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Human herpesvirus 6-specific T-cell immunity in allogeneic hematopoietic stem cell transplant recipients.

Maddalena NovielloFrancesca LorentinoElisabetta XueSara RaccaGiulia FurnariVeronica ValtolinaEdoardo CampodonicoRoee DvirMaria Teresa Lupo StanghelliniFabio GiglioSimona PiemonteseDaniela ClericiChiara OltoliniElena TassiValeria BerettaFrancesca FarinaDaniele ManninaAnna ArdemagniLuca VagoBernardi MassimoConsuelo CortiJacopo PeccatoriMassimo ClementiFabio CiceriChiara BoniniRaffaella Greco
Published in: Blood advances (2023)
Human Herpesvirus-6 (HHV-6) can reactivate after allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), and may lead to severe symptoms. HHV-6-specific immune responses after HSCT are largely unexplored. We conducted a prospective observational study on 208 consecutive adult patients who received allo-HSCT, to investigate HHV-6 reactivations and specific immune responses. IFN-γ-producing HHV-6-specific T cells were quantified by ELISpot assay. "HHV-6 reactivation" occurred in 63% of patients, at a median of 25 days (range 3-538) from allo-HSCT. Only 40% of these presented a "clinically relevant infection", defined according to center guidelines by the presence of classical HHV-6 End-Organ Diseases (EOD), based on European-Conference-on-Infections-in-Leukaemia (ECIL) guidelines, and other possible HHV6-related EODs. By multivariate analysis, we identified risk factors for HHV-6 reactivation: previous allo-HSCT (Hazard Ratio, HR=2.89; p-value<0.01), post-transplant cyclophosphamide (PT-Cy; HR=2.59; p-value<0.01), time-dependent steroids introduction (HR=3.64; p-value<0.01). The use of PT-Cy (HR=3.77; p-value<0.01) and steroids (HR=2.74; p-value<0.01) were associated with clinically relevant infections, whereas higher CD3+ cell counts (HR=0.23; p-value=0.02) seemed to be protective. Interestingly, circulating HHV-6-specific T cells were significantly higher in reactivating patients. Moreover, HHV-6-specific T-cell responses, quantified at >4 days after the first viremia detection, predicted clinically relevant infections (p-value<0.0001), with higher specificity (93%) and sensitivity (79%) than polyclonal CD3+ cells/μl (<100/µl; specificity=59%; sensitivity=36%). Overall survival and transplant-related mortality were not affected by time-dependent HHV-6 reactivation, while a significant association was observed between clinically relevant infections and acute graft-versus-host disease. These results shed light on the role of HHV-6 in allo-HSCT and may impact on HHV-6 monitoring and treatment.
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