Management of human cytomegalovirus infection in transplantation: Validation of virologic cut-offs for preemptive therapy and immunological cut-offs for protection

Human cytomegalovirus (HCMV) still causes major viral complications in the post-transplant period of both solid-organ (SO) and hematopoietic stem cell (HSC) transplant (T) recipients (R). Diagnosis of HCMV infection is mostly made by real-time PCR-based methodologies, which allow quantification of viral DNA in both blood and, if required, organ tissues or local secretions. HCMV infection/disease can be prevented by either universal prophylaxis or preemptive therapy. The latter approach has mostly been used in European Transplantation Centers upon reaching predetermined cut-off levels of viral load, predictive of high risk for HCMV disease. In our Department, these cut-offs are higher for SOTR (3×l0 ⁵ DNA copies/ml whole blood) and lower for HSCTR (3×l0 ⁴ DNA copies/ml). Antiviral therapy is continued until viral DNA disappearance from blood or tissues. However, the authentic long-term control of HCMV infection is achieved when HCMV-specific CD4 ⁺ and CD8 ⁺ T-cells are detected in blood or tissues. Proposed immunological cut-off levels conferring protection are: one HCMV-specific CD4 ⁺ and three CD8 ⁺ T-cells/μl blood for HSCTR, and 0.4 HCMV-specific T-cells/μl for both CD4 ⁺ and CD8f in SOTR. However, anti-rejection in SOTR and anti-GvHD in HSCTR steroid therapies make patients susceptible to HCMV infection, even in the presence of protective levels of specific T-cells.