HHV‐6 encephalitis may complicate the early phase after allogeneic hematopoietic stem cell transplantation: Detection by qualitative multiplex PCR and subsequent quantitative real‐time PCR

Abstract

Viral reactivation following hematopoietic stem cell transplantation (HSCT) can cause various complications especially viral encephalitis. In this prospective study, we investigated the correlation of post-HSCT viral reactivation in blood with CNS dysfunction. We employed a multiplex PCR that detects 13 kinds of viruses as a first-line screening test and real-time PCR for subsequent quantitative evaluation. Five hundred ninety-one whole blood samples were collected from 105 patients from before until 42 days after HSCT. Seven patients developed CNS dysfunction such as altered consciousness. In six of the seven, the multiplex PCR test detected HHV-6 DNA in at least one sample. In contrast, DNA from other viruses, such as CMV, EBV, HHV-7, adenovirus, and HBV was never detected in any of the seven patients throughout the study period. Quantitative measurement of whole blood HHV-6 DNA levels demonstrated four of the six HHV-6 DNA loads were elevated at successive time points during the CNS dysfunction. In addition, the virus DNA peaks were temporally associated with the development of CNS dysfunction. CSF was tested in two of the four patients and high HHV-6 DNA levels comparable to those in whole blood were confirmed in both. These four patients were, thus, suspected to have developed HHV-6 encephalitis, a rate of 3.8% in the study population. Our results suggest that early diagnosis of probable HHV-6 encephalitis can be improved by confirming high HHV-6 DNA load in blood.

Long‐term prognosis of human herpesvirus 6 reactivation following allogeneic hematopoietic stem cell transplantation

“…Of these patients four were diagnosed with HHV‐6 encephalitis, because the maximum blood HHV‐6 DNA load was high (median, 30 450 copies/μg PBL DNA; range, 3,800–29 000 000), and virus load peak in blood was generally coincident with development of CNS dysfunction. The detailed clinical and virological data have been described previously . In contrast, maximum blood HHV‐6 load in the remaining subjects, who did not manifest engraftment syndrome, HPS or HHV‐6 encephalitis, varied considerably from 52 to 82 000 000 copies/μg PBL DNA (median, 11 800 copies/μg PBL).…”

“…In this study, CNS dysfunction developed in seven patients ≤6 weeks after HSCT, but in no patients during subsequent follow up. Of these, four patients were diagnosed with HHV‐6 encephalitis, including one fatal case . Schmidt‐Hieber et al .…”

“…The definition of engraftment was neutrophil count >500/μL for 3 consecutive days and platelet count >50 000/μL without transfusion for 1 week. Patients with central nervous system (CNS) dysfunction developing ≤6 after HSCT have been described in detail in a previous report …”

“…Following HSCT, several virus species may reactivate, individually or simultaneously . Human herpesvirus 6 (HHV‐6) reactivation, especially early phase reactivation, typically defined as occurring within 40–50 days of HSCT, has been shown to be significant, and approximately 60% of allogeneic HSCT recipients had HHV‐6 reactivation ≤6 weeks after HSCT, sometimes presenting with encephalitis …”

Central Nervous System Infections

“…A challenge is the interpretation of detection of organisms that may latently infect neurons or leukocytes, such as EBV or HHV-6 (167). Quantitative PCR may be helpful in this regard, as higher viral loads in CSF compared to serum might be suggestive of neuroinvasive disease (78,168).…”