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Human herpesvirus-6 encephalitis in hematopoietic SCT recipients in Japan: a retrospective multicenter study

Bone Marrow Transplantation volume 43, pages 583–585 (2009)Cite this article

Recently, increasing evidence suggests that human herpesvirus-6 (HHV-6) reactivated in the central nervous system (CNS) could play an important role in the pathogenesis of neurological symptoms. In vitro, HHV-6 may infect astrocytes, oligodendrocytes and neurons,1, 2 and in vivo, HHV-6 was also detected in such cell types in an immunocompromised host.3 The first patient with fatal encephalitis during BMT was described in 1994.4 In the course of hematological SCT, the reactivation of HHV-6 in peripheral blood occurred at a rate of 17 to 70%,5, 6, 7 whereas the reactivation in cerebrospinal fluid associated with CNS symptoms occurred in only 5 (1.5%) of 338 BMT recipients.8 To date, the clinical entity of HHV-6 encephalitis has been established in patients with CNS symptoms and HHV-6 reactivation in the cerebrospinal fluid, and over 40 hematopoietic SCT (HSCT) recipients have been reviewed.9 The purpose of this study was to clarify the clinical characteristics of HHV-6 encephalitis in Japanese HSCT recipients. We collected data from 130 transplantation centers in a retrospective study. We analyzed adult patients with HHV-6 encephalitis undergoing allo-HSCT for hematological diseases from January 1999 to December 2003. The diagnostic criteria of HHV-6 encephalitis must be fulfilled regarding both the CNS symptoms and the detection of HHV-6 in cerebrospinal fluid. Other etiologies that may cause CNS impairment should be ruled out. Data were collected using a voluntary report form. Medical doctors reported cases of patients with encephalitis occurring after SCT, if calcineurin inhibitor-induced encephalopathy could be excluded and they were not infected with other pathogens such as herpes simplex, CMV or EBV. Most importantly, PCR methods should have been performed in such patients. This study did not involve patients whose cause of encephalitis could not be specified or who died too early for an adequate diagnosis. Transplantation was performed according to the protocol of each center. Prophylaxis against GVHD involved CYA or tacrolimus combined with MTX with or without corticosteroids. We conducted a survey of HHV-6 encephalitis in 5484 allo-SCT recipients. Twenty-three patients satisfied the criteria of HHV-6 encephalitis. The patient characteristics are summarized in Table 1. Regarding the pre-transplant status of the original diseases, half of the patients were refractory to the previous chemotherapy. Four patients had earlier undergone transplantation. There were 21 out of 23 patients who underwent transplantation from an HLA-mismatched related donor, unrelated donor, and using cord blood, and only 2 out of 23 from HLA-identical sibling donors. BMT was performed in 13 out of the 23 patients, whereas 5 out of the 23 patients received PBSCs. The remaining five patients underwent transplantation using cord blood. Sixteen of the patients received TBI involving a myeloablative conditioning regimen. In the remaining seven patients, fludarabine-based non-myeloablative therapy was used. Most of the patients received tacrolimus for GVHD prophylaxis, which reflects the mismatched HLA nature of the donor sources. The clinical characteristics of HHV-6 encephalitis are summarized in Table 2. The median onset of symptoms was day 22. In 15 patients, encephalitis occurred within 7 days, around the timing of granulocyte engraftment. Four major symptoms were noted: disturbance of consciousness (91%), loss of short-term memory (74%), convulsion (70%) and fever (61%). Five patients had hypoxia and some required mechanical ventilation. Cerebrospinal fluid analysis revealed an elevated cell count (lymphocytic pleocytosis) in 10 out of 23 patients. PCR analysis of cerebrospinal fluid samples was performed using quantitative or qualitative methods.

Table 1 Patients' characteristics
Full size table
Table 2 Features of HHV-6 encephalitis
Full size table

The median amount of viral DNA was 3.3 (0.8–500) × 103 copies/ml. In the examined range, nine out of nine patients showed subtype B of HHV-6. In the 18 patients who underwent magnetic resonance imaging in the acute phase, T2-weighted images showed a strong signal in the hippocampus, temporal lobe or limbic systems. Just before the onset of encephalitis, 10 patients received acyclovir for herpes simplex virus prophylaxis, one received gancyclovir for CMV prophylaxis, and one was administered both acyclovir and foscavir for herpes simplex virus and CMV prophylaxis. Just before the onset of encephalitis, 12 patients had commenced immunosuppressive treatment with steroids against GVHD, 11 received methylprednisolone at more than 0.5 mg/kg. As for treatment, all patients received ganciclovir and/or foscavir. Two patients were treated with a combination of ganciclovir at a dose of 5 mg/kg and foscavir. Five patients were switched from ganciclovir to foscavir. As a result, two patients died early before recovery from encephalitis, whereas 21 patients recovered from encephalitis, 10 of whom showed the after-effects of short-term memory impairment. Acute GVHD occurred in seven patients, became aggravated after the onset of encephalitis in five patients, and was fatal in one patient.

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Authors and Affiliations

  1. Department of Hematology, Matsuyama Red Cross Hospital, Ehime, Japan

    T Muta

  2. Hematopoietic Stem Cell Transplantation Unit, National Cancer Center, Tokyo, Japan

    T Fukuda

  3. Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. E-mail: muta-t@matsuyama.jrc.or.jp,

    M Harada

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Muta, T., Fukuda, T. & Harada, M. Human herpesvirus-6 encephalitis in hematopoietic SCT recipients in Japan: a retrospective multicenter study. Bone Marrow Transplant 43, 583–585 (2009). https://doi.org/10.1038/bmt.2008.359

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