Ganciclovir effectively prevents cytomegalovirus (CMV) disease in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but lateonset 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 Tlymphocyte responses, CD4 and CD8 Tcell 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/ mm 3 , postengraftment absolute lymphopenia levels lower than 100 lymphocytes/mm 3 , 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/mm 3 ) 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)

Allogeneic peripheral blood stem cell grafts contain about 10 times more T and B cells than marrow grafts. Because these cells may survive in transplant recipients for a long time, recipients of blood stem cells may be less immunocompromised than recipients of marrow. Immune reconstitution was studied in 115 patients randomly assigned to receive either allogeneic marrow or filgrastim-mobilized blood stem cell transplantation. Between day 30 and 365 after transplantation, counts of most lymphocyte subsets were higher in the blood stem cell recipients. The difference was most striking for CD4 T cells (about 4-fold higher counts for CD45RA high CD4 T cells and about 2-fold higher counts for CD45RA low/؊ CD4 T cells; P < .05). On assessment using phytohemagglutinin and herpesvirus antigen-stimulated proliferation, T cells in the 2 groups of patients appeared equally functional. Median serum IgG levels were similar in the 2 groups. The rate of definite infections after engraftment was 1.7-fold higher in marrow recipients (P ‫؍‬ .001). The rate of severe (inpatient treatment required) definite infections after engraftment was 2.4-fold higher in marrow recipients (P ‫؍‬ .002). The difference in the rates of definite infections was greatest for fungal infections, intermediate for bacterial infections, and lowest for viral infections. Death associated with a fungal or bacterial infection occurred between day 30 and day 365 after transplantation in 9 marrow recipients and no blood stem cell recipients (P ‫؍‬ .008). In conclusion, blood stem cell recipients have higher lymphocytesubset counts and this appears to result in fewer infections. (Blood. 2001;97:3380-3389)

Reconstitution of cellular immunity by 3 months after hematopoietic stem cell transplantation (HSCT) is a critical determinant of the long-term success of the transplantation. We analyzed the factors affecting recovery of cytomegalovirus (CMV)-specific CD4 ؉ and CD8 ؉ function at 3 months after HSCT by univariate and multivariable analyses including source of stem cells (bone marrow vs peripheral blood stem cells [PBSCs]), age, sex, graftversus-host disease (GVHD), steroid use, conditioning regimens, ganciclovir use, HLA matching, circulating CMV antigenemia, absolute CD4 ؉ and CD8 ؉ counts, and donor CMV serology. High-dose steroids and CD4 ؉ count less than 100 ؋ 10 9 /L were significant predictors of impaired CD4 ؉ functional recovery in the multivariable analysis. High-dose steroids, bone marrow as a source of stem cells, and CD8 ؉ count less than 50 ؋ 10 9 /L were associated with impaired CD8 ؉ function in the multivariable analysis. Steroids were found to impair both CD4 ؉ and CD8 ؉ function in a dose-dependent manner. In the absence of high-dose steroids, low-level subclinical CMV antigenemia was found to stimulate both CD4 ؉ and CD8 ؉ functional recovery in recipients of ganciclovir prophylaxis. There was no difference in immune reconstitution between those who received prophylactic ganciclovir versus antigenemia-guided pre-emptive therapy. Thus, absolute CD4 ؉ and CD8 ؉ counts less than 100 ؋ 10 9 /L and 50 ؋ 10 9 /L, respectively; bone marrow as the source of stem cells; and high-dose steroid use all predict delayed recovery of functional T-cell immunity at 3 months after transplantation. Subclinical CMV reactivation while on ganciclovir appears to be a potent stimulator of T-cell function. These findings have implications for vaccination and adoptive-immunotherapy strategies in this population.