Abstract
This prospective multicenter study aimed to determine the effects of human herpesvirus-6B (HHV-6B) reactivation on central nervous system (CNS) function in cord blood transplant (CBT) recipients. Our focus was to track HHV-6B reactivation and evaluate its association with delirium and cognitive function, specifically in the domains of verbal memory, attention/processing speed, and quality of life (QOL). A cohort of 38 patients participated in this study. Of the 37 patients evaluated, seven (18.9%) developed delirium, with six of these cases emerging after HHV-6B reactivation (median lag, 7 days). Evaluation of verbal memory showed that the final trial score for unrelated words at 70 days after transplantation was significantly lower than that before preconditioning (P = 0.004) among patients (n = 15) who experienced higher-level HHV-6B reactivation (median or higher maximum plasma HHV-6 DNA load for participating patients). Patients without higher-level reactivation did not show significant declines in verbal memory scores. QOL was assessed using the 36-item Short-Form Health Survey, and the social functioning score 1 year post-transplantation was significantly lower in patients who experienced higher-level HHV-6B reactivation than in those who did not. Our findings suggest that higher-level HHV-6B reactivation can detrimentally affect certain cognitive functions in CBT recipients.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Human herpesvirus (HHV)-6B, belonging to the Betaherpesvirinae subfamily, establishes latent infections in the majority of the general population. HHV-6B reactivation after allogeneic hematopoietic stem cell transplantation has been documented in approximately half of bone marrow or peripheral blood stem cell transplant recipients and in 90% of cord blood transplant (CBT) recipients [1, 2]. HHV-6B reactivation is associated with the development of HHV-6B encephalitis, a serious neurological complication post-transplantation. The incidence rates of HHV-6B encephalitis range from 0.5 to 1.2% in bone marrow or peripheral blood stem cell transplant recipients and 8–10% in CBT recipients [2]. Interestingly, despite the prevalent reactivation of HHV-6B, only a fraction of patients are diagnosed with HHV-6B encephalitis. Although most HHV-6B reactivations are deemed asymptomatic, it is conceivable that a robust HHV-6B reactivation may adversely affect the central nervous system (CNS) in a larger patient cohort than that currently diagnosed.
A single-center study by Zerr et al. showed a correlation between HHV-6B reactivation and the onset of delirium and neurocognitive deficits, notably in attention, processing speed, and concentration [ Kinetics of HHV-6 DNA copy number (upper row) and change of Delirium Rating Scale (DRS)-R scores (bottom row) for seven patients who developed delirium. In the upper row, the dashed line indicates the threshold for HHV-6 DNA detection. The arrow and denoted day indicate the first day of confirmed plasma HHV-6 DNA positivity. In the bottom row, the black and red lines show the DRS-R total and severity scores, respectively. The arrow and denoted day indicate the first day delirium was diagnosed
Among the five patients diagnosed with HHV-6B encephalitis by their attending physicians, two (KSRC-01 and YGTU-01) were also assessed to have developed delirium concurrent with the onset of HHV-6B encephalitis. In contrast, the remaining three patients did not exhibit signs of delirium (Supplementary Figure 1). In these three patients, HHV-6B encephalitis was diagnosed when subtle CNS symptoms became evident, prompting timely antiviral interventions.
Memory function
Of the initial cohort of 38 participants, 24 underwent S-PA assessments at two points: prior to preconditioning and at 70 days post-transplantation. The other 14 patients missed S-PA evaluations for various reasons: clinical deterioration or death (n = 6), unavailability of a clinical psychologist (n = 3), patient refusal (n = 2), administrative oversights (n = 2), or unspecified reasons (n = 1). Two patients who developed delirium and three patients who were diagnosed with HHV-6B encephalitis underwent S-PA testing.
Table 2 shows the S-PA scores in the final trial score for unrelated words obtained before preconditioning and 70 days after transplantation. A significant decline in scores was observed in patients with female gender, early disease status, MAC preconditioning, TBI < 8 Gy, and higher-level HHV-6B reactivation but not in patients with male gender, non-early disease status, RIC preconditioning, with TBI ≥ 8 Gy, and no higher-level HHV-6B reactivation. The changes in the final trial scores for unrelated words in patients who experienced higher-level HHV-6B reactivation and those who did not are illustrated in Fig. 3. Regarding the patient background in this subset, age, sex, disease status, and preconditioning regimen showed no significant differences between patients who experienced higher-level reactivation and those who did not. However, the incidence rate of acute GVHD was significantly higher in patients with higher-level HHV-6 reactivation than in those without higher-level HHV-6B reactivation (Table 3). A similar trend was observed in the analysis that excluded three patients diagnosed with HHV-6B encephalitis (Supplementary Table 2).
The changes in the final trial scores on the Standard Verbal Paired Associated Learning (S-PA) test for unrelated words before preconditioning and at 70 days after transplantation. Higher-level reactivation was defined as reactivation of HHV-6 DNA ≥ 16,134 copies/mL (the median value of the maximum plasma HHV-6 load in participating patients). aPaired t-test
As the mean score for unrelated words in all patients decreased from 4.9 to 3.4 (indicating a 1.5-point decrease), we further determined the factors associated with score reductions of ≥ 2 points (Table 4). The univariate analysis showed that only higher-level HHV-6B reactivation was significantly associated with a score drop of ≥ 2 points.
Attention and processing speed
Of the 38 participants, 22 underwent the WAIS-III Symbol Search Subtest at two points: prior to preconditioning and at 70 days post-transplantation. The remaining 16 participants did not complete the subtest for various reasons: clinical deterioration or death (n = 6), unavailability of a clinical psychologist (n = 3), patient refusal (n = 2), administrative oversight (n = 2), visual impairment preventing test completion (n = 1), or unspecified reasons (n = 2). One patient who developed delirium and two who were diagnosed with HHV-6B encephalitis underwent testing.
The Symbol Search Subtest scores did not significantly change from before preconditioning to 70 days after transplantation, and no variables, including disease status, preconditioning, TBI, acute GVHD, and peak HHV-6 DNA, were associated with changes in the scores (Supplementary Table 3).
QOL
Of the 38 participants, 19 completed the SF-36 version 2 at 70 days and 1 year post-transplantation. The remaining 19 participants were unable to complete the SF-36 for various reasons, including death (n = 11), clinical deterioration (n = 1), administrative oversight (n = 4), transfer to another hospital (n = 1), patient refusal (n = 1), and unspecified reasons (n = 1). Three patients who were diagnosed with HHV-6B encephalitis underwent SF-36 testing.
Table 5 presents the SF-36 scores. One year post-transplantation, the role/social component summary was significantly lower in patients aged ≥ 55 years and those who experienced higher-level HHV-6B reactivation than in younger patients and those who did not experience higher-level HHV-6B reactivation. Patients who had not experienced higher-level HHV-6B reactivation (n = 7) showed a significant improvement in this score between 70 days and 1 year after transplantation (mean score, 29.5 and 46.5, respectively; P = 0.031; paired t-test). Conversely, no improvement was observed in patients who experienced higher-level HHV-6B reactivation (n = 12) (mean scores, 33.8 and 32.5, respectively; P = 0.68; paired t-test).
Additionally, 19 patients completed the FACT-BMT testing at both the 70-day and 1-year post-transplantation. No variables were associated with the FACT-BMT trial outcome score, FACT-G total score, or FACT-BMT total score (Supplementary Table 4).
Discussion
The kinetics of HHV-6B reactivation after allogeneic stem cell transplantation is unique. Typically, patients experience short-term reactivation near neutrophil engraftment [5]. Occasionally, a rapid increase in plasma HHV-6 DNA levels can be detected. Such spikes in HHV-6B often precede the onset of HHV-6B encephalitis [2, 5], suggesting that higher-level HHV-6B reactivation can inflict damage to the CNS within a short span. We hypothesized that even in patients who were not diagnosed with HHV-6B encephalitis, significant HHV-6B reactivation might exert some effects on CNS functioning.
Delirium episodes were identified in seven patients through mental status monitoring. In six of these patients, delirium manifested for roughly 1 week (ranging between 3 and 11 days) after the detection of HHV-6 DNA in plasma. Zerr et al. have reported a temporal association between delirium episodes and HHV-6B reactivation during allogeneic stem cell transplantation [3], and Hill et al. have reported a quantitative association between HHV-6 reactivation and delirium in CBT recipients [20]. Our findings are consistent with these observations. Although the causal relationship between HHV-6B reactivation and delirium has not been well established currently [21], HHV-6B-associated delirium may be more common than previously recognized.
In the third trial of the recall of unrelated words, patients who experienced a higher-level HHV-6B reactivation showed a significantly lower score on day 70 after transplantation compared with their score before preconditioning. In contrast, those who did not experience higher-level HHV-6B reactivation showed no significant decline in their scores. Univariate analysis further showed a significant association between higher-level HHV-6B reactivation and a decline of ≥ 2 points in the unrelated word recall score. These results suggest that higher-level HHV-6B reactivation can influence verbal memory in CBT recipients. A significant reduction in S-PA scores was noted in the MAC group; however, this trend was not observed in the TBI > 8 Gy group. Given the similarity in mean score reductions between the TBI ≤ 8 Gy and > 8 Gy groups, the lack of a significant decline in the TBI > 8 Gy group may be attributed to its smaller sample size.
No significant decrease was observed when comparing the scores for attention/processing speed from pre-preconditioning to 70 days post-transplantation, even in patients with higher-level HHV-6B reactivation. Although declines in memory scores are occasionally associated with reductions in attention, our data indicate that the observed decrease in the verbal memory domains is not due to deficits in the attention/processing domain.
Zerr et al. found that HHV-6B reactivation was linked to deficits in attention and processing speed but not memory [3]. In contrast, our study, focusing solely on cord blood transplant recipients, indicated an association between higher-level HHV-6B reactivation (≥ 16,134 copies/mL) and memory impairment. This contrast may stem from differences in study designs and patient populations. Zerr et al.’s median HHV-6 DNA level was lower (873 copies/mL, interquartile range 175–4580 copies/mL), suggesting fewer cases with high reactivation. Additionally, their approach involved comparing proportions of cases with declines greater than 0.75 standard deviations, a method differing from our use of paired t-tests for overall score comparison. These methodological variations could explain the different attention processing speed deficits.
Evaluation of QOL assessed using the SF-36 revealed that at 1 year post-transplantation, social functioning was significantly lower in patients who experienced higher-level HHV-6B reactivation than in other patients. Notably, although social functioning significantly improved between 70 days and 1 year after transplantation in patients who did not experience higher-level HHV-6B reactivation, no analogous improvement was observed in those who experienced higher-level HHV-6B reactivation. The underlying reason for this observation remains unclear. However, higher-level HHV-6B reactivation may compromise functions vital for fulfilling social roles, such as memory.
A significant limitation of our study was the small number of patients examined. Acquiring a large sample size proved challenging because few facilities offered neurological evaluation by specialists. Moreover, the attending physicians often deemed the examination considerably taxing for patients who experienced transplant complications. Furthermore, many patients either deteriorated or died before undergoing QOL and cognitive function assessments. Due to the limited number of patients, multivariate analysis was not possible; factors other than HHV-6B may be associated with both viral reactivation and brain damage; however, this was difficult to assess in the present study.
Although our data may not be definitive, considering the limited number of patients analyzed, our findings offer a novel perspective suggesting that HHV-6B reactivation is associated with the subsequent onset of delirium, a decline in verbal memory score, and diminished social functioning. These observations highlight the potential benefits of adopting a preventative strategy against HHV-6B reactivation to preserve cognitive function and QOL in CBT recipients. To generalize these conclusions, validating them in a larger patient cohort is crucial.
