Assessment of the Impact of Human Herpesvirus 6 (HHV-6) Replication On Active Citomegalovirus (CMV) Infection After Allogeneic Stem Cell Transplantation (Allo-SCT).

In spite of significant advances in the diagnosis and treatment of CMV infection post-allogeneic SCT it continues to be associated with significant morbidity and mortality. The human herpesvirus 6 (HHV-6) reactivation has been associated with different complications, including delayed neutrophil and platelet engraftment, interstitial pneumonia, skin rash, severe graft versus host disease (GvHD), and central nervous system disorders. HHV-6 is considered an immunomodulatory and immunosuppressive agent, and thereby, it may the increase the risk of active CMV infection and disease in the transplantation setting

To determine if the HHV-6 facilitates the CMV reactivation or influences the kinetic of CMV replication and its specific immune replication during the first 100 days after allogeneic hematopoietic SCT.

Between Nov-05 and Feb-08, sixty-eight patients were monitored for plasma HHV-6 and CMV DNAemia by PCR once/week until day +100 after Allo-SCT. Characteristics of patients: median age: 45 yo (18-70); sex (M/F): 37/31. Diagnosis: AML/MDS(n=27), ALL(n=10), lymphoproliferative syndrome(n=17), MM (n=4), CML (n=3), Others(n=7). CMV seropositive (R/D)(%): 88/60. Cell source: PBSC: 53(78%);CB:13(19%);BM:2(3%). Conditioning treatment: RIC: 40 pts, myeloablative: 28 pts. pp65 antigenemia in PMN leucocytes (Light Diagnostics, Chemicon Intern). Positive if ≥1cel+/200.000. Plasma DNA-CMV: PCR-RT Abbott or Amplicor CMV Monitor Roche. Plasma DNA-HHV6: Q-PCR Alert Amplimix, Nanogen Adv. Diag., detection limit: 10 copies/mL plasma. Enumeration of pp65 and IE-1 IFNγ CD4⁺ and CD8⁺ T cells was performed by intracellular cytokine staining. (BD Fastimmune, BD-Beckton Dickinson). Pre-emptive antiviral treatment was initiated if pp65 Ag +.

HHV-6 DNAemia occurred in 27 out of 68 pts (40%), after a median time of 20 days post-SCT with a peak value of 345 copies (26-13,661) reached on the fourth week in the 52% of patients, with a median duration of 10 days (3-35). Twenty-three out of the 27 patients were HHV-6 seropositive before transplantation. Clearance of most episodes (21 out of 27) occurred in the absence of (val)ganciclovir treatment, which was initiated in the course of the remaining 6 episodes because of the development of antigenemia-positive active CMV infection. HHV-6 DNAemia was significantly associated with subsequent CMV DNAemia in univariate (P=.01), but not in multivariate analysis (P=.056) that included transplant from URD, HLA non identical donor, myeloablative conditioning, CBT, use of prednisone as GVHD prophylaxis and plasma HHV-6 DNA detection. HHV-6 DNAemia was not predictive of development of CMV DNAemia. Timing and kinetics of active CMV infection were comparable in patients either with or without a preceding episode of HHV-6 DNAemia. Occurrence of HHV-6 DNAemia had no impact on the level of CMV-specific T-cell immunity reconstitution early after transplant. The receipt of a graft from an unrelated donor was the principal variable associated with HHV-6 and CMV coactivation.

The results of this study suggest that a basal immunosuppressive state, specially the receipt of a graft from an unrelated donor, leads to HHV-6 and CMV coactivation, and argue against an effect of active HHV-6 infection on CMV replication either by a direct interaction or indirectly by suppressing CMV-specific T-cell responses.

No relevant conflicts of interest to declare.