Clinical characteristics of human herpesvirus 7 (HHV-7) reactivation following umbilical cord blood transplantation: A retrospective study

Abstract

Abstract Background: After allogeneic hematopoietic stem cell transplantation (allo-HSCT), immune reconstitution occurs through donor-derived lymphocytes. However, the use of immunosuppressive agents for graft-versus-host disease (GVHD) prophylaxis and treatment during this period leads to profound cellular and humoral immunodeficiency. Reactivation of herpesviruses such as human herpesvirus 6 (HHV-6), cytomegalovirus (CMV), and Epstein–Barr virus (EBV) is well documented in this setting. Although human herpesvirus 7 (HHV-7) reactivation has been sporadically reported after allo-HSCT, comprehensive studies are lacking, and its clinical relevance remains unclear. Objective: To elucidate the clinical characteristics of HHV-7 reactivation following umbilical cord blood transplantation (CBT). Methods: We retrospectively analyzed patients who underwent CBT at Toranomon Hospital between 2010 and 2024. Viral DNA detection was performed using a multiplex polymerase chain reaction (PCR) assay targeting herpes simplex virus type 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), EBV, CMV, HHV-6, HHV-7, HHV-8, adenovirus (ADV), BK virus (BKV), JC virus (JCV), and parvovirus B19. Samples included blood, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL), ascites, pleural effusion, and lymph node aspirates. A threshold of 1×10³ copies/mL was used to define clinically significant viral DNA levels. Multiplex PCR testing was performed at the discretion of the treating physician. Most patients received foscarnet (FOS) from day 7 to day 50 against HHV-6 reactivation. Results: A total of 1,625 CBT was performed during the study period. Among them, 1,325 patients (81.5%) underwent at least one multiplex PCR test, with a median of 4 tests per patient (range, 1–43), totaling 6,744 samples (blood n=5,328; CSF n=1,069; BAL n=140; ascites n=114; pleural effusion n=91; lymph node n=2). HHV-7 DNA was detected in 33 of 1,325 patients (2.5%) who underwent post-transplant viral surveillance. By specimen type, positivity was observed in blood (n=19, 1.5%), BAL (n=10, 8.0%), CSF (n=3, 0.6%), and lymph node (n=1, 50%), but not in ascitic or pleural fluid. To assess the timing of HHV-7 reactivation, the post-transplant period was divided into three intervals: days 0–30, 31–100, and >100. In blood samples, HHV-7 was not detected within the first 30 days but was found in 0.3% of patients during days 31–100 and in 2.7% after day 100. In BAL samples, detection rates were 0% in the first 30 days, 8.5% between days 31–100, and 8.6% after day 100. All CSF-positive cases (1.4%) occurred after day 100. The single lymph node–positive case was identified on day 158. HHV-7 was detected during ganciclovir (GCV) or valganciclovir (VGCV) treatment in 9 blood samples (47.4%) and 3 BAL samples (30.0%). Notably, reactivation under FOS treatment was exceedingly rare, with only one case identified—a BAL sample. Detection of HHV-7 alone was uncommon, and most cases involved co-detection with other viruses. In blood and BAL samples, EBV, CMV, and HHV-6 were frequently identified alongside HHV-7, each co-detected in approximately 30% of positive cases. Among patients with HHV-7 reactivation, 22 (66.7%) were receiving corticosteroid therapy at the time of detection, and these patients tended to show a higher number of co-detected viruses compared to those not receiving steroids. Of the 1,325 patients tested, only 8 (0.6%) had HHV-7 detected as the sole pathogen—7 in blood, 1 in BAL, and 1 in CSF. In longitudinal follow-up, HHV-7 reactivation was mostly transient and resolved spontaneously. Among the 8 patients with isolated HHV-7 detection, 4 exhibited clinical symptoms such as fever and rash consistent with viral infection and were thus considered to have HHV-7 disease. Discussion: Umbilical cord blood contains a high proportion of naïve lymphocytes, and CBT is associated with a higher incidence of infectious complications compared to other stem cell sources. While reactivation of DNA viruses is common in this setting, HHV-7 reactivation was infrequent in our cohort relative to other herpesviruses and was typically observed after cessation of FOS. HHV-7 reactivation appeared transient under immunosuppressed conditions and resolved spontaneously in most cases. Progression to clinically apparent HHV-7 disease occurred in 12.1% of HHV-7–positive patients, but no cases were considered directly attributable to HHV-7–related mortality.