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

Abstract

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.

Human herpesvirus type 6 reactivation after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide and antithymocyte globulin: risk factors and clinical impact

“…Two previous studies have reported a protective effect of higher lymphocyte counts (CD3+ lymphocytes ≥ 200/µL) against HHV6 reactivation. 35,39 Consistent with these results, our analysis revealed that patients with a low ALC on day +30 (\< 290/µL) had a higher incidence of HHV6 reactivation. This finding may serve as a valuable tool to help clinicians identify patients at higher risk of HHV6 reactivation, for whom a closer monitoring of HHV6 by PCR might be considered.…”

“…Regarding clinically significant HHV6 infections, our study demonstrates a low incidence (7%), whereas one study on HAPLO HCT with PT-Cy reported a rate of 16%, 18 and another analysis of PT-Cy with non-HAPLO donors reported a rate of 24%. 35 Taken together, our findings suggest the combination of ATG and PT-Cy does not present a higher risk of HHV6 reactivation or clinically significant HHV6 infections compared to PT-Cy without ATG in the HAPLO HCT setting.…”

Human Herpes Virus-6 (HHV-6) Reactivation after Hematopoietic Cell Transplant and Chimeric Antigen Receptor (CAR)- T Cell Therapy: A Shifting Landscape

“…Fortunately, HHV-6B encephalitis is still relatively rare, occurring in 1–3% of HCT recipients, though its incidence may be higher in specific groups (e.g., cord blood and T cell depleted transplants) [ 4 , 6 , 15 ]. Risk factors for reactivation and disease include umbilical cord blood transplant, T cell depleted allografts, human leukocyte antigen-mismatched or unrelated donors, acute GVHD and treatment with glucocorticoids [ 4 , 6 , 13 , 15 , 20 ].…”

“…PTCy for GVHD prophylaxis is more widely used in the setting of increasingly performed haploidentical and unrelated donor transplants [ 23 ]. PTCy is associated with increased risk for infections post-HCT in several studies [ 20 , 24 , 25 , 26 , 27 ]. A study of 2765 HCT recipients by the Center for International Blood and Marrow Transplantation Research showed an association between PTCy use and increased risk for non-CMV herpesvirus infection, primarily driven by HHV-6B, which was in turn associated with increased non-relapse mortality [ 24 ].…”

“…A study of 2765 HCT recipients by the Center for International Blood and Marrow Transplantation Research showed an association between PTCy use and increased risk for non-CMV herpesvirus infection, primarily driven by HHV-6B, which was in turn associated with increased non-relapse mortality [ 24 ]. In another prospective study with weekly HHV-6 testing among 208 adult allogeneic HCT recipients, PTCy use was an independent risk factor for HHV-6 reactivation [ 20 ].…”