Correlations of HHV-6 viral load and plasma IL-6 concentration with HHV-6 encephalitis in allogeneic stem cell transplant recipients

Abstract

This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n ¼ 3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n ¼ 3) or CNS dysfunction because of an unidentified cause (n ¼ 2). Realtime PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (X10 4 copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was o10 4 copies/ ml. We next analyzed plasma concentrations of IL-6, IL-10 and tumor necrosis factor-a among patients who displayed high-level plasma HHV-6 DNA and found elevated IL-6 concentrations preceding HHV-6 infection in patients who developed CNS dysfunction. (Mean ± s.d.: 865.7 ± 1036.3 pg/ml in patients with CNS dysfunction; 56.5±192.9 pg/ml in others; P ¼ 0.01). These results suggest that high-level HHV-6 load is necessary for the development of HHV-6 encephalitis, and systemic inflammatory conditions before HHV-6 infection form the preparatory conditions for progression to encephalopathy.

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

“…10,45,46 However, several lines of evidence suggest that other cellular factors in addition to CD46 are crucial to the establishment of active HHV-6 infection in vivo. 41 Ogata et al 47 demonstrated that serum IL-6 levels increase dramatically in patients experiencing HHV-6 reactivation, showing a correlation between high levels of IL-6 in serum and CSF and the development of encephalitis. Several other studies have also suggested a significant role for IL-6 in the development of encephalitis through various proposed mechanisms.…”

“…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.…”

“…Although these two articles included data for the prevalence of HHV-6 encephalitis, they did not confirm this diagnosis by HHV-6 DNA detection in CSF, and were thus excluded from the final meta-analysis (Ogata 2008, Ogata 2010). …”

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: What we do and do not know

“…[1][2][3][4][5][6] The duration of displaying positive HHV-6 DNA in plasma is only 1-2 weeks in most cases. 3,5,7,8 HHV-6B accounts for most reactivation events. 1,12 Risk factors for displaying HHV-6 reactivation are HLA mismatch, 3,4 steroid treatment, 1,3 transplants from unrelated donors 2,3 and umbilical cord blood transplantation (UCBT).…”

“…1,[3][4][5][6][7][8] The first case of HHV-6 encephalitis after allo-HCT was described in 1994 by Drobyski et al 9 Since then, a significant amount of information regarding the incidence, risk factors, therapy and outcomes has been reported. Over the past decade, HHV-6 encephalitis has become well known as a significant complication of allo-HCT.…”