High Incidence of Early Human Herpesvirus-6 Infection in Children Undergoing Haploidentical Manipulated Stem Cell Transplantation for Hematologic Malignancies

Abstract

Human herpesvirus-6 (HHV-6) infection is increasingly recognized among allogeneic hematopoietic stem cell transplantation (HSCT) recipients, with 30% at risk of reactivation in the haploidentical setting. It has been associated with encephalitis, acute graft-versus-host disease, and graft failure. Here we report 2 cohorts of pediatric haploidentical manipulated HSCT in which, despite many differences, HHV-6 reactivation and disease occurred with very high incidence compared with data reported in the literature and represented the main early post-transplant infectious complication compared with other viral, bacterial, or fungal infections. The 2 cohorts were recruited at the pediatric transplant centers of Perugia (n = 13), Barcelona (n = 10), and Madrid (n = 15). All patients received myeloablative conditioning regimens and 2 different types of ex vivo graft manipulation: CD34 selection and regulatory T cell/conventional T cell infusion in 13 patients and CD45RA T cell depletion in 25 patients. Antiviral prophylaxis was acyclovir in 33 and foscarnet in 5 patients. HHV-6 DNAemia was checked by quantitative or qualitative PCR. In vitro experiments demonstrated that donor CD4 T cells are the reservoir of HHV-6 and suggested a role of the graft composition in both transplant settings (rich in CD4 T cells) in the high rate of HHV-6 infections. All patients presented very early HHV-6 DNAemia after transplantation, and although viremic, 9 patients (24%) developed symptomatic limbic encephalitis. All patients responded to antiviral treatment, and none died of infection, although 2 experienced long-term neurologic sequelae (22%). Moreover, 6 patients presented organ involvement in absence of other causes: 1 hepatitis, 1 pneumonia, 2 gastroenteritis, and 2 multiorgan involvement(1 encephalitis, pneumonia, and gastritis; 1 pneumonia and enteritis). Incidences of other viral, bacterial, and fungal diseases were lower in both cohorts. In vitro, HHV-6 was found to infect only CD4 fraction of the graft. Co-culturing CD4 T cells with CD56 natural killer (NK) cells eliminated the virus, demonstrating the main role of NK cells in the antiviral immune response. All 38 pediatric patients undergoing these manipulated haploidentical HSCTs showed HHV-6 reactivation, and 14 of 38 developed HHV-6 disease with similar features in terms of timing, morbidity, response to treatment, and outcome. The graft composition in both transplant platforms, rich in CD4 T cells and poor in NK cells, seems to play a key role. HHV-6 DNAemia surveillance was useful to diagnose and treat preemptively HHV-6 infection.

Epidemiology of viral infections among children undergoing hematopoietic stem cell transplant: Α prospective single‐center study

“…In the multivariate analysis, the clinical risk factors significantly associated with the development of several viral infections post‐HSCT were the type of donor, recipient's age HLA compatibility and stem cell source. Our results are comparable to other studies …”

Low incidence of HHV‐6 reactivation in haploidentical hematopoietic stem cell transplantation with corticosteroid as graft‐vs‐host disease prophylaxis compared with cord blood transplantation

“…Despite the use of methylprednisolone and ATG as GVHD prophylaxis and a reduced‐intensity conditioning regimen, respectively, it remains unclear whether the lack of HHV6 reactivation in our reduced‐intensity haplo‐SCT could be interpreted by the difference in graft sources in which donors will have memory T cells against HHV‐6. Based on the two recent pediatric studies of an unexpected high incidence of HHV‐6 reactivation in CD34‐positive selection‐based T‐cell depleted manipulated haplo‐SCT, we observed the lowest incidence of HHV‐6 reactivation in our haplo‐SCT even among various haplo‐SCT including post‐transplant cyclophosphamide method. Although their CD45RA T‐cell depletion method could offer the advantage of preserving the memory T cells beneficial for controlling viral reactivations, such as CMV and HHV‐6, they observed only good control of CMV reactivation, but not HHV‐6 .…”

“…based T-cell depleted manipulated haplo-SCT,24,25 we observed the lowest incidence of HHV-6 reactivation in our haplo-SCT even among various haplo-SCT including post-transplant cyclophosphamide method. Although their CD45RA T-cell depletion method could offer the advantage of preserving the memory T cells beneficial for controlling viral reactivations, such as CMV and HHV-6, they observed only good control of CMV reactivation, but not HHV-6 24,25.…”

“…Based on the two recent pediatric studies of an unexpected high incidence of HHV‐6 reactivation in CD34‐positive selection‐based T‐cell depleted manipulated haplo‐SCT, we observed the lowest incidence of HHV‐6 reactivation in our haplo‐SCT even among various haplo‐SCT including post‐transplant cyclophosphamide method. Although their CD45RA T‐cell depletion method could offer the advantage of preserving the memory T cells beneficial for controlling viral reactivations, such as CMV and HHV‐6, they observed only good control of CMV reactivation, but not HHV‐6 . Conversely, in our unmanipulated haplo‐SCT, which uses neither in vitro T‐cell depletion nor post‐transplant cyclophosphamide, frequent CMV antigenemia developed despite the low incidence of HHV‐6 reactivation, although the underlying mechanism of this opposite incidence remains unclear.…”

Harnessing T Cells to Control Infections After Allogeneic Hematopoietic Stem Cell Transplantation

“…Most of the cell therapy experience regards treatment of CMV and EBV infections. However, patients with multiple infections have a worse outcome ( 19 ), and in the pediatric population or in recipients of haplo-HSCT, the impact of other viral infections, such as adenovirus or HHV6, has important implications for overall survival ( 8 , 87 ). Thus, the possibility to produce in a single process VSTs specific for multiple viruses is crucial for progress in the field.…”