence of CMV pneumonia was 16.7 percent and the mortality rate was 85 percent.2 Previous clinical trials of methods for the prevention or treatment of CMV pneumonia have resulted in similarly high rates of mortality.5 6 7 8 9 10 11 12 13 14 Combined therapy with ganciclovir and intravenous immune globulin, however, has recently been shown to improve survival in patients with this disease.15 16 17 These observations have raised the question of whether CMV pneumonia in transplant recipients can be prevented. Because bone marrow and renal toxicity has been attributed to ganciclovir, our approach was to expose only patients with evidence of active pulmonary CMV infection to prophylaxis with this drug. Therefore, the primary goal of this randomized clinical study was to determine whether treatment with ganciclovir could effectively prevent subsequent pulmonary disease in subjects with asymptomatic pulmonary CMV infection. In addition, we describe the prevalence and natural history of subclinical pulmonary CMV infection in patients with bone marrow transplants.
Methods
Preparation for Bone Marrow Transplantation
Patients were prepared for bone marrow transplantation with either fractionated total-body irradiation in combination with etoposide,18 with or without cyclophosphamide (80 mg per kilogram of body weight on day 2 before transplantation), or high-dose chemotherapy alone.19 The day of bone marrow transplantation was defined as day 0. One patient received his graft from a partially matched related donor, whereas all the others received grafts from siblings with identical genotypes. Prophylaxis for graft-versus-host disease (GVHD) was given as described elsewhere20; it included an anti—pan-T-lymphocyte immunotoxin (Xomazyme-H65, Xoma, Berkeley, Calif). All patients received biweekly immune globulin at a dose of 500 mg per kilogram intravenously (Gammagard, Hyland Division/Baxter Healthcare, Glendale, Calif.) from day 9 before transplantation through day 180 afterward, plus trimethoprim–sulfamethoxazole given in a 10-day course before transplantation and then twice weekly afterward. In addition, the patients received daily amphotericin B (2.5 mg per square meter of body-surface area) for antifungal prophylaxis. The patients were informed of the investigational nature of this study and gave written informed consent. The protocol was approved by the institutional review boards of the City of Hope National Medical Center and Stanford University Hospital.
Clinical Protocol
Recipients of allogeneic bone marrow transplants were evaluated for the presence of pulmonary CMV by bronchoalveolar lavage or days 35 and 49. Patients were considered eligible for this study if they or their donors had a CMV antibody titer before transplantation ≥1:16 (if measured at City of Hope National Medical Center), or ≥1:8 (if measured at Stanford University Hospital), no radio-graphic evidence of active pulmonary disease, and no fever or respiratory symptoms, such as cough or dyspnea, on clinical evaluation on day 34. CMV antibody titers were determined by indirect immunofluorescence (Electro-Nucleonics, Columbia, Md.) at the City of Hope National Medical Center and by latex agglutination (Becton Dickinson Immunocytochemistry Systems, Mountain View, Calif.) at Stanford University Hospital. Patients with a neutrophil count ≤1.0×109 per liter (1000 per cubic millimeter) or a serum creatinine level ≥177 μmol per liter (2 mg per deciliter) were excluded from the study.
Patients positive for CMV according to either cytologic studies or shell-vial cell culture (see below) of the bronchoalveolar-lavage specimen taken on day 35 were randomly assigned to prophylaxis with ganciclovir (Syntex, Palo Alto, Calif.) (group 1) or to observation (group 2). Stratification was based on the presence or absence of graft-versus-host disease on day 35 and on the patient's age (≤25 or >25 years). The CMV-negative patients did not undergo randomization but were followed (group 3).
Patients randomly assigned to ganciclovir prophylaxis received 5 mg per kilogram intravenously twice daily for two weeks. The protocol was amended after the first nine patients were enrolled to include maintenance therapy (5 mg per kilogram each day intravenously for five days per week) until day 120; these nine subjects (including two in group 1 and two in group 2) were excluded from all but the intention-to-treat analyses. The patients in groups 2 and 3 were observed similarly for the development of pneumonia until day 120. Patients in whom CMV pneumonia developed were treated with ganciclovir and intravenous immune globulin, as described elsewhere.15 The patients in groups 1 and 2 were followed with chest radiography twice weekly. The dosage of ganciclovir was modified according to the manufacturer's recommendations. The fluid balance in each patient was recorded three times daily, and diuretic agents were given for any fluid retention ≥1000 ml.
Bronchoalveolar Lavage and Virologic Evaluation
Fiberoptic bronchoscopy with bronchoalveolar lavage has been described elsewhere in detail.21 , 22 The lavage fluid was processed immediately and examined for the presence of CMV inclusion bodies and other pathogens. For rapid detection of CMV, shell-vial cell cultures were prepared.23 , 24 This test uses foreskin fibroblasts infected by supernatant from the lavage fluid, then stained immunochemically; it usually gives results within 24 hours. In addition, bronchoalveolar-lavage fluid was cultured for CMV and other pathogens by conventional methods. Throat swabs for culture were obtained simultaneously with blood and urine for CMV culture to document concomitant upper respiratory viral infection. For purposes of randomization, CMV-positive bronchoalveolar-lavage fluid was defined as supernatant fluid that was positive on shell-vial cell culture or lavage cells that had characteristic CMV inclusion bodies in the absence of other pathogens.
Definition and Radiographic Documentation of CMV Interstitial Pneumonia
CMV pneumonia was defined as a clinical syndrome characterized by radiographic evidence of interstitial pulmonary infiltrates in a patient with CMV-positive bronchoalveolar-lavage fluid, in the absence of any. other clinical, microbiologic, or histopathological abnormalities that could explain the respiratory disease. If interstitial pneumonia developed within seven days after bronchoalveolar lavage in a patient positive for CMV, CMV was presumed to be the cause; after seven days, patients underwent a second diagnostic bronchoalveolar-lavage procedure to confirm the diagnosis of CMV and exclude other infectious causes. The validity of the radiographic diagnosis of interstitial pneumonia was confirmed retrospectively by a blinded review of the radiographs by an experienced radiologist, with appropriate control radiographs included in the review.
Statistical Analysis
The proportions of patients with CMV pneumonia in groups 1 and 2 were initially compared with use of a patient-by-patient sequential probability ratio test, which maintained an overall alpha level of 0.05 for the study.25 As soon as a statistically significant difference was identified, randomization of patients into the study was terminated. Base-line characteristics of the three groups were compared with the Kruskal—Wallis, Pearson's chi-square, and Fisher's exact tests. In the final comparison of the two randomly assigned groups (groups 1 and 2), failure was defined as the development of CMV interstitial pneumonia on or before day 120 or death from any cause before that date. Fisher's exact test was used to compare the incidence of CMV interstitial pneumonia in groups 1 and 2. The relative risk of failure (i.e., the proportion of patients in whom treatment failed in the treatment group divided by the proportion who had CMV pneumonia or died in the observation group) was calculated, along with the 95 percent confidence interval for the relative risk.26 Logistic regression was used to compare the development of CMV interstitial pneumonia in groups 1 and 2, with adjustment for any differences between the groups with respect to base-line characteristics. Fisher's exact test and Pearson's chi-square test were used to examine the association of potentially prognostic variables with the development of CMV pneumonia and with a positive lavage-fluid sample collected on day 35 in groups 2 and 3. All patients who had CMV pneumonia within 120 days of bone marrow transplantation and those who survived 120 days with no pneumonia were included in the analyses related to pneumonia; the patients in all three groups were included in the analyses related to the results of bronchoalveolar lavage. The Kaplan–Meier product-limit method and the log-rank test were used to examine end points involving the time to an event. A significance level of 0.05 was used for all analyses, and two-sided alternative hypotheses were assumed throughout.
Results
Between September 1987 and March 1990, 104 patients with hematologic cancers of various stages participated in this study (Table 1Table 1
Characteristics of the 104 Participants in the Study, According to Study-Group Assignment and Results of Bronchoalveolar-Lavage Culture for CMV on Day 35.). In March 1990, after 31 patients in groups 1 and 2 had reached day 120 after bone marrow transplantation, a statistically significant difference in the rate of CMV pneumonia was identified with the sequential probability ratio test. At that time, the nine other patients in groups 1 and 2 had not yet reached day 120, and they continued to be followed. Among these 40 patients, 20 were randomly assigned to group 1 (prophylactic ganciclovir), and 20 to group 2 (observation). An additional 64 patients from whom bronchoalveolar-lavage fluid negative for CMV was obtained on day 35 were included in group 3. The base-line characteristics of all patients are summarized in Table 1. There were no significant differences among the three groups with respect to any variable except for a significantly higher proportion of patients with low pretransplantation CMV titers in group 3, as compared with group 2 (P = 0.02). The groups were balanced for age and for the presence of any graft-versus-host disease at day 35 (Grade 0 vs. Grades I to IV) in the randomization process. Group 1, however, had a higher rate of acute graft-versus-host disease of Grade II or higher than group 2 (25 vs. 5 percent; P = 0.18).Radiographic Verification of Interstitial Pneumonia
A total of 31 patients in the three study groups were given diagnoses of CMV pneumonia, and for 30 of these 31 patients, chest radiographs presumed to be positive for interstitial pneumonia were identified for review (a radiograph for 1 patient in group 3 was unavailable for coding). Of the patients who could be studied, 29 were confirmed to have interstitial infiltrates. The remaining patient was found to have normal films and was therefore considered to be negative for CMV interstitial pneumonia in this analysis. All the sets of radiographs from the patients who had not been given a clinical diagnosis of interstitial pneumonia were interpreted as showing no interstitial infiltrates on review.
Effect of Ganciclovir Prophylaxis on the Development of CMV Interstitial Pneumonia
To examine the effect of ganciclovir prophylaxis, a full intention-to-treat analysis was performed with all 40 randomized patients, as well as an analysis that excluded 7 patients who could not be evaluated with respect to CMV pneumonia.
On the basis of the Kaplan–Meier product-limit estimates of the probability of CMV pneumonia and the log-rank test, a large treatment effect was found when groups 1 and 2 were compared (P = 0.0013) (Fig. 1Figure 1
Kaplan–Meier Product-Limit Estimates of the Probability of CMV Pneumonia in Recipients of Bone Marrow Transplants.). The risk of CMV pneumonia in group 1 was found to be reduced to the level in group 3 (Fig. 1). The risk of CMV pneumonia or death before day 120 in group 1 was one third that in the observation group (group 2) (relative risk, 0.33; P = 0.015) (Table 2Table 2
Rate at Which the 40 Patients Positive for CMV by Culture of Lavage Fluid Obtained on Day 35 Had CMV Interstitial Pneumonia or Died, According to Treatment Assignment.). Only 4 of 18 treated patients (22 percent) had CMV pneumonia or died before day 120, as compared with 10 of 15 untreated patients (67 percent). When all 40 randomized patients were included, the results were similar (5 of 20 [25 percent] vs. 14 of 20 [70 percent]; relative risk, 0.36; P = 0.010). A significant decrease in the risk of CMV pneumonia after treatment with ganciclovir was also observed when we adjusted for the presence of acute graft-versus-host disease of Grade II or higher by logistic regression (P<0.001). When the analysis of treatment effect was repeated for patients without severe graft-versus-host disease, the risk of pneumonia for the patients in group 1 was even lower as compared with that for the patients in group 2 (relative risk, 0.19). Three of five patients in group 1 with severe graft-versus-host disease (60 percent) did not respond to treatment; of these, one patient received no maintenance treatment with ganciclovir, CMV pneumonia developed in another after only two doses of ganciclovir, and the drug was discontinued after two days in the third because of progressive azotemia. Two additional patients in group 1 died of other causes; thus, no patient who completed the full course of induction and maintenance therapy with ganciclovir had CMV pneumonia.Virologic Results at Days 35 and 49 and the Development of CMV Pneumonia
The details of the results of virologic tests of specimens obtained on days 35 and 49 are summarized in Figure 2.Figure 2
Results of CMV Cultures and Cytologic Studies of Specimens Obtained on Days 35 and 49, According to Study Group. Fifty-nine of the 104 asymptomatic subjects (57 percent) who had bronchoalveolar lavage on day 35 underwent a repeated procedure on day 49. Of the 20 patients in group 1, 2 had CMV pneumonia before day 49. Of the 18 patients in group 1 who were retested, 6 (33 percent) remained positive on day 49 (3 on shell-vial cell culture and 3 according to cytologic studies); 1 had CMV pneumonia between day 50 and day 120, after treatment with ganciclovir was stopped because of initial protocol restrictions. All 10 of the patients in group 2 who had a repeated bronchoalveolar lavage remained CMV-positive. CMV-associated interstitial pneumonia developed later in 5 of these 10 (50 percent). Among the 64 patients in group 3 with negative bronchoalveolar-lavage specimens, 3 (5 percent) had CMV-associated pneumonia that was diagnosed before day 49. Results of a second bronchoalveolar lavage were available for 31 of the remaining 61 patients (51 percent), 16 of whom (52 percent) tested positive on day 49. CMV pneumonia was diagnosed subsequently in 6 (38 percent) of the 16 CMV-positive patients; 4 of the 30 patients who were not retested (13 percent) also had CMV-associated interstitial pneumonia subsequently. None of the 14 patients with negative bronchoalveolar-lavage fluid on days 35 and 49 later had CMV pneumonia.Association of CMV Pneumonia with Virologic and Clinical Variables
Seventy of the 84 patients in groups 2 and 3 were followed either through day 120 or to the development of CMV pneumonia; 5 patients in group 2 and 9 patients in group 3 could not be evaluated or died before day 120 without evidence of CMV pneumonia. For the 70 patients who could be evaluated, Table 3Table 3
Association of Potentially Prognostic Variables with the Development of CMV Interstitial Pneumonia in the 70 Patients under Observation Only.* summarizes the associations found between CMV pneumonia and the potentially prognostic variables studied. On the basis of the shell-vial cell culture, the presence of CMV in the bronchoalveolar-lavage specimen obtained on day 35 was a risk factor significantly associated with an increased risk of CMV pneumonia. Nine of 14 patients positive for CMV (64 percent) had CMV pneumonia, as compared with 13 of 56 patients negative on shell-vial cell culture (23 percent) (relative risk, 2.77; P = 0.008). Additional variables found to be significantly associated with the development of CMV pneumonia were a lavage-fluid culture prepared by conventional methods that was positive for CMV (relative risk, 5.77; P<0.0001), a CMV-positive buffy-coat culture from blood obtained on day 35 (relative risk, 3.63; P = 0.001), and positive cytologic studies (relative risk, 2.65; P = 0.03). The presence of CMV in the cultures of urine or throat cells obtained on day 35 was not significantly associated with the development of CMV pneumonia. Nor did age, type of preparative regimen before transplantation (i.e., with or without total-body irradiation), or the presence of active graft-versus-host disease on day 35 appear to be a significant risk factor for the development of CMV pneumonia. A Kaplan–Meier product-limit estimate showed that the concentration of CMV (plaque-forming units per milliliter) in bronchoalveolar-lavage fluid on day 35 was not associated with either the risk of CMV pneumonia or the severity or bilaterality of subsequent infiltrates (data not shown).Characteristics of Patients with Asymptomatic Pulmonary CMV Infection on Day 35
The variables found to be significantly associated with a CMV-positive shell-vial cell culture of bronchoalveolar-lavage fluid were a CMV-positive buffy-coat culture from blood obtained on day 35 (relative risk, 5.45; P<0.0001), a CMV-positive lavage-fluid culture prepared by conventional methods (relative risk, 4.22; P<0.0001), a CMV-positive urine culture (relative risk, 3.73; P = 0.003), a CMV-positive throat culture (relative risk, 2.90; P<0.0001), a pre-transplantation CMV titer >1:64 (relative risk, 2.71; P = 0.002), and age ≤25 (relative risk, 1.74; P = 0.03). In the patients we studied, irradiation before transplantation was associated with a marginally increased risk (relative risk, 1.70; P = 0.15). Diagnosis, disease status, and the presence of acute graft-versus-host disease of Grade II or higher on day 35 were not significantly associated with CMV-positive bronchoalveolar-lavage fluid.
Side Effects Related to Ganciclovir
Only one patient required dose modification during the first two weeks of treatment, but most patients required such modifications during the maintenance phase, as noted above. The only side effect that differed significantly in frequency between the treatment and observation groups was the maximal serum creatinine level (P = 0.029). Four patients in group 1 had maximal serum creatinine levels ≥221 μmol per liter (2.5 mg per deciliter) on days 35 through 120 (mean duration of observation, 67.8 days), as compared with none in group 2 (mean duration of observation, 28.4 days). Dose modifications were required in 14 patients in group 1 because of creatinine levels ≥133 μmol per liter (1.5 mg per deciliter), and in 7 patients because of neutropenia (neutrophil count, ≤1.0×109 per liter [1000 per cubic millimeter]). Seven patients in group 2 had a maximal creatinine level ≥133 μmol per liter. The median number of hospital days after bone marrow transplantation was similar in groups 1 and 2 (56.5 and 66.0 days, respectively; P = 0.60). However, 45 percent of the patients in group 2 had more than two hospitalizations, as compared with 15 percent of those in group 1 (P = 0.08).
Side Effects of the Bronchoalveolar-Lavage Procedure
Patients generally tolerated the bronchoalveolar lavage on day 35 without complications. There was no mortality associated with the procedure. The only morbidity occurred in two patients who had fever and a pulmonary infiltrate in the lung segments subjected to lavage within 24 hours after the procedure. In both cases, the abnormalities resolved promptly with the administration of broad-spectrum antibiotics.
Discussion
This study addressed the question of whether aggressive diagnostic intervention with documentation and prophylactic treatment of subclinical CMV pulmonary infection can prevent CMV pneumonia in recipients of allogeneic bone marrow transplants. In our study, the only treatment failures in the ganciclovir group occurred in patients who received only part of their assigned treatment. The study was designed with use of the sequential probability ratio test so that the determination of results would minimize unnecessary random assignments to the observation group. The preliminary finding of significance was made in late March 1990, and randomization was halted thereafter. Subsequently, all patients not already enrolled who had asymptomatic pulmonary CMV infection were offered prophylactic ganciclovir therapy. At that time, nine patients had already been randomly assigned to treatment but had not yet reached 120 days of follow-up. Six of these nine had been randomly assigned to receive prophylactic ganciclovir. The remaining three patients were at the 98th, 105th, and 112th day after transplantation. Two of the three had been receiving both ganciclovir and immune globulin since January 1990, for the treatment of interstitial pneumonia with onset at day 45 in one, and for the treatment of invasive CMV gastroenteritis with onset at day 42 in the other. We thought that the risk of starting the remaining patient in the observation group on ganciclovir so late after transplantation (day 98) was not justified by the benefits. In addition, this patient had passed the period of peak risk for CMV pneumonia and was being treated as an outpatient. Therefore, we decided to complete the observation of this patient to allow evaluation of the end point of pneumonia. The patient remained alive and well, with no interstitial pneumonia.
The rapid method of culture used to evaluate bronchoalveolar-lavage fluid was sensitive in the delineation of infection, allowing the timely initiation of prophylaxis in the patients in group 1.27 Only 6 of 53 patients in group 3(11 percent) had a positive culture by conventional long-term methods, and 5 (9 percent) were eventually given a diagnosis of CMV pneumonia on days 41 through 62. Therefore, these findings validated the results of rapid CMV culture with respect to the assignment of risk. However, 13 of 61 patients (21 percent) with CMV-negative bronchoalveolar-lavage fluid on day 35 subsequently had CMV pneumonia, yielding a negative predictive value of 79 percent for this procedure. Although it may be possible to increase the sensitivity of early diagnosis of CMV with the use of newer methods of detecting virus, such as in situ antigen and DNA detection or the polymerase chain reaction, it is likely that in some patients CMV infection will develop after day 35. For these patients, earlier detection of CMV in blood cultures, which were as predictive as positive results of bronchoalveolar-lavage culture or examination, might make possible antiviral prophylaxis. Application of the shell-vial technique to blood cultures, or other rapid methods, should be explored in this regard.28
Previous studies have suggested that prophylactic acyclovir therapy can decrease the incidence of CMV as well as herpes simplex virus infection in patients who are seropositive for CMV at the time of marrow transplantation.29 Although comparative clinical trials will be required to determine whether ganciclovir is more efficacious than acyclovir in these circumstances, our studies suggest that ganciclovir is very effective in preventing disease in a population of patients with well-defined risk factors. Moreover, ganciclovir is approximately 50 times more active in vitro against CMV than acyclovir.30 Although recent progress in the treatment of CMV pneumonia has led to decreased mortality from this infection, a substantial number of patients still die of other CMV-related complications. Successful prophylaxis would allow them to avoid the difficult, costly, and prolonged therapy required to treat established CMV pneumonia.
In view of the low rate of toxicity in this trial, one could consider giving prophylactic ganciclovir to all recipients of allogeneic bone marrow transplants except those who remain CMV-seronegative, since the cost of treating these patients when they are sick is probably higher than the cost of unnecessary prophylaxis in the entire group. This approach, however, would unnecessarily expose approximately half our patients to ganciclovir, increase the risk of infection, and possibly prolong inpatient hospital care. Admittedly, this approach does not protect the patients who are CMV-negative on day 35 and in whom pneumonia will eventually develop. Therefore, additional studies are needed to identify the patients who would benefit most from ganciclovir prophylaxis. This study, however, documents that the early detection of CMV pulmonary infection with prospective bronchoalveolar lavage, followed by treatment of asymptomatic infection with ganciclovir, can prevent CMV pneumonia in most recipients of bone marrow transplants who are at risk for this disease. Moreover, the majority of our patients had few toxic effects from ganciclovir or none at all. Therefore, the approach described here has become part of the method of management at our institutions.
Supported by grants (2PO1-CA-30206 and 1PO1-CA-49605) from the National Cancer Institute and by a grant from Syntex Corp., Palo Alto, Calif.
We are indebted to Mrs. Annette S. Brown for assistance in the preparation of the manuscript.
Source Information
From the Departments of Hematology and Bone Marrow Transplantation (G.M.S., S.J.F.), Respiratory Diseases (D.A.H.), Biostatistics (J.C.N.), and Virology and Pediatric Infectious Diseases (J.A.Z.), City of Hope National Medical Center, Duarte, Calif., and the Division of Respiratory Diseases, Department of Medicine, Stanford University Medical Center, Stanford, Calif. (S.R.D.). Address reprint requests to Dr. Schmidt at the City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010.
* The following institutions and investigators participated in the City of Hope—Stanford—Syntex CMV Study Group: City of Hope National Medical Center, Duarte, Calif. — J. Martin Hogan, M.D., Cheryl Faucett, M.S., L. Robert Hill, Ph.D., Francis J. Wall, Ph.D., Ghislaine Gallez-Hawkins, M.Sc, Angela Morton-Blackshere, R.A., Auayporn P. Nademanee, M.D., Margaret R. O'Donnell, M.D., Pablo Parker, M.D., David S. Snyder, M.D., Eileen Smith, M.D., Anthony Stein, M.D., Kim Margolin, M.D., and George Somlo, M.D.; University of Southern California/Los Angeles County Medical Center, Los Angeles —Andrea A. Kovacs, M.D.; Bone Marrow Transplantation Program, Stanford University Medical Center. Stanford, Calif. — Nelson J. Chao, M.D., and Karl G. Blume, M.D.; Syntex Research, Division of Syntex (USA), Palo Alto, Calif. — Bernadette DeArmond, M.D., William Buhles, Ph.D., Charles Du-Mond, Ph.D., and Veronica Sullivan. R.S.M.S.
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