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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-03-0993.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Programs in Infectious Diseases Immunology,
Biostatistics, and Longterm Follow-up, Fred Hutchinson Cancer Research
Center, and the University of Washington, Seattle.
Ganciclovir effectively prevents cytomegalovirus (CMV) disease in
the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but late-onset CMV disease is increasingly observed. We designed a prospective cohort study to define the incidence and risk factors for late CMV infection in patients who
undergo HSCT. CMV-seropositive patients were studied prospectively for
CMV infection (quantitative pp65 antigenemia, quantitative CMV-DNA,
blood culture), T-cell immunity (CMV-specific CD4+ T-helper
and CD8+ cytotoxic T-lymphocyte responses, CD4 and CD8
T-cell count, absolute lymphocyte count), and other
transplantation-related factors. Univariate and multivariable
analyses were used to assess the risk for late CMV infection and
disease and to assess overall survival. Late CMV disease developed in
26 of 146 (17.8%) patients a median of 169 days after transplantation
(range, 96-784 days); the mortality rate was 46%. Thirty-eight percent
of patients surviving late disease had a second episode a median of 79 days after the first episode. At 3 months after transplantation,
preceding detection of CMV pp65 antigenemia, CD4 T-cell counts lower
than 50 cells/mm3, postengraftment absolute lymphopenia
levels lower than 100 lymphocytes/mm3, undetectable
CMV-specific T-cell responses, and graft-versus-host disease (GVHD)
were associated with late CMV disease or death. After 3 months,
continued detection of pp65 antigenemia or CMV DNA in plasma or
peripheral blood leukocytes and lymphopenia (fewer than 300 lymphocytes/mm3) were strong predictors of late CMV disease
and death. In conclusion, CMV viral load, lymphopenia, and CMV-specific
T-cell immunodeficiency are predictors of late CMV disease and death
after allogeneic stem cell transplantation. Prevention strategies
should be targeted at patients in whom CMV reactivated during the first
3 months and those with poor CMV-specific immunity or low CD4 counts.
(Blood. 2003;101:407-414) Ganciclovir effectively prevents cytomegalovirus
(CMV) disease during the first 3 months after allogeneic hematopoietic
stem cell transplantation (HSCT) when it is administered to the patient during engraftment,1,2 for pp65 antigenemia,3
or for the detection of CMV DNA by polymerase chain reaction
(PCR),4 and its use improves survival in selected patients
at high risk.4-7 However, recent clinical studies have
shown that most cases of CMV disease now develop after 3 months,3,4,8-12 when many patients are treated by their
referring physicians rather than at specialized cancer centers.
CMV-specific T-cell immunity and CMV viral load are important in
predicting early CMV disease after HSCT.13-16 Ganciclovir therapy, as well as graft-versus-host disease (GVHD) and its treatment, can delay the recovery of CMV-specific T-cell immunity after marrow transplantation.17-19 Thus, CMV-specific immunodeficiency
may persist after the discontinuation of ganciclovir therapy, leading
to excess late CMV disease and CMV-related death. In the first 3 months after transplantation, CMV viremia, quantitative pp65 antigenemia, and
DNA load are risk factors for the development of CMV disease, independent of GVHD.15,16,20,21 High CMV DNA load is also associated with poor survival in HIV-infected persons independent of
CD4 lymphocytopenia and HIV load.22 Here we examine, in a prospective study, the interrelationship between CMV load, CMV-specific T-cell immunity, and death in patients who have undergone HSCT and
are at risk for late CMV disease.
Patients
Virologic monitoring
Immunologic monitoring CMV-specific CD4+ T-helper (TH) and CD8+ cytotoxic T lymphocyte (CTL) responses, as well as CD4 and CD8 cell counts, were tested between days 80 and 100 and between days 140 and 150 after transplantation. In vitro expansion of CMV-specific CTLs was performed from peripheral blood mononuclear cells (PBMCs) as previously described using skin fibroblasts as stimulators and targets.19 To establish fibroblast lines, autologous skin or skin from HLA-matched donors was used. HLA-restricted CTL activity was determined by a 5-hour chromium-release assay. The panel of target cells used for each cytotoxicity assay included autologous and HLA-mismatched CMV-infected and mock-infected fibroblasts. Specific lysis was calculated by the standard formula, with maximum release reflecting counts per minute (cpm) from incubation of targets with 1% Nonidet P40-solution (Sigma, St Louis, MO), and spontaneous release, which should not exceed 30% of maximum release, reflecting cpm from targets incubated with medium alone. A positive result was defined as specific lysis of CMV-infected target cells greater than 10% above that of mock-infected targets.19 CMV-specific CD4+ Th responses and responses to phytohemagglutinin (PHA) were determined by a lymphoproliferative assay using 2 × 105 PBMCs per well in triplicate.19 A stimulation index of 3 or greater was considered positive.19 CD4 and CD8 T-lymphocyte counts were determined concurrently with CMV-specific T-cell responses (ie, days 80-100 and 140-150) by labeling PBMCs with specific monoclonal antibodies and subsequent analysis by 3-color flow cytometry.26Definitions CMV disease was defined as the demonstration of CMV in tissue by culture or histology or in bronchoalveolar lavage (BAL) by culture, direct fluorescence antibody stain, or cytology in the presence of new or changing pulmonary infiltrates.3 CMV retinitis was defined by ophthalmologic criteria. CMV-associated graft failure was defined as an absolute neutrophil count lower than 500 neutrophils/mm3 and the presence of CMV disease in marrow, detected by PCR and immunohistology, in the absence of other causes. CMV sinus disease was defined as the detection of CMV in sinus biopsy samples by culture or immunohistology and typical inflammatory changes in the absence of other pathogens. CMV-associated syndromes without tissue documentation were not considered. A second episode was defined as any manifestation that occurred after the completion of treatment and the disappearance of the initial symptoms. CMV-associated mortality was defined as death within 6 weeks of diagnosis of CMV disease or CMV identified in autopsy specimens.3 Acute and chronic GVHD were defined as described.27,28Statistical analysis CMV infection and disease incidence were estimated using cumulative incidence estimates, treating death before the event of interest as a competing risk event.29 Survival curves were estimated using the method of Kaplan and Meier.30 Hazard ratios and 95% confidence intervals were obtained for selected risk factors using univariate and multivariable Cox proportional hazards regression models for late CMV disease and death.31 In all time-to-event analyses, time was censored at second transplantation or at the end of follow-up. CMV virologic monitoring, chronic GVHD, CD4 counts, absolute lymphocyte counts, aspergillosis disease, and CMV disease (for death analysis, see Table 5) were included as time-dependent covariates in the regression models unless otherwise noted. Additional candidate risk factors were evaluated in the multivariable models as noted (Tables 1-7). Forward and backward elimination stepwise regression models were used to determine which variables should be included in the multivariable models. All reported P values are 2-sided.
Incidence and outcome of late CMV infection and disease One hundred forty-six consecutive CMV-seropositive recipients of transplanted allogeneic marrow underwent baseline immunologic evaluation and were followed up prospectively (Table 1). Median follow-up among surviving patients was 4.9 years (range, 2.9-7.8 years). The incidence of CMV infection in the first 200 days is depicted in Table 2. In approximately 50% of patients, CMV reactivated during follow-up. The median number of tests per patient after day 80 was similar for the 3 methods: pp65 antigenemia, 7 tests (range, days 1-32); plasma PCR, 6 tests (range, days 0-10); PBL PCR, 6 tests (range, days 0-11). The last tests were performed on days 169 (range, days 83-268), 169 (range, days 56-236), and 163 (range, days 77-245), respectively (Table 2).CMV disease occurred in 26 (17.8%) patients (pneumonia [n = 10], pneumonia with gastrointestinal disease [n = 2], gastrointestinal disease [n = 10], sinus disease [n = 3], graft failure [n = 1]) at a median of 169 days after transplantation (range, 96 to 784 days). All first cases were diagnosed after death. Seventy-three percent of first cases of late disease occurred within the first year of transplantation, 92% within 18 months, and 96% within 2 years. The first case of CMV disease was fatal in 8 (31%) of 26 patients. Seven [39%] of 18 of those who survived the initial episode had a second episode of late CMV disease a median of 79 days (range, 54-703 days) after the first episode (pneumonia [n = 3], gastrointestinal disease [n = 3], sinus disease [n = 1]). In 5 (33%) of 15 episodes of CMV pneumonia, significant pulmonary copathogens were present (Aspergillus fumigatus [n = 2], respiratory syncytial virus [n = 2], Nocardia asteroides [n = 1]); 2 additional patients had concomitant disseminated candidiasis or gram-negative sepsis, respectively, without isolation of these pathogens from lung tissue or BAL. Forty-six percent of patients with CMV disease died within 6 weeks of diagnosis, or CMV was detected in them at autopsy. More patients died of pneumonia than of other manifestations of late CMV disease (9 [60%] of 15 pneumonia episodes vs 4 [22%] of 18 other episodes, respectively). CMV pneumonia with pulmonary copathogens or concomitant severe disseminated infections was fatal in 6 (86%) of 7 patients compared with 3 (38%) of 8 in patients without copathogens. Of the 146 patients followed up in this cohort, 13 (8.9%) died with CMV disease. Immune reconstitution The proportion of patients with postengraftment lymphopenia and with CD4 and CD8 T-cell counts lower than 50 cells/mm3 between days 80 and 100 are shown in Table 1. By day 150, increases to more than 50 cells/mm3 occurred in 39% (CD4) and 36% (CD8) of patients who had low counts at baseline, resulting in 26% and 19% of patients, respectively, with counts lower than 50 cells/mm3. During the surveillance period (starting at 95 days after transplantation), absolute lymphocyte counts lower than 100 lymphocytes/mm3 and lower than 300 lymphocytes/mm3 were detected in 16% and 39% of patients, respectively.CMV-specific CD4+ TH responses were absent in 62% of 137 patients between days 80 and 100. Fifty-four percent of patients with detectable CD4+ T-helper responses at day 100 lost these responses by day 150 in association with corticosteroid use, whereas 12.5% of patients with negative responses at day 100 had positive responses by day 150. Overall, by day 150, 26 (35%) of 75 patients with follow-up test results had detectable CD4+ T-helper responses. CMV-specific CD8+ CTL responses were measured in a subset of patients. Twenty (67%) of 33 patients did not have CD8+ CTL responses at day 100. Four (40%) of 10 patients with detectable CD8+ CTL responses at day 100 lost these responses by day 150 in association with increased immunosuppression. Failure of a CMV-specific CD4+ TH response to develop was highly associated with a nondetectable CD8+ CTL response (23 of 24 tests). There was only one weak-positive CD8+ CTL response (17% specific lysis) at day 150 in the absence of a positive CD4+ TH response. This occurred in a patient who had positive CD4+ TH and CD8+ CTL responses at day 100 and was subsequently treated with steroids. Positive CD4+ TH responses were associated with positive CD8+ CTL responses in 10 (37%) of 27 patients. Because of the close association between negative CD4+ TH and CD8+ CTL responses in this and earlier studies,13,19 for subsequent analyses, the absence of CMV-specific CD4+ TH responses was used to assess the impact of CMV-specific T-cell responses. Risk factors for late CMV disease Baseline patient characteristics, quantitative CMV antigenemia before day 95, and CMV-specific immune reconstitution parameters between days 80 and 100 were analyzed first by Cox regression models and by cumulative incidence curves. Factors significant for the development of late CMV disease in univariate analysis were presence of antigenemia during the first 3 months, absolute lymphopenia after engraftment, low CD4 and CD8 counts, and acute grades 2-4 or chronic clinical-extensive GVHD. GVHD was significant in the time-to-event analysis but only suggestive in the regression models (Table 3, Figure 1). In a multivariable model for late CMV disease using parameters that were known between days 80 and 100, antigenemia remained significant, yet the absence of CMV-specific T-cell responses, low CD4 counts, and GVHD were no longer statistically significant (Table 3). When lymphopenia was removed from the multivariable model (to account for the interrelationship of lymphocyte counts and CD4 subsets), low CD4 counts, GVHD, and antigenemia before day 80 remained significant for late CMV disease (data not shown). A model that included all patients with CMV disease, except 2 with isolated CMV sinusitis, confirmed the significance of CMV antigenemia before day 95 in univariate and multivariable models. In addition, CD4 counts remained significant in the multivariable model (relative risk [RR], 2.4; 95% confidence interval [CI], 1.0-5.9).
The significance of continued surveillance after the first analysis 3 months after transplantation was then evaluated in multivariable models, including virologic parameters and lymphopenia, as a time-varying parameter while controlling for additional factors. The first model evaluated absolute lymphopenia and showed a strong association of lymphopenia with late CMV disease (Table 4). Then virologic surveillance parameters were analyzed in separate univariate and multivariable models (Table 5). This analysis showed a strong association between detection of CMV antigenemia and CMV DNA with CMV disease. This association persisted for antigenemia and plasma DNA detection after controlling for lymphopenia and CD4 T-cell counts (Table 5). Only late disease events up to 1 month after the last test were considered in these analyses. An analysis that excluded the 2 patients with isolated CMV sinusitis yielded results similar to those shown in Table 5 (data not shown). In an additional analysis, the last test value was kept until the end
of follow-up. In this analysis, viral monitoring parameters (antigenemia and CMV DNA in PBLs) were significantly associated with
disease in univariate analysis but not in multivariable models (data
not shown). Thus, antigenemia and CMV DNA load were significant predictors for late CMV disease only until approximately 1 month after
the monitoring; the last test value was not predictive for long-term
prediction of CMV disease. The cumulative incidence of late CMV disease
in patients with and without CMV detection is shown in Figure
2.
Risk factors for death The first analysis included factors known at day 95 after transplantation. This analysis identified postengraftment lymphopenia, pp65 antigenemia before day 95, low CD4 and CD8 counts, and lack of CMV-specific T-cell responses in univariate analysis (Table 5). In a multivariable model that included these factors, GVHD, and other transplantation-related factors, only lack of CMV-specific T-helper responses remained significant. The impact on mortality of CMV-specific T-cell immunodeficiency at 3 months is shown in Figure 3.
The significance of surveillance parameters and late transplantation
events
This study demonstrates that late CMV disease is frequent in seropositive allograft recipients who receive ganciclovir before day 100, has a high relapse rate, is associated with poor outcome, and can be predicted by immunologic and viral factors. Reactivation of CMV during the first 3 months and lack of CMV-specific immunity appear to be the underlying pathophysiologic processes in this late reactivation. The incidence rate of 17.8% may be an underestimation of the true incidence because we only considered biopsy- or BAL-proven cases. CMV pneumonia is the leading manifestation of late disease, followed by gastrointestinal disease. The fatality rate for late CMV disease is similar to that for the first 100 days after transplantation. Relapses occurred in 39% of patients who survived the first episode of late CMV disease after a median of 79 days. Thus, patients with late disease should receive extended maintenance treatment of at least 3 months and perhaps longer with continued immunosuppression. Alternatively, close virologic monitoring should be continued after standard courses of antiviral treatment. An important question was whether late CMV disease and overall outcomes
can be assessed 3 months after transplantation, when most published
anti-CMV strategies end and patients are often sent back to their
referring physicians.32 CMV antigenemia during the first 3 months was the strongest risk factor in multivariable models; however,
delayed lymphocyte engraftment, low CD4 counts, and GVHD also seemed to
be important. Whether GVHD itself or its treatment is responsible for
the observed risk cannot be determined from these data. The association
of CMV-specific immunodeficiency at 3 months with late CMV infection
and disease was modest after controlling for other factors, and the
reason may be twofold. First, only 37% of patients with detectable
CD4+ Th responses had positive CD8+ CTL
responses Perhaps the most unexpected result of this study is the strong association of late death with virologic factors, independent of GVHD, CMV-specific T-cell function, lymphopenia, and CMV disease. Although an association of high CMV viral load and death has been reported in patients who undergo HSCT or who have HIV infection,21,22,36 these studies did not control for CMV-specific T-cell function. Mechanistically, the association between high viral load and death may not only result from direct effects of CMV, such as fatal pneumonia, but also from immunomodulatory effects of CMV that may result in an increased susceptibility to late bacterial and fungal infection. This phenomenon has recently been described in CMV-seronegative recipients of seropositive stem cell transplants.37 Numbers in our study were too small to draw a definitive conclusion regarding this effect. In conclusion, late CMV disease is an important and potentially fatal complication in recipients of seropositive allografts. Depending on the patient risk profile at any individual cancer center, the incidence of late disease may be as high as 18% of patients who are alive at 3 months after transplantation. Although CMV load and CMV-specific T-cell immunity determine the risk for late CMV disease and outcome, clinical parameters present 3 months, such as prior CMV reactivation, GVHD, or low CD4 counts, are surprisingly useful in predicting a patient's long-term risk for CMV infection and disease and could define a target population for late prevention strategies.38 Although these results were obtained in recipients after myeloablative transplantation, initial results from recipients of nonmyeloablative transplants suggest that late complications of CMV are also common and that CMV reactivation during the first 3 months is a significant risk factor for late disease.39 This study shows that continued surveillance for CMV load or antigenemia or low lymphocyte counts is useful in assessing patient risk for late CMV disease and death in the long-term follow-up period. Options for the prevention of late CMV disease include extended antiviral prophylaxis or continuation of preemptive therapy based on quantitative antigenemia or CMV DNA testing.40 Because CMV disease may still develop in a substantial number of patients who have negative antigenemia findings or undetectable DNA (Figure 2), a preemptive strategy may not be effective without a weekly monitoring schedule. However, increased monitoring raises issues of cost, feasibility, and adherence, especially when patients live in remote areas. The fact that CMV viral load was independently associated with death extends results from HIV-infected subjects to the transplant population and suggests that indirect effects of CMV may be responsible for the observed effect. These data also support long-term suppressive prophylaxis given to all patients at risk rather than preemptive therapy based on virologic markers, and they provide the intriguing possibility that the prevention of CMV infection might reduce the long-term mortality rate more than expected. Nevertheless, issues of toxicity (with valganciclovir), efficacy (with valacyclovir), drug resistance, and further delay of CMV-specific immune-reconstitution remain. A randomized trial is ongoing to compare these strategies. Immunologic strategies such as adoptive transfer of donor-derived, CMV-specific T-cell clones may be available in the near future.41,42
We thank Kristen White and Patricia Woogerd for performing immunologic assays and antigenemia testing, Carol Bevan and Laurence Stensland for PCR testing, Chris Davis and Gary Schoch for data services, and the primary physicians and nurses involved in the study for their cooperation. Biotest Diagnostic Corporation (Denville, NJ) provided the monoclonal antibodies for antigenemia testing.
Submitted April 1, 2002; accepted July 23, 2002.
Prepublished online as Blood First Edition Paper, September 12, 2002; DOI 10.1182/blood-2002-03-0993.
Supported by grants CA 18029 and CA 15704 from the National Institutes of Health and grant 94-52 from the Milheim Foundation for Cancer Research (Denver, CO).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Michael Boeckh, Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109; e-mail: mboeckh{at}fhcrc.org.
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© 2003 by The American Society of Hematology.
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E.-J. Wils, E. Braakman, G. M. G. M. Verjans, E. J. C. Rombouts, A. E. C. Broers, H. G. M. Niesters, G. Wagemaker, F. J. T. Staal, B. Lowenberg, H. Spits, et al. Flt3 Ligand Expands Lymphoid Progenitors Prior to Recovery of Thymopoiesis and Accelerates T Cell Reconstitution after Bone Marrow Transplantation J. Immunol., March 15, 2007; 178(6): 3551 - 3557. [Abstract] [Full Text] [PDF]
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R. G. Meyer, C. M. Britten, D. Wehler, K. Bender, G. Hess, A. Konur, U. F. Hartwig, T. C. Wehler, A. J. Ullmann, C. Gentilini, et al. Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell-depleted reduced-intensity transplantation Blood, January 1, 2007; 109(1): 374 - 382. [Abstract] [Full Text] [PDF]
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M. S. Albano, P. Taylor, R. F. Pass, A. Scaradavou, R. Ciubotariu, C. Carrier, L. Dobrila, P. Rubinstein, and C. E. Stevens Umbilical cord blood transplantation and cytomegalovirus: posttransplantation infection and donor screening Blood, December 15, 2006; 108(13): 4275 - 4282. [Abstract] [Full Text] [PDF]
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D. Lilleri, G. Gerna, C. Fornara, L. Lozza, R. Maccario, and F. Locatelli Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants Blood, August 15, 2006; 108(4): 1406 - 1412. [Abstract] [Full Text] [PDF]
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J. D. Roback Vaccine-Enhanced Donor Lymphocyte Infusion (veDLI) Hematology, January 1, 2006; 2006(1): 486 - 491. [Abstract] [Full Text] [PDF]
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K. Perruccio, A. Tosti, E. Burchielli, F. Topini, L. Ruggeri, A. Carotti, M. Capanni, E. Urbani, A. Mancusi, F. Aversa, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation Blood, December 15, 2005; 106(13): 4397 - 4406. [Abstract] [Full Text] [PDF]
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R. Seggewiss, K. Lore, E. Greiner, M. K. Magnusson, D. A. Price, D. C. Douek, C. E. Dunbar, and A. Wiestner Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner Blood, March 15, 2005; 105(6): 2473 - 2479. [Abstract] [Full Text] [PDF]
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C. Gilbert and G. Boivin Human Cytomegalovirus Resistance to Antiviral Drugs Antimicrob. Agents Chemother., March 1, 2005; 49(3): 873 - 883. [Full Text] [PDF]
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T. J. Manley, L. Luy, T. Jones, M. Boeckh, H. Mutimer, and S. R. Riddell Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection Blood, August 15, 2004; 104(4): 1075 - 1082. [Abstract] [Full Text] [PDF]
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Z. Wang, C. La Rosa, S. Mekhoubad, S. F. Lacey, M. C. Villacres, S. Markel, J. Longmate, J. D. I. Ellenhorn, R. F. Siliciano, C. Buck, et al. Attenuated poxviruses generate clinically relevant frequencies of CMV-specific T cells Blood, August 1, 2004; 104(3): 847 - 856. [Abstract] [Full Text] [PDF]
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B. Senechal, A. M. Boruchov, J. L. Reagan, D. N. J. Hart, and J. W. Young Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83 Blood, June 1, 2004; 103(11): 4207 - 4215. [Abstract] [Full Text] [PDF]
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E. Kondo, Y. Akatsuka, K. Kuzushima, K. Tsujimura, S. Asakura, K. Tajima, Y. Kagami, Y. Kodera, M. Tanimoto, Y. Morishima, et al. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles Blood, January 15, 2004; 103(2): 630 - 638. [Abstract] [Full Text] [PDF]
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M. Hakki, S. R. Riddell, J. Storek, R. A. Carter, T. Stevens-Ayers, P. Sudour, K. White, L. Corey, and M. Boeckh Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation Blood, October 15, 2003; 102(8): 3060 - 3067. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-globin and as copies per
milliliter plasma.
CMV disease, GVHD, late aspergillosis