Legal Medicine 54 (2022) 102007

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Legal Medicine
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Case Report

Fatal human herpes virus 6B myocarditis: Postmortem diagnosis of HHV-6B

based on CD134+ T-cell tropism
Atsushi Yamada *, 1, Toshiaki Takeichi, Kyoka Kiryu, Satoshi Takashino, Masaki Yoshida,
Osamu Kitamura
Department of Legal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Human herpes virus 6 (HHV-6) is one of the most important pathogens of viral myocarditis, and is often
Human herpes virus 6 responsible for sudden death in young adults. A 59-year-old immunocompetent man died of serious lymphocytic
Fatal myocarditis myocarditis, and his peripheral blood sample showed HHV-6 DNAemia. Recently, HHV-6 cell entry and reac­
CD134
tivation have been suggested to be regulated by the expression of specific CD receptors on T lymphocytes. Here,
T-cell tropism
Immunofluorescence assay
we report a case of HHV-6 myocarditis diagnosed using an experimental method focused on this unique cell
tropism. The interaction between HHV-6 and CD expression was assessed using an immunofluorescence assay.
Colocalization between HHV-6B and CD134 was detected in lymphocytes infiltrating the myocardium, which
was highly suggestive of an active HHV-6B infection and could be a useful criterion for postmortem diagnosis of
HHV-6B myocarditis in the acute phase.

1. Introduction
Sudden cardiac death is one of the most common causes of death,
with a higher frequency, especially in young adults. The pathological
changes in sudden cardiac death are not only limited to myocardial
infarction, but could also include coronary stenosis and all forms of
myocarditis [1]. Myocarditis is an inflammatory disease of the
myocardium. The incidence of myocarditis is estimated to be 22 cases
per 100,000 population or approximately 1.5 million cases globally, and
is responsible for 5%–20% of sudden death cases in young adults [3,11].
Among the infectious etiologies, parvovirus B19 and human herpes virus
6 (HHV-6), are the most frequent pathogens according to a large
epidemiological survey conducted in Western countries [2–4]. The
clinical symptoms of acute HHV-6 myocarditis are often nonspecific,
such as fever, syncope, and tachycardia; thus, clinical diagnosis is
sometimes difficult. Because the initial manifestations of the disease
may include sudden and unexplained death, postmortem investigation is
often required for forensic pathologists. Furthermore, a specific diag­
nostic criterion for suspected HHV-6 myocarditis has not yet been
established. Here, we report a case of fatal HHV-6 myocarditis, diag­
nosed using a new method based on the unique cell tropism of HHV-6.
HHV-6 is classified into two distinct genomic variants, HHV-6A and
HHV-6B, and fundamental differences between these two variants have
recently been determined. HHV-6 is a T-lymphotropic virus that repli­
cates in T cell. During virus entry into human cells, HHV-6A and HHV-6B
ligands bind to CD46 and CD134, respectively (Fig. 1) [5,6]. Addition­
ally, HHV-6 can establish chromosomal integration, which presumably
establishes latent infection (Fig. 1) [7–9]. Upregulation of each receptor
render the cell susceptible to HHV-6 infection and is a significant factor
in HHV-6 reactivation and replication [8]. We applied these unique cell
tropisms to evaluate our case by immunofluorescence assay and to assess
its potential as a definitive diagnostic criterion for active HHV-6
myocarditis in forensic investigations.
2. Case presentation
A 59-year-old Caucasian man complained of intermittent fever, and
loss of appetite 4 days before his death. He was immunocompetent and
healthy, with the exception of temporal asthma. Systemic corticosteroid
had been used shortly for dermatological reasons 6 weeks prior. After
finishing his meal, he experienced sudden chest pain and went into
cardiopulmonary arrest; he could not be resuscitated. A judicial autopsy
was performed two days later.

* Corresponding author.
E-mail address: yamalegm@ks.kyorin-u.ac.jp (A. Yamada).
1
ORCID: 0000-0001-7598-5877.

https://doi.org/10.1016/j.legalmed.2021.102007
Received 10 June 2021; Received in revised form 27 November 2021; Accepted 23 December 2021
Available online 27 December 2021
1344-6223/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
A. Yamada et al.
Fig. 1. A schematic illustration of specific entry receptors CD46/CD134 and
chromosomally integrated HHV-6. The HHV-6A and HHV-6B ligands bind to
CD46 and CD134 respectively. Each CD receptor is essential for virus entry into
the host cell. Following primary infection, HHV-6 can integrate into the host
genome, establishing chromosomally integrated HHV-6 (ciHHV-6), which is
presumed to be a latent form of HHV-6.
2.1. Autopsy findings
The deceased was 180 cm tall with a body weight of 81.9 kg, and no
signs of injury. Neither erythematous eruptions nor post-inflammatory
pigmentation was observed. Internally, the pericardial sac contained
40 mL of turbid fluid. The weight of the heart was 447 g, with a cloudy
epicardial surface, and a globular and rounded apex (Fig. 2A). The gross
transverse section of the heart showed diffuse myocardial turbid change
with moderate congestion and the left ventricle was slightly dilated
(Fig. 2B). Evaluation of cardiac valves and coronary arteries was unre­
markable. Pathologically, massive interstitial inflammatory infiltrate
seeping through the myocytes was evident without the presence of any
fibrotic changes. The vast majority of the cells were lymphocytes, with
scattered neutrophils and plasma cells (Fig. 3). The absence of eosino­
phil, giant cell and granuloma focal aggregation was confirmed. The
histological features of asthma included mucous plugs, edema, inflam­
matory infiltration of eosinophils or neutrophils, thickening of the
subepithelial basement membrane, smooth muscle cell hyperplasia, and
goblet cell hyperplasia were not observed. The conduction system and
atria were not investigated in this study. Polymerase chain reaction
(PCR) assay of the blood sample showed that the copy number of HHV-6
DNA was 230 copies/106cells (high-level viremia > 20 copies/106cells).
PCR results were negative for other relevant myocarditis viruses, spe­
cifically parvovirus B19, Epstein-Barr virus, and cytomegalovirus.
Fig. 2. Macroscopic view of the heart during autopsy. The surface of the heart shows a cloudy epicardium, and the shape is globular with a rounded apex (Fig. 2A).
The gross transverse section of the heart shows a diffuse myocardial turbid change with moderate congestion, and the left ventricle is slightly dilated (Fig. 2B).
2
Legal Medicine 54 (2022) 102007
Fig. 3. Micrograph (hematoxylin–eosin staining) shows massive interstitial
inflammatory infiltrate seeping through the myocytes was evident without the
presence of any fibrotic changes. Most of the cells are lymphocytes, with
scattered neutrophils and plasma cells.
Toxicological screening and measurement of ethanol in the blood
showed no significant findings.
2.2. Immunofluorescence assay
We evaluated whether HHV-6 cell tropism was involved in primary
HHV-6 myocarditis. The distribution and localization of HHV-6A, or
HHV-6B viral particles and the cell surface expression of CD receptors,
were investigated by immunofluorescence assay according to a previ­
ously published method used to diagnose HHV-6 encephalitis [10]. The
antibodies used for the immunofluorescence assay were anti-HHV-6A
(MAB8537; Sigma-Aldrich, St. Louis, MO), anti-HHV-6B (MAB8535;
Sigma-Aldrich, St. Louis, MO), anti-CD46 (ab273583; Abcam, Burlin­
game, CA), and anti-CD134 (ab203220; Abcam, Burlingame, CA). Sec­
ondary antibodies conjugated to a fluorescent dye (Alexa Fluor 647 anti-
mouse for green or Alexa Flour 488 anti-rabbit for red fluorescence)
were then added. The cells were sealed using ProLong™ Diamond
Antifade Mountant with DAPI (P36971; Invitrogen/ThermoFisher Sci­
entific, Waltham, MA) and observed under a fluorescence microscope
(Keyence BZ-X700). HHV-6B and CD134 colocalization was detected in
lymphocytes (Fig. 4A–C). HHV-6B was observed as diffuse cytoplasmic
particles (Fig. 4A), whereas CD134 appeared as speckled granules in the
cytoplasm (Fig. 4B). In contrast, double labeling for HHV-6A and CD46
showed no significant labeling (data not shown).
A. Yamada et al.
Fig. 4. The myocardial specimens were double-labeled with anti-HHV-6B (A, C; green) and anti-CD134 (B, C; red) and observed under a fluorescence microscope.
Nuclei were counterstained with DAPI (A-C; blue). Colocalization between HHV-6B, observed as diffuse cytoplasmic particles, and CD134, speckled granules, were
detected in same lymphocyte (Fig. 4A–C). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
3. Discussion
According to a large epidemiological survey conducted in Western
countries, HHV-6 is one of the most important pathogens in adult
myocarditis [2–4]. Although, its precise epidemiology is unknown,
myocarditis is estimated to be responsible for 5%–20% of sudden death
in young adults [3,11]. Comprehensive knowledge of HHV-6 myocar­
ditis is valuable for forensic pathologists in cases of sudden unexpected
death. Clinically, symptoms of fatal HHV-6 myocarditis are nonspecific
such as fever, dyspnea, syncope, abdominal pain, and tachycardia
[12,13]. In our case, chest pain may have been associated with aggra­
vated pericarditis. Electrocardiography is not mandatory to diagnose
myocarditis because it might also be normal or show nonspecific ab­
normalities, but it is generally essential to exclude other cardiac dis­
eases. According to previous reports, HHV-6 infection myocarditis is
rarely symptomatic in the early stages and has a progressively worse
prognosis [12]. A higher incidence of heart failure in HHV6 myocarditis
compared to parvovirus B19 has been reported [14]. The efficacy of
antiviral, immunosuppressive, and intravenous immunoglobulin ther­
apy has not been established [15]. General conventional treatment of
cardiac symptoms, including heart failure and arrhythmias, is per­
formed routinely. At present, no specific biomarker has been identified
for suspected HHV-6 myocarditis, unlike Epstein-Barr virus infection
where markers have been identified [16]. Several approaches have been
developed to diagnose HHV-6 myocarditis based on histology, immu­
nohistochemistry, and viral genome detection by molecular techniques
[13,17–19]. A high viral load, and HHV-6 associated protein expression
in the specimen, are suggested to be supportive findings. However, the
viral genome can be detected in the myocardium without histological
changes [7]. Recent studies have revealed that HHV-6 can establish
integration within the nuclear genome, which presumably establishes
latent infection [7–9]. The prevalence of chromosomally integrated
HHV-6 (ciHHV-6) is 0.5%–0.8% in Western populations and increase to
2.9% in hospitalized patients [9,20]. Blood samples taken from in­
dividuals with ciHHV-6 are suggested to show high viral load, above 104
DNA copies/μg, as every cell in the body has the potential to harbor
complete HHV-6 genome [19]. The clinical detection of HHV-6 genome
from the myocardium and blood cannot be interpreted as a definitive
diagnosis of active HHV-6 myocarditis, as intercurrent or latent infec­
tion is indistinguishable.
HHV-6 is classified into two distinct variants, HHV-6A and HHV-6B.
Most primary infections are due to HHV-6B, which causes exanthema
subitem in childhood following the decline of maternal immunity, and
subsequently establishes latency in the host immune system [8]. Nearly
90% of adults are seropositive for HHV-6B [21]. The pathogenesis of
HHV-6A is still unclear; however, its association with neurological dis­
eases, such as Alzheimer’s disease and multiple sclerosis has been re­
ported [22,23]. As for HHV-6 myocarditis, the HHV-6B genomes is
found in 95% of cases while the HHV-6A genome is only found in 5% of
3
Legal Medicine 54 (2022) 102007
cases [7,19]. HHV-6 is a lymphotropic virus that replicates T cells.
Recently, a fundamental difference between these two variants was
determined. In the process of virus entry into human cells, the HHV-6A
ligand binds to CD46, in contrast, CD134 is the specific receptor for
HHV-6B [5,6,24]. The correlation between cell surface expression of
each CD receptors and HHV-6 reactivation and replication has been
demonstrated [5,25]. Along with subsequent viral replication, the in­
flammatory response accelerates, and causes organ damage [26].
Recently, HHV-6B reactivation from latency has been shown to be
involved in specific conditions, such as the upregulation of CD134 in T
cell, particularly in patients with allogeneic hematopoietic stem cell
transplantation, patients with drug-induced hypersensitivity syndrome,
or drug rash with eosinophilia and systemic symptoms [21,25,27].
CD134 is also known as OX40, which is a member of the TNF receptor
superfamily associated with a co-stimulator for T cell activation [24].
CD134 upregulation is a significant factor in HHV-6B reactivation and
replication, and renders the cells susceptible to HHV-6B infection.
In this report, we successfully demonstrated HHV-6B infection in
CD134 positive lymphocytes, which presented as massive interstitial
inflammatory infiltrate in the myocardium. We concluded that high
HHV-6B genome copy numbers were associated with an active inflam­
matory response. Our study falls short in assessing the affection with
potentially lymphomonocytic infiltration in the conduction system and
atria. Cardiac conduction systems including the perineural nerve
sheaths near the conduction system, should be investigated in cases of
HHV-6 myocarditis [1]. To our knowledge, this is the first report to
demonstrate the applicability of diagnosing active HHV-6B myocarditis
by assessing specific lymphotropic mechanisms. HHV-6B is a T-lym­
photropic virus with life-long persistence following primary infection in
childhood. Although, the productivity of infectious viruses from ciHHV-
6 has been confirmed in vitro, whether this condition increases virus-
related risk in humans is still unclear [8]. Additionally, an association
between latent HHV-6 infection with dilated cardiomyopathy has been
supported [28]. It is conceivable that almost all humanity is at a po­
tential risk of HHV-6B-associated cardiomyopathy. In this case,
although the deceased was immunocompetent with no medical history
of serious illness, systemic corticosteroid therapy 6 weeks prior was
suspected to be a potential risk of HHV-6B activation. In conclusion,
assessing CD134 positive T-cell tropism using an immunofluorescence
assay could strongly corroborate an active HHV-6B infection and could
be a robust criterion for postmortem diagnosis of HHV-6B myocarditis in
the acute phase.
4. Ethics approval
This study was performed in line with the principles of the Decla­
ration of Helsinki. Approval was granted by the ethics committee of our
university (registered number 1159-01).
A. Yamada et al. Legal Medicine 54 (2022) 102007

Funding multidisciplinary approach, Circulation 128 (23) (2013), https://doi.org/10.1161/

CIRCULATIONAHA.113.001801.
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Presentation, patterns of myocardial damage, and clinical course of viral
The authors declare that they have no known competing financial myocarditis, Circulation 114 (15) (2006) 1581–1590, https://doi.org/10.1161/
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