High Incidence of Human Herpes Virus 6-Associated Encephalitis/Myelitis following a Second Unrelated Cord Blood Transplantation

Abstract

Human herpes virus (HHV)6-associated limbic encephalitis and/or myelitis is one of the life-threatening central nervous system complications following allogeneic hematopoietic stem cell transplantation (HSCT). Recent reports have shown significant correlations of these complications with unrelated cord blood transplantation (UCBT). We retrospectively analyzed 228 allogeneic HSCT recipients in our single institution; 13 patients (5.7%) were diagnosed with HHV6-associated encephalitis/myelitis. This complication was documented in 8 of 51 UCBT recipients (15.7%) and 5 of 177 recipients (2.8%) transplanted with bone marrow or peripheral blood stem cells, indicating a higher incidence of this complication occurring in UCBT recipients (P = .0005). In addition, HHV6-associated encephalitis/myelitis occurred more frequently in recipients who underwent 2 or more HSCTs (7 of 59 recipients [11.9%]), compared to those who received only 1 HSCT (6 of 169 recipients [3.6%], P = .018). Of note, the incidence of this complication increased to 28.6% (6 of 21 recipients), when the analysis was restricted to a second or more UCBT recipients. All 13 patients presented preengraftment immune response prior to the onset of encephalitis. Two patients manifested typical symptoms at the onset of HHV6-associated encephalitis/myelitis, such as memory dysfunction, disorientation, and consciousness disturbance. However, 4 patients presented only with dysesthesia and pruritus, described as typical manifestations of patients with calcineurin-inhibitor-induced pain syndrome (CIPS), and the remaining 7 showed both symptoms, indicating that CIPS-like symptoms might be manifestations of HHV6-associated myelitis. Thus, physicians should be alert to this rare but often fatal complication, particularly for those who receive 2 or more HSCTs using UCB.

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

“…However, this prevalence level is most likely an underestimate because some patients develop encephalitis/myelitis with positive imaging findings in the limbic area and high levels of DNA in the plasma, but are unable to undergo lumbar puncture for various clinical reasons, including severe thrombocytopenia or deteriorated general condition. 11 Ogata et al 47 reported that, in cases where lumbar puncture is not possible, CNS dysfunction concomitant with high-level HHV-6 DNA detected in plasma via real-time PCR may be used to diagnose HHV-6 encephalitis in the absence of CSF testing. This group also found that encephalitis was only associated with plasma DNA loads of 410 4 , although CNS dysfunction was associated with low levels of plasma HHV-6 DNA.…”

“…This group also found that encephalitis was only associated with plasma DNA loads of 410 4 , although CNS dysfunction was associated with low levels of plasma HHV-6 DNA. Mori et al 11 have diagnosed HHV-6 encephalitis when such patients meet two of the following three criteria: (1) typical clinical manifestations, (2) detection of HHV-6 DNA in the peripheral blood or (3) limbic encephalopathy based on the selective involvement of the temporal lobe on magnetic resonance imaging. It must also be recognized that high levels of HHV-6 DNA can be due to ciHHV-6, and we therefore chose not to include patients without detection of HHV-6 in the CSF in our estimation.…”

“…[48][49][50] The higher rate of HHV-6 reactivation in CBT patients, and subsequent secretion of IL-6, may create an increased risk for the development of HHV-6 encephalitis. 11 HHV-6 encephalitis is typically defined as the presence of CNS dysfunction, a positive PCR result for HHV-6 in the CSF, and the absence of other identified causes of CNS dysfunction. 51,52 Here we have summarized the prevalence data for all studies that have confirmed HHV-6 encephalitis via positive CSF PCR DNA test.…”

“…Data from this article has been included in the meta-analysis for HHV-6 reactivation, but not for HHV-6 encephalitis, as the authors did not confirm diagnosis by CSF positivity. Another article (Mori 2010) included only partial data for HHV-6 encephalitis that was confirmed by CSF positivity. This partial data has been included in the meta-analysis for HHV-6 encephalitis.…”

“…In particular, a distinct increase in HHV-6 reactivation and encephalitis following CBT (compared with HSCT with other stem cell sources) has emerged in the recent literature. 10,11 HHV-6 is the collective name for HHV-6A and HHV-6B, 12,13 two closely related beta-herpesviruses that establish primary infection in early childhood and maintain lifelong persistent infection with a combined seroprevalence of 490% in adults. [14][15][16][17] Of the two, HHV-6B is the variant implicated in nearly all documented cases of HHV-6 reactivation following HSCT, which typically occurs within 30 days of HSCT.…”