Abstract
In allogeneic hematopoietic stem-cell transplantation (HSCT) recipients, outcome of human cytomegalovirus (HCMV) infection results from balance between viral load/replication and pathogen-specific T-cell response. Using a cut-off of 30,000 HCMV DNA copies/ml blood for pre-emptive therapy and cut-offs of 1 and 3 virus-specific CD4+ and CD8+ T cells/µl blood for T-cell protection, we conducted in 131 young patients a prospective 3-year study aimed at verifying whether achievement of such immunological cut-offs protects from HCMV disease. In the first three months after transplantation, 55/89 (62%) HCMV-seropositive patients had infection and 36/55 (65%) were treated pre-emptively, whereas only 7/42 (17%) HCMV-seronegative patients developed infection and 3/7 (43%) were treated. After 12 months, 76 HCMV-seropositive and 9 HCMV-seronegative patients (cumulative incidence: 90% and 21%, respectively) displayed protective HCMV-specific immunity. Eighty of these 85 (95%) patients showed spontaneous control of HCMV infection without additional treatment. Five patients after reaching protective T-cell levels needed pre-emptive therapy, because they developed graft-versus-host disease (GvHD). HSCT recipients reconstituting protective levels of HCMV-specific T-cells in the absence of GvHD are no longer at risk for HCMV disease, at least within 3 years after transplantation. The decision to treat HCMV infection in young HSCT recipients may be taken by combining virological and immunological findings.
Highlights
Human cytomegalovirus (HCMV) still represents the most important viral infection in allogeneic hematopoietic stem cell transplantation (HSCT) recipients [1]
Following the identification of the most sensitive diagnostic procedures for detection and quantification of HCMV in blood [2,3,4,5,6], prevention of HCMV infection/disease was achieved by adoption of either universal prophylaxis or pre-emptive therapy [7,8,9]
Development of HCMV Infection Among the 89 HCMV-seropositive patients, HCMV infection occurred in 55 patients (62%) in the course of the first 3 months after transplantation, and in 6 additional patients between 4 and 8 months after transplant (Fig. 1A)
Summary
Human cytomegalovirus (HCMV) still represents the most important viral infection in allogeneic hematopoietic stem cell transplantation (HSCT) recipients [1]. Results reported on this subject have been somewhat controversial, due to use of different methodologies for evaluating virus-specific immunity (MHC-peptide tetramer technology or intracellular cytokine staining following stimulation with peptide pools or HCMV-infected cell lysate), the conclusion of some authors was that HCMV-specific CD8+ Tcells were sufficient to provide permanent protection against HCMV reactivation [12,13]. Our recently introduced methodology for assessment of specific immunity, based on T-cell stimulation by autologous, monocyte-derived, HCMV-infected dendritic cells [16], has been shown to provide a comprehensive evaluation of both CD4+ and CD8+ T-cell response in immunocompromised hosts [17]
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