Bone Marrow Transplantation (2020) 55:1004–1013

https://doi.org/10.1038/s41409-019-0752-5

REVIEW ARTICLE

Clinical practice recommendations for the diagnosis and

management of human herpesvirus-6B encephalitis after allogeneic
hematopoietic stem cell transplantation: the Japan Society for
Hematopoietic Cell Transplantation
Masao Ogata 1 Naoyuki Uchida2 Takahiro Fukuda3 Kazuhiro Ikegame4 Tomohiko Kamimura5
● ● ● ● ●

Makoto Onizuka6 Koji Kato7 Hikaru Kobayashi8 Yoji Sasahara9 Masashi Sawa10 Akihisa Sawada11
● ● ● ● ● ●

Daiichiro Hasegawa12 Masayoshi Masuko13 Toshihiro Miyamoto7 Shinichiro Okamoto14

● ● ●

Received: 1 August 2019 / Revised: 6 November 2019 / Accepted: 6 November 2019 / Published online: 19 November 2019
© The Author(s), under exclusive licence to Springer Nature Limited 2019

Abstract
Reactivation of human herpesvirus (HHV)-6B is relatively common after allogeneic hematopoietic stem cell transplantation
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(HSCT) and HHV-6B diseases may consequently develop. Among them, HHV-6B encephalitis is a serious and often fatal
complication. The aim of these clinical practice recommendations is to provide diagnostic and therapeutic guidance for
HHV-6B encephalitis after allogeneic HSCT. In this evidence-based review, we critically evaluated data from the published
literature. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to
assist in generating recommendations. We have summarized the findings that contribute to decision-making and we have
provided our recommendations. In cases where rigorous clinical data are unavailable, recommendations have been
developed in discussions with physicians who have relevant expertize.

Introduction (HSCT) to critically review published articles. Grading of

The Guidelines Committee of the Japan Society for Hema-
topoietic Cell Transplantation (JSHCT) convened a panel of
experts on human herpesvirus (HHV)-6B encephalitis fol-
lowing allogeneic hematopoietic stem cell transplantation
Recommendations Assessment, Development and Evalua-
tion (GRADE) [1–3] methodology was used to assist in
moving from evidence to decision-making and generating
recommendations. Many recommendations, however, were
based on expert opinion because rigorous clinical data were

* Masao Ogata 8
Department of Hematology, Nagano Red Cross Hospital,
mogata@oita-u.ac.jp
Nagano, Japan
1 9
Department of Hematology, Oita University Hospital, Oita, Japan Department of Pediatrics, Tohoku University Graduate School of
2 Medicine, Miyagi, Japan
Department of Hematology, Toranomon Hospital, Tokyo, Japan
10
3 Department of Hematology and Oncology, Anjo Kosei Hospital,
Hematopoietic Stem Cell Transplantation Division, National
Aichi, Japan
Cancer Center Hospital, Tokyo, Japan
11
4 Department of Hematology/Oncology, Osaka Women’s and
Division of Hematology, Department of Internal Medicine, Hyogo
Children’s Hospital, Osaka, Japan
College of Medicine, Hyogo, Japan
12
5 Department of Hematology/Oncology, Hyogo Prefectural Kobe
Department of Hematology, Harasanshin Hospital,
Children’s Hospital, Hyogo, Japan
Fukuoka, Japan
13
6 Division of Stem Cell Transplantation, Niigata University Medical
Department of Hematology and Oncology, Tokai University
and Dental Hospital, Niigata, Japan
School of Medicine, Kanagawa, Japan
14
7 Division of Hematology, Department of Medicine, Keio
Department of Medicine and Biosystemic Science, Kyushu
University School of Medicine, Tokyo, Japan
University Graduate School of Medical Science, Fukuoka, Japan
Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis. . . 1005

Table 1 Points to consider regarding HHV-6B encephalitis after allogeneic hematopoietic stem cell transplantation

Reactivation of HHV-6B following • Positive results for HHV-6 DNA in plasma are observed in about half of recipients and are
allogeneic HSCT concentrated between 2 and 6 weeks after transplantation.
• Cord blood transplantation is a strong risk factor for HHV-6B reactivation.
HHV-6B-related diseases after allogeneic HSCT • HHV-6B has a causal role in HHV-6B encephalitis after HSCT.
• HHV-6B is possibly associated with myelitis, lung disease, fever, bone marrow suppression/
graft failure, gastrointestinal disease, liver disease, cognitive decline, skin rash, myocarditis,
cytomegalovirus infection, acute GVHD, and relapse of primary disease.
Symptoms and findings of HHV-6B encephalitis • Development of HHV-6B encephalitis is concentrated between 2 and 6 weeks (especially
week 3) after transplantation.
• Symptoms include altered consciousness, memory impairment, convulsions, dysesthesia,
and autonomic nervous symptoms.
• HHV-6B encephalitis may develop with hyponatremia.
• Limbic encephalitis is a relatively characteristic finding of HHV-6B encephalitis but this
may not be observed on MRI, especially during the early disease onset.
Incidence and risk factors of HHV-6B • Incidences of HHV-6B encephalitis are estimated to be 0.5–1.2% for recipients of a BM
encephalitis after allogeneic HSCT transplant or a peripheral blood stem cell transplant, and 8–10% for recipients of a cord
blood transplant.
• Risk factors for HHV-6B encephalitis include a cord blood transplant, male sex, HLA-
mismatched transplantation, transplantation from unrelated donors, steroid use, and immune
reactions, such as pre-engraftment immune reactions, acute GVHD, or engraftment
syndrome.
• HLA-haploidentical transplantation may be a risk factor for HHV-6B encephalitis.
Prognosis of patients with HHV-6B encephalitis • The prognosis is poor: many patients die from to encephalitis or other subsequent
complications.
• About half of survivors will retain CNS sequelae, such as memory impairment.
HHV-6 human herpesvirus 6, HSCT hematopoietic stem cell transplantation, GVHD graft-versus-host disease, MRI magnetic resonance imaging,
BM bone marrow, HLA human leukocyte antigen, CNS central nervous system

not available. A list of considerations that contribute to
decision-making is shown in Table 1. Our recommendations
for the diagnosis and management of HHV-6B encephalitis
are summarized in Table 2.
A previous version of the JSHCT guidelines regarding
HHV-6 was written in Japanese and released in February
2018 (https://www.jshct.com/uploads/files/guideline/01_
03_03_hhv6.pdf). In this new English version of the
guidelines, the content has been comprehensively updated.
HHV-6B reactivation and HHV-6B-related
diseases after HSCT
HHV-6 is classified as two distinct species, HHV-6A and
HHV-6B. Most posttransplant HHV-6 reactivation is of
HHV-6B [4]. HHV-6 reactivation is usually defined by the
presence of HHV-6 DNA in peripheral blood. Many PCR
measurement systems cannot distinguish between HHV-6A
and HHV-6B, although some are able to do so using
melting curves and specific probes [5]. If plasma HHV-6
DNA is monitored 1–2 times per week after allogeneic
HSCT, positive conversion is observed in 30–70% of
patients [4, 6–9]. Positive results are concentrated between
2 and 6 weeks after transplantation [6]. The duration of
positivity is <3 weeks in most cases [6, 7, 10]. Cord blood
transplantation (CBT) [7, 8, 11] and transplantation from
unrelated [6, 9] or HLA-mismatched [6–8] donors are pre-
transplant risk factors associated with HHV-6B reactivation,
while graft-versus-host disease (GVHD) [7] and steroids
[4, 6, 7] are posttransplant risk factors.
HHV-6B reactivation can lead to various posttransplant
complications (Table 1). Encephalitis is a well-documented
complication of HHV-6B reactivation that occurs in allo-
geneic HSCT recipients. This causal association can be
demonstrated by application of the Bradford Hill criteria,
which are standard criteria for establishing epidemiological
evidence of a causal relationship [12]. The causal role of
HHV-6B in encephalitis has been shown in studies of
autopsy specimens by demonstrating HHV-6 mRNA and
proteins within the hippocampus and other limbic areas
[13–16].
Differentiation of inherited chromosomally
integrated HHV-6 (ciHHV-6)
ciHHV-6 status may lead to erroneous diagnosis of HHV-
6B encephalitis. ciHHV-6 is a unique form of HHV-6A and
HHV-6B infection [17] in which the complete HHV-6
genome becomes integrated into the telomere of every
chromosome and is vertically transmitted. The frequency of
1006 M. Ogata et al.

Table 2 Summary of recommendations for the diagnosis and management of HHV-6B encephalitis after allogeneic hematopoietic stem cell
transplantation
Recommendations Strength of
recommendations

Differentiation of inherited
chromosomally integrated HHV-6
(ciHHV-6)
Diagnosis of HHV-6B encephalitis
Treatment of HHV-6B encephalitis
Prevention of HHV-6B encephalitis
CSF cerebrospinal fluid
• The panel recommends confirmatory testing for ciHHV-6 when very high Strong
sustained levels of HHV-6 DNA are detected in whole blood (1–10 × 106
copies/mL) or when various levels of HHV-6 DNA persist in plasma or serum
• The panel suggests that HHV-6 DNA levels in whole blood be quantified or, if Weak
possible, HHV-6 DNA in cellular samples from donor be tested when donor
ciHHV-6 is suspected
• The panel suggests that testing for HHV-6 DNA in somatic cells, such as hair Weak
follicle cells (head or body), be evaluated when recipient ciHHV-6 is suspected
• The panel recommends that HHV-6B encephalitis be diagnosed by the presence Strong
of CNS symptoms such as altered mental status, memory disturbance, or seizure,
positive results for HHV-6 DNA in cerebrospinal fluid, and the exclusion of
other causes of CNS symptoms
• When HHV-6 DNA is detected in CSF, false positives and ciHHV-6 should be Strong
excluded
• The panel recommends empiric antiviral therapy in patients with suspected Strong
HHV-6B encephalitis while a diagnostic evaluation is being conducted
• The panel suggests foscarnet as the primary treatment Weak
• The panel suggests ganciclovir as the secondary choice Weak
• The panel suggests that combination antiviral therapy with foscarnet and Weak
ganciclovir be considered for patients with documented HHV-6B encephalitis in
clinically severe cases
• The panel recommends the maximum dose be administered where possible Strong
(foscarnet; 180 mg/kg/day, ganciclovir; 10 mg/kg/day)
• The panel suggests that the treatment of HHV-6B encephalitis be continued for a Weak
minimum of 3 weeks
• The panel does not recommend routine monitoring of blood HHV-6 DNA for Weak
predicting HHV-6B encephalitis
• The panel does not recommend routine use of prophylactic antivirals to prevent Weak
HHV-6B encephalitis

ciHHV-6 is 0.2–2.9% [17]. Whether the integrated virus can
cause disease in the setting of allogeneic HSCT remains
unknown. ciHHV-6 is suspected when very high sustained
levels of HHV-6 DNA are detected in whole blood (1–10 ×
106 copies/mL) or when various levels of HHV-6 DNA
persist in plasma or serum [17, 18]. In such cases, the panel
recommends that ciHHV-6 be excluded using confirmatory
testing (strong recommendation) to avoid erroneous diag-
nosis of active HHV-6 infection.
When the donor has ciHHV-6, HHV-6 DNA in blood
becomes detectable concomitant with engraftment [7, 18].
Levels of HHV-6 DNA in plasma and whole blood of
ciHHV-6 patients differ greatly [17]. The panel suggests
that HHV-6 DNA levels in whole blood be quantified when
donor ciHHV-6 is suspected (weak recommendation); the
value will be similar to the white blood cell count in patients
with ciHHV-6 (1–10 × 106 copies/mL) [17, 18]. If possible,
testing for HHV-6 DNA in whole blood or other cellular
samples from the donor is suggested to determine donor
ciHHV-6 (weak recommendation). When the recipient has
ciHHV-6, HHV-6 DNA is detectable in blood before
transplantation. A definitive diagnosis is made by demon-
strating HHV-6 DNA in somatic cells. Tests for HHV-6
DNA using hair follicles [7, 18] are suggested because
specimens can be easily collected (weak recommendation).
Incidence and risk factors of HHV-6B
encephalitis after allogeneic HSCT
CBT is a strong risk factor for HHV-6B encephalitis.
Incidences of HHV-6B encephalitis are estimated to be
0.5–1.2% for recipients of a bone marrow or peripheral
blood stem cell transplant, and 8–10% for recipients of CBT
[7, 19–21]. Inflammatory reactions, including pre-
engraftment immune reaction [22], engraftment syndrome
[6, 10], and GVHD [6, 19] are also risk factors for HHV-6B
encephalitis (Table 1). Small-scale studies show high inci-
dences of HHV-6B encephalitis in recipients of haploi-
dentical HSCT [23, 24]; however, it is not confirmed
Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis. . .
whether haploidentical HSCT is a risk factor for HHV-6B
encephalitis.
Symptoms and findings of HHV-6B
encephalitis
Most cases of HHV-6B encephalitis develop between 2 and
6 weeks after transplantation, most frequently in week 3
after transplantation [6, 25–27]. Memory disturbance,
altered consciousness, and convulsions are the major
symptoms [6, 27]. Initially, patients may complain of for-
getfulness or medical staff may notice abnormal behavior in
conversation with the patient. In typical cases, neurological
symptoms progress and patients may develop convulsions;
however, patients may only exhibit memory impairment.
The incidence of convulsions is 30–70% [16, 25–27]. In
patients with an aggressive course, neurological symptoms
worsen by the hour, and many of these patients require
artificial ventilation because of repeated convulsions and
respiratory depression [6]. According to a retrospective
study [26], 40 of 131 patients (28%) required intubation.
Patients may complain of dysesthesia and intermittent pain
in the extremities [22, 26]. Symptoms of the autonomic
nervous system, such as hyperhidrosis, sinus tachycardia
attacks, and high blood pressure [22, 26] may develop.
Hyponatremia may develop concomitantly with HHV-6B
encephalitis, possibly because of inappropriate secretion of
antidiuretic hormone [16, 28–30]. In a retrospective study
[26], the symptoms at diagnosis of HHV-6 encephalitis
(n = 145) were altered consciousness (62%), disorientation
(52%), memory disturbance (48%), seizure (32%), dys-
esthesia (22%), and autonomic symptoms (6.2%).
HHV-6B encephalitis typically exhibits an MRI sig-
nature of hyperintense lesions on T2-weighted, fluid-
attenuated inversion recovery imaging of bilateral hippo-
campus and amygdala [6, 16, 26, 31]. However, brain MRI
appears normal within 7 days of HHV-6B encephalitis onset
in most patients [31]. In addition, a retrospective MRI study
showed that limbic encephalitis finding was observed only
in 60% of patients with HHV-6B encephalitis [26].
Abnormal findings may be identified in the basal ganglia
and various regions of the cortex [26].
Diagnosis of HHV-6B encephalitis
Several studies have used similar criteria to diagnose post-
transplant HHV-6B encephalitis: (i) presence of CNS
symptoms, (ii) positive PCR results for HHV-6 DNA in
cerebrospinal fluid (CSF), and (iii) the absence of other
identified causes of CNS dysfunction [7, 12, 26, 27, 31, 32];
all criteria should be fulfilled. Although the sensitivity and
1007
specificity of these criteria for the diagnosis of HHV-6B
encephalitis are unknown, they have been widely applied,
and no obvious problems have been reported. The panel
recommends using the above criteria to diagnose HHV-6B
encephalitis (strong recommendation) (Table 2).
HHV-6 DNA in CSF is generally recognized as a reliable
marker for the diagnosis of HHV-6B encephalitis, and its
importance has been confirmed in many observational stu-
dies [7, 25, 26, 32–34]. However, the demonstration of
HHV-6 DNA alone cannot establish the diagnosis of HHV-
6B encephalitis. When HHV-6 DNA is detected in CSF,
false positives [35–37] and ciHHV-6 should be excluded
(strong recommendation). Hill et al. reported that 14 of 51
cases in which HHV-6 DNA was demonstrated in CSF after
transplantation did not conform to typical HHV-6 CNS
dysfunction [35]. HHV-6 is latent in lymphocytes and,
therefore, if mononuclear cells are present in CSF, false-
positive PCR detection of HHV-6 DNA can occur. In
individuals with ciHHV-6, CSF PCR testing for HHV-6
DNA will be positive in patients with CSF pleocytosis [17].
Positive results for HHV-6 DNA in CSF, especially low
viral levels, must be interpreted carefully in conjunction
with symptoms and negative results for other etiologies.
What is the significance of HHV-6 DNA in blood sam-
ples for the diagnosis of HHV-6B encephalitis? A pro-
spective observation study [7] and a large retrospective
study [19] showed that higher levels of plasma HHV-6
DNA are associated with an increased risk of developing
HHV-6B encephalitis. However, high levels of HHV-6
DNA in blood samples are frequently observed in CBT
cases [7]. In addition, HHV-6B encephalitis that develops
without an accompanying high level of HHV-6 DNA in the
blood has been reported [33]. We recommend demonstrat-
ing the presence of HHV-6 DNA in CSF by performing a
lumbar puncture whenever possible to diagnose HHV-6B
encephalitis.
There are diagnostic pitfalls when diagnosing HHV-6
encephalitis. A minority of patients had CSF pleocytosis
[7, 25, 27] and CSF protein levels are often normal [7, 25]
in patients with HHV-6B encephalitis. Limbic encephalitis
findings are often not detected by brain MRI, especially
within the first week after onset [31]. HHV-6B encephalitis
therefore can be missed if abnormal MRI findings are used
as a diagnostic basis of HHV-6B encephalitis.
It is important to consider a broad range for CNS dys-
function. Other pathogens, including Epstein–Barr virus,
herpes simplex virus, JC virus, varicella zoster virus,
cytomegalovirus, adenovirus [38, 39], bacteria, fungi
(Aspergillus), tuberculosis, and Toxoplasma may be
responsible for CNS symptoms. Among noninfectious dis-
eases, posterior reversible encephalopathy syndrome is
important to consider as a differential disease [40]. Con-
sideration of transplant-related thrombotic microangiopathy
1008
is warranted with the appearance of coexisting erythrocyte
fragmentation and organ damage [41]. Memory impairment
and delirium may be caused by narcotic and benzodiazepine
drugs. Other possible causes include encephalopathy caused
by preconditioning drugs [42], cytokine release syndrome,
cerebrovascular disorders, CNS invasion of malignant cells,
electrolyte disorders, and metabolic encephalopathy result-
ing from advanced dysfunction of the liver and kidney.
Treatment of HHV-6B encephalitis
Although data concerning relationship between the timing
of treatment initiation and prognosis are limited, early
initiation of antiviral therapy in patients with suspected
HHV-6B encephalitis is warranted while a diagnostic eva-
luation is being conducted. Delayed initiation of treatment
allows HHV-6B to replicate in the brain and will result in a
poor prognosis and sequelae. If HHV-6B encephalitis is
suspected and CSF PCR results are not obtained within
several hours, the panel recommends starting empiric ther-
apy prior to the confirmation of positive results for HHV-6
DNA in CSF (strong recommendation) (Fig. 1).
Several organizations recommend antiviral agents, such
as foscarnet or ganciclovir as first-line therapy [36, 37, 43].
Cidofovir is considered second line because of strong
nephrotoxicity and poor penetration into CSF [36]. How-
ever, no randomized, controlled trials have been conducted
to confirm the clinical effects of these agents for patients
with HHV-6B encephalitis.
Foscarnet and ganciclovir are covered by health insur-
ance in Japan for the treatment of cytomegalovirus infection
after HSCT in patients with normal renal function at the
dose: foscarnet, 180 mg/kg/day (60 mg/kg administered
three times daily at 8-h intervals, or 90 mg/kg administered
twice daily at 12-h intervals), and ganciclovir, 10 mg/kg/day
(5 mg/kg administered twice daily at 12-h intervals). Fos-
carnet was approved in Japan in March 2019 for HHV-6
encephalitis after HSCT in patients with normal renal
function at the dose: 180 mg/kg/day (60 mg/kg administered
three times daily at 8-h intervals). In these guidelines, fos-
carnet 180 mg/kg/day and ganciclovir 10 mg/kg/day are
defined as maximum doses.
In a retrospective Japanese study [26], 74 of 133
patients were treated with foscarnet, 49 patients were
treated with ganciclovir, and ten patients were treated with
a combination of both. In terms of early treatment
response (disappearance or obvious improvement of CNS
symptoms after starting therapy), foscarnet tended to be
superior to ganciclovir (83.8% vs. 71.4%, P = 0.10). The
percentages of “death owing to HHV-6B encephalitis”
and “sequelae or death owing to HHV-6B encephalitis”
were not significantly different between patients receiving
M. Ogata et al.
ganciclovir or foscarnet. However, the percentage of
death from any cause within 30 days after the onset of
HHV-6B encephalitis was significantly lower in patients
treated with foscarnet compared with patients without
foscarnet treatment (12% vs. 31%, P = 0.008). A possible
reason for this discrepancy is that ganciclovir might cause
myelosuppression, thereby increasing the risk of sub-
sequent infectious disease. Another possibility is that
patients with renal insufficiency may have been more
likely to receive ganciclovir and more likely to die from
factors unrelated to the antiviral they received. These
retrospective study results require careful interpretation;
however, the panel suggests foscarnet as the primary
treatment, based on the currently available data (weak
recommendation). Use of ganciclovir is suggested if fos-
carnet is difficult to use because of renal impairment or
other reasons (weak recommendation).
Combination therapy with foscarnet and ganciclovir may
be considered for patients with HHV-6B encephalitis in
clinically severe cases [36, 44, 45]. However, there is no
available evidence on the clinical usefulness or toxicity of
combination therapy. The panel suggests that combination
therapy with foscarnet and ganciclovir be considered in
select patients with documented HHV-6B encephalitis, such
as rapidly progressing cases with convulsions (weak
recommendation).
Regarding the antiviral dose, the early treatment
response was significantly better in patients treated with
the maximum dose compared with those treated with non-
maximum doses (foscarnet, 93% vs. 74%, P = 0.044;
ganciclovir, 84% vs. 58%, P = 0.047) [26]. It should be
noted that the ganciclovir non-maximum doses had poor
efficacy. The percentage of patients who developed
sequelae or mortality associated with encephalitis was
significantly lower for patients treated with the maximum
dose of foscarnet or ganciclovir compared with patients
treated with non-maximum doses (56% vs. 75%, P =
0.022). For both foscarnet and ganciclovir, administration
of the maximum dose is recommended where possible
(strong recommendation). If renal dysfunction is
observed, the dose of either foscarnet or ganciclovir needs
to be adjusted appropriately.
Evidence to guide the optimal duration of treatment is
lacking. A study using autopsy samples demonstrated active
HHV-6 infection even if HHV-6 DNA became undetectable
in CSF [13]. Zerr recommends that the treatment of HHV-
6B encephalitis be continued for a minimum of 3 weeks
[45]. The panel also recommends continuing treatment for
at least 3 weeks (weak recommendation).
There is no high-quality evidence to recommend strate-
gies for cases in which clinical symptoms do not sub-
stantially improve or HHV-6 DNA does not disappear from
the plasma or CSF. The panel recommends an
Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis. . .
CNS symptoms after HSCT
Evaluation and examination
• Evaluation of CNS symptoms
• Baseline patient characteristics
• Examination of CSF: HHV-6 and other pathogens
• Brain CT, MRI1)
• Necessary blood tests
Are there any other identified etiologies for CNS dysfunction?
(e.g. diagnosis of PRES based on MRI, appearance of tumor cells
in the CSF)
YES NO
Therapy for other
identified diseases
Start empiric therapy
Administer foscarnet 60 mg/kg three times daily at 8-hour intervals (adjust dose as appropriate,
based on renal function)
If it is difficult to use foscarnet because of renal impairment or other reasons, administer ganciclovir 5
mg/kg twice daily at 12-hour intervals (adjust dose as appropriate, based on renal function).
Fig. 1 Expert opinion of the decision-making processes to start empiric
therapy for HHV-6B encephalitis in patients who develop central
nervous system dysfunction after allogeneic hematopoietic stem cell
transplantation. We suggest that this flowchart be adopted at hospitals
where PCR results cannot be obtained immediately. 1) In some
patients with HHV-6B encephalitis, MRI may not show any
abnormalities during the early period after onset. The main reason to
perform MRI is to check for findings of PRES. It is recommended to
individualized approach that takes into consideration the
progression and severity of illness as well as patient
comorbidities. General strategies for salvage therapy
include (i) extending the treatment period, (ii) switching to
foscarnet or combination therapy in patients treated with
ganciclovir, (iii) combination therapy with ganciclovir in
patients treated with foscarnet, and (iv) considering the use
of cidofovir (expert opinion). There are only limited clinical
data regarding the effectiveness of cidofovir for HHV-6
encephalitis [46]. Our opinion regarding the practical stra-
tegies for patients who receive a diagnosis of HHV-6B
encephalitis is shown in Fig. 2.
Below, we present expert opinion regarding clinical
practice. When using foscarnet, frequent monitoring of
renal function with dose adjustment for changes in creati-
nine clearance is important, as is adequate hydration.
Electrolyte abnormalities should be corrected as electrolyte
1009
Evaluation for possible HHV-6 encephalitis
1. CBT, HLA-mismatched unrelated HSCT
2. Onset in weeks 2 to 6
3. Memory disturbance, dysesthesia
4. PIR, GVHD, ES preceding CNS dysfunction
5. Corticosteroid use
6. Hyponatremia
Is the possibility of HHV-6 encephalitis high?
YES NO
Decide indication of
empiric therapy for
individual patients
How was the result of HHV-6 DNA in the CSF?
(within a couple of days after examination)
HHV-6 DNA positive HHV-6 DNA negative
Diagnosis of HHV-6 encephalitis Rule out the possibility of
(carefully exclude other causes) HHV-6 encephalitis
repeat MRI 1–2 weeks later if a definite diagnosis of HHV-6B ence-
phalitis is eventually made. CNS central nervous system, HSCT
hematopoietic stem cell transplantation, CSF cerebrospinal fluid, CT
computed tomography, MRI magnetic resonance imaging, PRES
posterior reversible encephalopathy syndrome, CBT cord blood
transplantation, HLA human leukocyte antigen, PIR pre-engraftment
immune reactions, GVHD graft-versus-host disease, ES engraftment
syndrome
imbalance will increase the risk of seizures. Therapeutic
effect is assessed according to CNS symptoms and HHV-6
DNA in the CSF, which should be evaluated 1–2 weeks
after initiating treatment. For patients in whom CSF col-
lection is difficult, HHV-6 DNA in the blood may be used
as an alternative marker to evaluate therapeutic effect [45].
In this case, it is desirable to assess plasma rather than
whole blood. After reaching peak levels, HHV-6 DNA
shows a delayed decrease in whole blood compared with
plasma, probably because of latent infection of leukocytes
[47]. Findings of HHV-6 DNA in whole blood may mis-
guide clinicians into using excessive treatment. Electro-
encephalography is suggested for patients who have no
clinically apparent seizures. Anticonvulsants should be
administered preventively if an electroencephalogram indi-
cates seizure activity. In patients who develop clinical
convulsion or deterioration of other conditions, an
1010 M. Ogata et al.

Early treatment

Administer foscarnet 60 mg/kg three times daily at 8-hour intervals (adjust

dose as appropriate based on renal function).

If it is difficult to use foscarnet because of renal impairment or other reasons,

administer ganciclovir 5 mg/kg twice daily at 12-hour intervals (adjust dose as
appropriate based on renal function).

In patients who have clinically significant conditions and potentially poor

prognosis, consider providing combination therapy1).
Administer foscarnet 60 mg/kg three times daily at 8-hour intervals +
ganciclovir 5 mg/kg twice daily at 12-hour intervals.

Evaluation of therapeutic effect

• CNS symptoms (after 1 week of treatment)

• HHV-6 DNA in CSF (after 1–2 weeks of treatment)

• Alleviation of symptoms • Lack of symptom alleviation

and and/or
• Negative conversion of HHV-6 DNA in CSF • No negative conversion of HHV-6 DNA in CSF

3–4 weeks of treatment - Extend the treatment period (at least 1 week after
confirmation of negative conversion of HHV-6 DNA in CSF,
up to 6 weeks).
- Switch to foscarnet or consider combination therapy in
patients treated with ganciclovir (Note: there are reports of
ganciclovir resistance).
- Consider concurrent ganciclovir in patients treated with
foscarnet alone.
- Consider use of cidofovir 2).
- Reevaluate the diagnosis if symptoms persist despite
negative conversion of HHV-6 DNA.

Fig. 2 Expert opinion regarding practical strategies for patients with
documented HHV-6B encephalitis. The strategies were developed
with reference to UpToDate [45]. 1) Combination therapy with fos-
carnet and ganciclovir may be considered for patients with docu-
mented HHV-6B encephalitis in clinically severe cases (weak
recommendation). There is no available evidence on the clinical use-
fulness or toxicity of combination therapy. 2) There are only limited
clinical data concerning the effect of cidofovir; its effectiveness is
therefore unknown. CNS central nervous system, CSF
cerebrospinal fluid

individualized approach is needed, including artificial Prevention of HHV-6B encephalitis

respiratory management.
Prognosis of patients with HHV-6B
encephalitis
In a retrospective study (n = 145, median observation per-
iod of patients who survived; 1651 days), outcomes were as
follows: 20% survived, 13% died from encephalitis, 44%
died from other complications, and 23% died from under-
lying diseases [26]. Even among survivors, 57% of patients
retained sequelae, such as memory impairment, lethargy,
disorientation, behavioral abnormalities, and epilepsy [26].
In patients who develop HHV-6B encephalitis, various
complications, including acute GVHD, secondary graft failure
or development of other infectious diseases, can cause death
[22, 23, 25–27, 48]. HHV-6 may be directly or indirectly
associated with the occurrence of these complications [49].
In patients who develop HHV-6B encephalitis, plasma
HHV-6 DNA levels typically increase suddenly and CNS
symptoms develop in parallel with high levels of HHV-6
DNA in plasma [7]. Therefore, their measures cannot pre-
dict the onset of HHV-6B encephalitis. Nonrandomized
studies show that preemptive antiviral therapy guided by
monitoring cannot predict or prevent the development of
HHV-6B encephalitis because of the dynamic kinetics of
plasma HHV-6 DNA [50, 51]. However, monitoring may
be useful in detecting HHV-6B encephalitis among patients
who develop CNS dysfunction, as well as for early diag-
nosis [7]. Although the panel does not recommend routine
monitoring of blood HHV-6 DNA for predicting HHV-6B
encephalitis (weak recommendation) (Table 2), we do not
deny the usefulness of monitoring for high-risk patients,
such as CBT recipients. For high-risk patients, monitoring
of plasma HHV-6 DNA twice a week during 2–6 weeks
Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis. . .
after transplantation might assist the early diagnosis of
HHV-6B encephalitis (expert opinion). However, whether
this monitoring will improve the outcome is unknown.
Regarding prophylactic administration of antiviral drugs, a
nonrandomized study showed that HHV-6B encephalitis
could not be prevented in CBT recipients by prophylactic
administration of foscarnet 90 mg/kg (days 7–27) [52].
Therefore, the panel does not recommend routine antiviral
prophylaxis for the prevention of HHV-6B encephalitis
(weak recommendation). Although prophylactic adminis-
tration may help to alleviate the severity of HHV-6B
encephalitis, reduce the mortality rate from encephalitis, and
improve sequelae [52], such effects of prophylactic antiviral
therapy need to be evaluated in clinical trials.
Limitations of the guidelines
Recommendations for treatment strategies are mainly based
on studies of the Japanese population. Genetic factors affect
the progression of viral infections [53] and may be asso-
ciated with increased risk of HHV-6 infection [54]. Inci-
dence and clinical features of HHV-6B encephalitis might
therefore differ between Japanese patients and non-Japanese
patients although available data from outside Japan also
showed similar risk factors and poor outcomes. We think
our recommendations can be applied to individuals in non-
Japanese populations but further studies are needed to
substantiate this.
Acknowledgements We thank Jeremy Allen, PhD, from Edanz Group
(www.edanzediting.com/ac) for editing a draft of this manuscript.
Author contributions MO, NU, and TF are members of the HHV-6
Guidelines Subcommittee of the Japan Society for Hematopoietic Cell
Transplantation (JSHCT). KI, TK, MO, KK, HK, YS, MS, AS, DH,
MM, and TM are members of the Guidelines Committee of the
JSHCT. All authors reviewed and approved the final version of the
manuscript.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
References
1. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-
Coello P, et al. GRADE: an emerging consensus on rating
quality of evidence and strength of recommendations. BMJ.
2008;336:924–6.
1011
2. Guyatt GH, Oxman AD, Kunz R, Jaeschke R, Helfand M, Liberati
A, et al. Incorporating considerations of resources use into grading
recommendations. BMJ. 2008;336:1170–3.
3. Jaeschke R, Guyatt GH, Dellinger P, Schunemann H, Levy MM,
Kunz R, et al. Use of GRADE grid to reach decisions on clinical
practice guidelines when consensus is elusive. BMJ. 2008;337:
a744.
4. Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M.
Clinical outcomes of human herpesvirus 6 reactivation after
hematopoietic stem cell transplantation. Clin Infect Dis.
2005;40:932–40.
5. Gautheret-Dejean A, Agut H, Flamand L, Lautenschlager I,
Krueger GRF, Ablashi D. Practical diagnostic procedures for
HHV-6A, HHV-6B, and HHV-7. Human herpesviruses HHV-6A,
HHV-6B, and HHV-7 diagnosis and clinical management. 3rd ed.
Kidlington, Oxford, UK: Elsevier; 2014. p. 9–34.
6. Ogata M, Kikuchi H, Satou T, Kawano R, Ikewaki J, Kohno K,
et al. Human herpesvirus 6 DNA in plasma after allogeneic stem
cell transplantation: incidence and clinical significance. J Infect
Dis. 2006;193:68–79.
7. Ogata M, Satou T, Kadota J, Saito N, Yoshida T, Okumura H,
et al. Human herpesvirus 6 (HHV-6) reactivation and HHV-6
encephalitis after allogeneic hematopoietic cell transplantation: a
multicenter, prospective study. Clin Infect Dis. 2013;57:671–81.
8. Yamane A, Mori T, Suzuki S, Mihara A, Yamazaki R, Aisa Y,
et al. Risk factors for developing human herpesvirus 6 (HHV-6)
reactivation after allogeneic hematopoietic stem cell transplanta-
tion and its association with central nervous system disorders. Biol
Blood Marrow Transpl. 2007;13:100–6.
9. Hentrich M, Oruzio D, Jager G, Schlemmer M, Schleuning M,
Schiel X, et al. Impact of human herpesvirus-6 after haemato-
poietic stem cell transplantation. Br J Haematol. 2005;128:66–72.
10. Ogata M, Satou T, Kawano R, Takakura S, Goto K, Ikewaki J,
et al. Correlations of HHV-6 viral load and plasma IL-6 con-
centration with HHV-6 encephalitis in allogeneic stem cell
transplant recipients. Bone Marrow Transpl. 2010;45:129–36.
11. Sashihara J, Tanaka-Taya K, Tanaka S, Amo K, Miyagawa H,
Hosoi G, et al. High incidence of human herpesvirus 6 infection
with a high viral load in cord blood stem cell transplant recipients.
Blood. 2002;100:2005–11.
12. Zerr DM, Ogata MHHV-6A, Flamand L, Lautenschlager I,
Krueger GRF, Ablashi D. and HHV-6B in recipients of hemato-
poietic cell transplantation. Human herpesviruses HHV-6A,
HHV-6B, and HHV-7 diagnosis and clinical management. 3rd ed.
Kidlington, Oxford, UK: Elsevier; 2014. p. 217–34.
13. Fotheringham J, Akhyani N, Vortmeyer A, Donati D, Williams E,
Oh U, et al. Detection of active human herpesvirus-6 infection in
the brain: correlation with polymerase chain reaction detection in
cerebrospinal fluid. J Infect Dis. 2007;195:450–4.
14. Drobyski WR, Knox KK, Majewski D, Carrigan DR. Brief report:
fatal encephalitis due to variant B human herpesvirus-6 infection
in a bone marrow-transplant recipient. N Engl J Med.
1994;330:1356–60.
15. Wainwright MS, Martin PL, Morse RP, Lacaze M, Provenzale
JM, Coleman RE, et al. Human herpesvirus 6 limbic encephalitis
after stem cell transplantation. Ann Neurol. 2001;50:612–9.
16. Seeley WW, Marty FM, Holmes TM, Upchurch K, Soiffer RJ,
Antin JH, et al. Post-transplant acute limbic encephalitis: clinical
features and relationship to HHV6. Neurology. 2007;69:156–65.
17. Pellett PE, Ablashi DV, Ambros PF, Agut H, Caserta MT, Des-
camps V, et al. Chromosomally integrated human herpesvirus 6:
questions and answers. Rev Med Virol. 2012;22:144–55.
18. Clark DA, Ward KN. Importance of chromosomally integrated
HHV-6A and -6B in the diagnosis of active HHV-6 infection.
Herpes. 2008;15:28–32.
1012
19. Hill JA, Koo S, Guzman Suarez BB, Ho VT, Cutler C, Koreth J,
et al. Cord-blood hematopoietic stem cell transplant confers an
increased risk for human herpesvirus-6-associated acute limbic
encephalitis: a cohort analysis. Biol Blood Marrow Transpl.
2012;18:1638–48.
20. Scheurer ME, Pritchett JC, Amirian ES, Zemke NR, Lusso P,
Ljungman P. HHV-6 encephalitis in umbilical cord blood trans-
plantation: a systematic review and meta-analysis. Bone Marrow
Transpl. 2013;48:574–80.
21. Ogata M, Fukuda T, Teshima T. Human herpesvirus-6 encepha-
litis after allogeneic hematopoietic cell transplantation: What we
do and do not know. Bone Marrow Transpl. 2015;50:1030–6.
22. Mori Y, Miyamoto T, Nagafuji K, Kamezaki K, Yamamoto A,
Saito N, et al. High incidence of human herpes virus 6-associated
encephalitis/myelitis following a second unrelated cord blood
transplantation. Biol Blood Marrow Transpl. 2010;16:1596–602.
23. Sisinni L, Gasior M, de Paz R, Querol S, Bueno D, Fernandez L,
et al. Unexpected high incidence of human herpesvirus-6 ence-
phalitis after naive T cell-depleted graft of haploidentical stem cell
transplantation in pediatric patients. Biol Blood Marrow Transpl.
2018;24:2316–23.
24. Greco R, Crucitti L, Noviello M, Racca S, Mannina D, Forcina A,
et al. Human herpesvirus 6 infection following haploidentical
transplantation: immune recovery and outcome. Biol Blood
Marrow Transpl. 2016;22:2250–5.
25. Zerr DM. Human herpesvirus 6 and central nervous system dis-
ease in hematopoietic cell transplantation. J Clin Virol. 2006;37:
S52–S56.
26. Ogata M, Oshima K, Ikebe T, Takano K, Kanamori H, Kondo T,
et al. Clinical characteristics and outcome of human herpesvirus-6
encephalitis after allogeneic hematopoietic stem cell transplanta-
tion. Bone Marrow Transpl. 2017;52:1563–70.
27. Muta T, Fukuda T, Harada M. Human herpesvirus-6 encephalitis
in hematopoietic SCT recipients in Japan: a retrospective multi-
center study. Bone Marrow Transpl. 2009;43:583–5.
28. Toriumi N, Kobayashi R, Yoshida M, Iguchi A, Sarashina T,
Okubo H, et al. Risk factors for human herpesvirus 6 reactivation
and its relationship with syndrome of inappropriate antidiuretic
hormone secretion after stem cell transplantation in pediatric
patients. J Pediatr Hematol Oncol. 2014;36:379–83.
29. Kawaguchi T, Takeuchi M, Kawajiri C, Abe D, Nagao Y,
Yamazaki A, et al. Severe hyponatremia caused by syndrome of
inappropriate secretion of antidiuretic hormone developed as
initial manifestation of human herpesvirus-6-associated acute
limbic encephalitis after unrelated bone marrow transplantation.
Transpl Infect Dis. 2013;15:E54–57.
30. Murakami K, Kohashi S, Sakurai M, Kato J, Toyama T, Koda Y,
et al. Hyponatremia associated with human herpesvirus-6 (HHV-
6) encephalitis after allogeneic hematopoietic stem cell trans-
plantation: a presentation different from HHV-6 myelitis. Int J
Hematol. 2017;106:436–40.
31. Bhanushali MJ, Kranick SM, Freeman AF, Cuellar-Rodriguez JM,
Battiwalla M, Gea-Banacloche JC, et al. Human herpes 6 virus
encephalitis complicating allogeneic hematopoietic stem cell
transplantation. Neurology. 2013;80:1494–500.
32. Fujimaki K, Mori T, Kida A, Tanaka M, Kawai N, Matsushima T,
et al. Human herpesvirus 6 meningoencephalitis in allogeneic
hematopoietic stem cell transplant recipients. Int J Hematol.
2006;84:432–7.
33. Zerr DM, Gupta D, Huang ML, Carter R, Corey L. Effect of
antivirals on human herpesvirus 6 replication in hematopoietic
stem cell transplant recipients. Clin Infect Dis. 2002;34:309–17.
34. Wang FZ, Linde A, Hagglund H, Testa M, Locasciulli A,
Ljungman P. Human herpesvirus 6 DNA in cerebrospinal fluid
specimens from allogeneic bone marrow transplant patients: does
it have clinical significance? Clin Infect Dis. 1999;28:562–8.
M. Ogata et al.
35. Hill JA, Boeckh MJ, Sedlak RH, Jerome KR, Zerr DM. Human
herpesvirus 6 can be detected in cerebrospinal fluid without
associated symptoms after allogeneic hematopoietic cell trans-
plantation. J Clin Virol. 2014;61:289–92.
36. Dewhurst S. Human herpesvirus type 6 and human herpesvirus
type 7 infections of the central nervous system. Herpes
2004;11:105a–111a.
37. Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos
KL, et al. The management of encephalitis: clinical practice
guidelines by the infectious diseases society of America. Clin
Infect Dis. 2008;47:303–27.
38. Schmidt-Hieber M, Schwender J, Heinz WJ, Zabelina T, Kuhl JS,
Mousset S, et al. Viral encephalitis after allogeneic stem cell
transplantation: a rare complication with distinct characteristics of
different causative agents. Haematologica. 2011;96:142–9.
39. Abidi MZ, Hari P, Chen M, Kim S, Battiwala M, Dahi PB, et al.
Virus detection in the cerebrospinal fluid of hematopoietic stem
cell transplant recipients is associated with poor patient outcomes:
a CIBMTR contemporary longitudinal study. Bone Marrow
Transpl. 2019;54:1354–60.
40. Siegal D, Keller A, Xu W, Bhuta S, Kim DH, Kuruvilla J, et al.
Central nervous system complications after allogeneic hemato-
poietic stem cell transplantation: incidence, manifestations, and
clinical significance. Biol Blood Marrow Transpl. 2007;
13:1369–79.
41. Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J,
et al. Diagnostic and risk criteria for HSCT-associated thrombotic
microangiopathy: a study in children and young adults. Blood.
2014;124:645–53.
42. Beitinjaneh A, McKinney AM, Cao Q, Weisdorf DJ. Toxic leu-
koencephalopathy following fludarabine-associated hematopoietic
cell transplantation. Biol Blood Marrow Transpl. 2011;17:300–8.
43. Ward KN, Hill JA, Hubacek P, de la Camara R, Crocchiolo R,
Einsele H et al. Guidelines from the 2017 European conference on
infections in leukaemia for management of HHV-6 infection in
patients with hematological malignancies and after hematopoietic
stem cell transplantation. Haematologica 2019. https://doi.org/10.
3324/haematol.2019.223073.
44. de Souza Franceschi FL, Green J, Cayci Z, Mariash E, Ezzeddine
M, Bachanova V, et al. Human herpesvirus 6 is associated
with status epilepticus and hyponatremia after umbilical cord
blood transplantation. Can J Infect Dis Med Microbiol.
2014;25:170–2.
45. Zerr DM. Human herpesvirus 6 infection in hematopoietic cell
transplant recipients. Hirsch MS, Boeckh M, Thormer AR, editors.
UpToDate. https://www.uptodate.com/contents/human-herpesvirus-
6-infection-in-hematopoietic-cell-transplant-recipients?search=HHV-
6%20encephalitis&source=search_result&selectedTitle=1~150&usa
ge_type=default&display_rank=1. Accessed 27 Jul 2019.
46. Pohlmann C, Schetelig J, Reuner U, Bornhauser M, Illmer T,
Kiani A, et al. Cidofovir and foscarnet for treatment of human
herpesvirus 6 encephalitis in a neutropenic stem cell transplant
recipient. Clin Infect Dis. 2007;44:e118–20.
47. Takano K, Ogata M, Kawano R, Satou T, Nashimoto Y, Shirao K.
Comparison of HHV-6 DNA detection in plasma and whole blood
in allogeneic hematopoietic stem cell transplant recipients: fre-
quent false-positive results for active HHV-6 infection using
whole blood samples. Int J Hematol. 2018;108:535–42.
48. Nakayama T, Okada F, Ando Y, Honda K, Ogata M, Goto K,
et al. A case of pneumonitis and encephalitis associated with
human herpesvirus 6 (HHV-6) infection after bone marrow
transplantation. Br J Radio. 2010;83:e255–8.
49. de Koning C, Admiraal R, Nierkens S, Boelens JJ. Human her-
pesvirus 6 viremia affects T-cell reconstitution after allogeneic
hematopoietic stem cell transplantation. Blood Adv.
2018;2:428–32.
Clinical practice recommendations for the diagnosis and management of human herpesvirus-6B encephalitis. . .
50. Ogata M, Satou T, Kawano R, Goto K, Ikewaki J, Kohno K, et al.
Plasma HHV-6 viral load-guided preemptive therapy against
HHV-6 encephalopathy after allogeneic stem cell transplantation:
a prospective evaluation. Bone Marrow Transpl. 2008;41:279–85.
51. Ishiyama K, Katagiri T, Hoshino T, Yoshida T, Yamaguchi M,
Nakao S. Preemptive therapy of human herpesvirus-6 encephalitis
with foscarnet sodium for high-risk patients after hematopoietic
SCT. Bone Marrow Transpl. 2011;46:863–9.
52. Ogata M, Takano K, Moriuchi Y, Kondo T, Ueki T, Nakano N,
et al. Effects of prophylactic foscarnet on HHV-6 reactivation and
1013
HHV-6 encephalitis in cord blood transplant recipients: a pro-
spective multicenter trial with a historical control group. Biol
Blood Marrow Transpl. 2018;24:1264–73.
53. Kenney AD, Dowdle JA, Bozzacco L, McMichael TM, St Gelais
C, Panfil AR, et al. Human genetic determinants of viral diseases.
Annu Rev Genet. 2017;51:241–63.
54. Leite JL, Manfrinatto JA, Mazzali M, Ward LS. Polymorphisms at
exon 4 of p53 and the susceptibility to herpesvirus types 6 and 1
infection in renal transplant recipients. Transpl Int. 2006;
19:732–7.