Retrospective Analysis of 23 Cases with Human Herpesvirus-6 Associated Encephalitis after Allogeneic Hematopoietic Cell Transplantation.
Authors: Fukuda Takahiro , Fujimaki Katsumichi , Taniguchi Shuichi , Tanaka Masatsugu , Gondo Hisashi , Akiyama Hideki , Shindo Takero , Karasuno Takahiro , Yoshihara Satoshi , Ishikawa Jun , Ashida Takashi , Misawa Mahito , Ogata Masao , Choi Ilseung , Maruta Atsuo , Kawano Tomoko , Myojo Tomohiro , Masuoka Kazuhiro , Muta Tsuyoshi , Kato Koji , Henzan Hideho , Mori Takehiko , Ikeda Masayuki , Yoshikawa Tetsushi , Harada Mine 
Published: April 2020

Abstract
&lt;Background&gt; Cases of human herpesvirus-6 (HHV-6) associated central nervous system (CNS) dysfunction such as encephalitis after hamatopoietic cell transplantation (HCT) have been increasingly reported. However, clinical features, appropriate diagnostic methods, treatments and outcomes of HHV-6 encephalitis are not fully understood.
&lt;Methods&gt; A questionnaire was sent to transplant centers in Japan, and adult allogeneic HCT recipients with CNS dysfunction who had HHV-6 DNA detected by polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) were retrospectively analyzed.
&lt;Results&gt; We describe 23 cases with HHV-6 associated encephalitis. Median age was 38 (range; 18–63) years. Underlying diagnosis included acute leukemia (AML, N=8; ALL, N=6), lymphoma (N=5), and others (N=4); 12 of whom had refractory or relapsed disease before HCT. Patients received bone marrow or peripheral blood stem cell from HLA-matched (N=2) or mismatched (N=9) related donors, unrelated donors (N=7), or umbilical cord blood (N=5). Conditioning included high-dose TBI-containing myeloablative regimens (N=16) and reduced-intensity regimens (N=7). In majority of cases, GVHD prophylaxis contained tacrolimus and methotrexate. Median onset of CNS dysfunction was day 22 (range; days 12–614) after HCT; 17 of whom had CNS symptoms within 7 days of neutrophil engraftment. Symptoms included coma/impaired consciousness (N=21; 91%), amnesia/loss of short-term memory (N=17; 73%), seizure (N=16; 70%), and fever (N=14; 61%). All patients had HHV-6 DNA in the CSF identified by qualitative (N=9) or quantifiable (N=14) PCR. Median HHV-6 DNA levels in the CSF was 3.3 (range; 0.8–500) x 103 copies/ml. HHV-6 typing study revealed subtype B virus in all 8 cases examined. No other causative agents were detected. Analysis of the CSF samples revealed increased WBCs in 10 of 22 patients (45%). Brain MRI scans showed abnormal findings within the temporal lobe in 17 patients (73%). Treatment for HHV-6 encephalitis included ganciclovir (N=17), foscarnet (N=11), intraveneous immunoglobulin (N=13), acyclovir (N=4), vidarabine (N=1), and donor lymphocyte infusion (N=1), and 5 were switched from ganciclovir to foscarnet due to ineffectiveness or toxicities. Although the clinical status appeared to improve after treatment in 21 of 23 patients (91%), 10 had a sequela such as memory problem.
&lt;Summary&gt; These data suggest that HHV-6 may cause severe CNS disease after HCT, and detection of viral DNA in the CSF appeared to be useful for the rapid diagnosis and early anti-viral treatment. The presence of amnesia and abnormal findings within the temporal lobe may be a useful diagnostic indicator of HHV-6 associated encephalitis after HCT. In this analysis, majority of HHV-6 encephalitis cases were those who received cord blood transplant or grafts from unrelated or HLA-mismatched donors. Prospective studies are warranted to determine accurate diagnostic methods and appropriate treatment for HHV-6 encephalitis in high-risk patients.