Atypical CD4+/CD8+ Lymphocytosis and Prolonged Pancytopenia Associated with Human Herpesvirus-6 Reactivation after Autologous Peripheral Blood Stem Cell Transplantation

Introduction Reactivation of latent human herpesvirus-6 (HHV6) is often seen after allogeneic hematopoietic cell transplantation (HCT). As HHV6 reactivation occurs in pancytopenia, it is not associated with acute alterations in peripheral leukocytes. Although prolonged pancytopenia and graft failure have been associated with HHV6 after allogeneic HCT, they have not been reported after autologous HCT. We describe atypical lymphocytosis with CD4+/CD8+ cells followed by prolonged bone marrow hypoplasia in a patient who developed HHV6 reactivation after autologous peripheral blood stem cell transplantation (PBSCT) for multiple myeloma (MM). Case Report A 63-year-old man with IgA kappa MM in first complete response (CR) underwent autologous PBSCT after a preparative regimen of melphalan (200 mg/m 2 i.v.); CD34+ cell dose was 10.94 × 10 6 /kg. Pre-transplant evaluation included positive IgG antibodies against HSV and HHV6 (titer 1:320), negative titers against CMV, VZV and HIV. He received prophylactic acyclovir and fluconazole. On day +1, he developed neutropenic fever, resolving with empiric antibiotics. On day +7, he was pancytopenic with recurrent fever and diffuse erythematous macular and papular rash. Blood and urine cultures were negative. On day +11, total white blood cell count abruptly increased to 11.2 × 10 9 /L, with approximately 60% atypical lymphocytes; the absolute neutrophil count (ANC) was zero. By day +14, fever and rash had resolved; the atypical lymphocytosis was then followed by prolonged pancytopenia (Figure 1). On day +34, persistent pancytopenia and concerns for graft failure led to a second autologous PBSC infusion. The patient was discharged on day +54. Results Flow cytometry of peripheral blood on day +11 showed atypical lymphocytes positive for CD4 and CD8 (Figure 2). Quantitative PCR was positive for HHV6 with 250 copies/mL and negative for CMV and EBV. Bone marrow aspirate and biopsy on day +31 showed marked erythroid hyperplasia (M:E ratio 0.18) and a small population (1.7%) of T-cells coexpressing CD4 and CD8. On day +38, the ANC was 0.99 × 10 6 /L. Conclusion This instructive case demonstrates that HHV6 reactivation after autologous PBSCT can be associated with atypical lymphocytosis of characteristic CD4+/CD8+ cells and subsequent prolonged pancytopenia. HHV6 is known to induce expression of CD4 in CD8+ lymphocytes, and that viral reactivation likely led to the observed CD4+/CD8+ lymphocytosis, an immunophenotype otherwise confined to intrathymic lymphocytes during T-cell maturation. As autologous HCT remains a component of MM comprehensive therapy, transplant infectious diseases specialists and HCT physicians are encouraged to have a low index of suspicion for HHV6 reactivation when assessing MM patients who develop persistent fevers, rashes, atypical lymphocytosis or prolonged marrow hypoplasia after autologous HCT.