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Journal of Clinical Microbiology, December 2001, p. 4585-4587, Vol. 39, No. 12
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.12.4585-4587.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Fatal Myocarditis Associated with Acute Parvovirus
B19 and Human Herpesvirus 6 Coinfection
Jacques
Rohayem,1
Jürgen
Dinger,2
Rainer
Fischer,3
Karin
Klingel,4
Reinhard
Kandolf,4 and
Axel
Rethwilm1,*
Institut für
Virologie,1 Klinik für
Kinderheilkunde,2 and Institut für
Pathologie,3 Medizinische Fakultät "Carl
Gustav Carus," Technische Universität Dresden, 01307 Dresden,
and Abteilung für Molekulare Pathologie, Institut
für Pathologie, Universität Tübingen, 72076 Tübingen,4 Germany
Received 3 August 2001/Returned for modification 4 September
2001/Accepted 11 September 2001
 |
ABSTRACT |
We report on the case of a healthy young boy who developed a
fulminant myocarditis due to acute coinfection with erythrovirus (parvovirus B19) and human herpesvirus 6 (HHV-6) in the absence of an antiviral immune response. We suggest that the HHV-6-induced immunosuppression enhanced dissemination of parvovirus B19, which led
to fatal myocarditis.
 |
CASE REPORT |
An 11-year-old boy was admitted with
a 3-day history of fever that progressed within a few hours to acute
distress. He had no notable medical history; in particular, there were
no signs of a preexisting immunodeficiency. On examination he was
lethargic and cyanotic with tachypnea and had a fever (41.3°C). His
blood pressure was 73/31 mm Hg, and his pulse was 201 beats/min.
Erythema and exudates on the tonsils were noted, as were cervical
lymphadenopathies and a rash involving both arms and the neck.
Examination of the head, lungs, and abdomen was normal. There were no
focal neurological signs. He was intubated. Intravenous dopamine and
dobutamine were given. Arterial blood gas analysis showed a pH of 7.26 and partial O2 pressure of 3.48 kPa, with
an O2 saturation level of 43.4%. Cardiac arrest
occurred suddenly; resuscitation efforts were successful only for a
short time, and the patient died of congestive heart failure 55 min later.
Biochemical laboratory findings were normal except for C-reactive
protein (64.5 mg/liter; normal level, <10 mg/liter), creatinine kinase
(6.60 µkat/liter; normal level, 0.10 to 3.17 µkat/liter), and
troponin T (0.59 ng/ml; normal level, <0.1 ng/ml) levels. The white
blood cell count was 5 × 109/liter, with
lymphocytopenia (lymphocyte count, 0.35 × 109/liter) and thrombocytopenia (platelet
count, 36 × 109/liter).
Postmortem examination of the heart revealed enlargement of both
ventricles, with pericardial and subpleural petechial hemorrhage. Histopathological examination showed a diffuse myocarditis with interstitial infiltrates of mononuclear cells (predominantly
CD8+ lymphocytes). Histological examination of
the pharynx revealed diffuse interstitial infiltrates of mononuclear cells.
Serological results did not indicate acute infection with adenovirus,
herpes simplex virus type 1 or 2, Epstein-Barr virus, cytomegalovirus,
influenza type A or B virus, coxsackievirus type A or B, echovirus, or
hantavirus. Testing for parvovirus B19-specific antibodies was
performed by a commercially available enzyme immunoassay (Medac) with
baculovirus-expressed VP1 and VP2 proteins as antigens. Testing for
human herpesvirus 6 (HHV-6)-specific antibodies was performed by an
indirect immunofluorescence technique with MT4 cells infected with
HHV-6 variant B (HHV-6B), strain Z29, and HSB-2 cells infected with
HHV-6 variant A (HHV-6A), strain GS. Testing for immunoglobulin G (IgG)
and IgM antibodies to parvovirus B19 and HHV-6A and HHV-6B was
negative. Bacteriological cultures of blood specimens and cerebrospinal
fluid were negative. Attempts to isolate virus from the patient's
blood, cerebrospinal fluid, lung, spleen, and brain tissue were unsuccessful.
Nucleic acid isolation was performed with the QiaAmp viral kit (Qiagen)
for body fluids or by the method of Chomczynski and Sacchi
(5) for samples recovered postmortem. All samples that tested positive were extracted a second time and reanalyzed. On the
basis of the parvovirus B19 DNA sequence (GenBank accession number
AB030694), a nested PCR was performed to amplify a region of the gene
for capsid proteins VP1 and VP2. Primers P1 (5'-GTA CAG GAG GTA
CAG CAT C; base pairs 3728 to 3746) and P2 (5'-ACC CAC TCC
TTG CTG ATA C; base pairs 4176 to 4158) were used for the
first-round PCR, and primers P3 (5'-AGA GGG CTG CAG TCA ACA C; base pairs 3786 to 3804) and P4 (5'-GGT GGT ATG GCT GAG
ACA C; base pairs 4075 to 4057) were used for the nested
reaction. Parvovirus B19 DNA was detected in the patient's spleen
tissue, lung tissue, brain tissue, and myocardium (Table
1). For the detection of HHV-6 DNA by
nested PCR, primers that amplify a region of the gene for the putative
large tegument protein gene were used (2, 10). HHV-6 DNA
was detected in the pharynx, spleen tissue, and lung tissue (Table 1).
Amplimers were molecularly cloned with the TOPO-TA cloning kit
(Invitrogen). DNA sequences were determined on an ABI PRISM 377 DNA
sequencer with an ABI PRISM dye terminator cycle sequencing kit
(Applied Biosystems). The parvovirus B19 DNA sequence detected in
spleen tissue and the myocardium showed 99% similarity to that of
parvovirus B19 isolate Rm (GenBank accession number AB030694). The
HHV-6 DNA sequences detected in the pharynx, spleen tissue, and lung
tissue showed 99 and 97% similarities to those of HHV-6B strains Z29 and HST, respectively (GenBank accession numbers AF157706 and AB021506,
respectively). Except for the detection of Epstein-Barr virus DNA in
the spleen, no other viral DNA or RNA was detected (Table 1). In situ
DNA and RNA hybridization analyses (9) of
paraffin-embedded myocardial specimens showed that they were positive
for parvovirus B19 DNA and negative for enterovirus RNA.
Discussion.
Both parvovirus B19 and HHV-6 are ubiquitous
viruses that usually cause mild diseases in childhood. Parvovirus B19
is the causative agent of erythema infectiosum, also called fifth
disease. Parvovirus B19 infection has been reported to be a rare but
severe cause of myocarditis in infants and children (7, 11,
13). HHV-6 is the causative agent of exanthema subitum, also
called sixth disease. On the basis of its biological properties and
genomic sequences, HHV-6 has been divided into two subgroups, defined as HHV-6A and HHV-6B (1). Primary HHV-6 infections are
caused almost exclusively by HHV-6B (6).
To our knowledge, this is the first report of a patient with fatal
myocarditis due to parvovirus B19 in the course of a concomitant
HHV-6
infection. Our patient presented with clinical symptoms
compatible with
both primary parvovirus B19 and primary HHV-6
infections, i.e., a 4-day
history of fever, cervical lymphadenopathy,
erythema, and exudates of
the tonsils, as well as a cutaneous
rash involving both the arms and
the legs. A diffuse pharyngitis
is compatible with a viral infection
transmitted by the respiratory
route. The lymphocytopenia is compatible
with an immunosuppression
caused by an acute viral infection.
Thrombocytopenia is compatible
with a primary parvovirus B19 infection
(
3,
12). The postmortem
examination of the heart showed a
histology typical of that caused
by viral myocarditis, and in situ
hybridization analysis confirmed
myocardial invasion with parvovirus
B19. Amplified HHV-6 sequences
showed the highest degrees of homology
to HHV-6B.
All these findings and the patient's clinical history provide strong
evidence for a primary coinfection with parvovirus B19
and HHV-6,
although no serological response to either virus was
detected. The
absence of serological markers is not surprising.
IgM responses to
HHV-6 can be detected only 5 to 7 days following
the onset of symptoms,
and many infected children may not develop
detectable IgM responses
(
4). IgM responses to parvovirus B19
can be detected only
3 to 4 days following the onset of symptoms.
The clinical history of
our patient was only 4
days.
We suggest that HHV-6 induced a severe immunosuppression that enhanced
the dissemination of parvovirus B19, leading to fulminant
myocarditis.
HHV-6 is thought to exhibit a unique spectrum of
biological properties
that make it an immunosuppressive agent
of its own (
8). To
date, two reports have described severe
HHV-6-associated illness: one
in an 11-month-old child (
14)
and another in a 37-year-old
man (
15), both of whom were immunocompetent.
In both
patients, an immunosuppression caused by HHV-6 was hypothesized.
Our
patient was rather old to have a primary HHV-6 infection,
which may
have resulted in more severe
complications.
Although quite unusual, this case report underlines the importance of
recognizing a primary coinfection with two viruses,
each of which by
itself usually causes a benign
infection.
 |
ACKNOWLEDGMENTS |
We thank Tino Schwarz and Hans Nitschko for communicating the
parvovirus B19-specific primer sequences and Claudia Seiler for
technical assistance.
 |
FOOTNOTES |
*
Corresponding author. Mailing address: Institut
für Virologie, Medizinische Fakultät, TU Dresden,
Fetscherstr. 74, 01307 Dresden, Germany. Phone: 49-351-458 6200. Fax:
49-351-458 6314. E-mail:
Axel.Rethwilm{at}mailbox.tu-dresden.de.
 |
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Journal of Clinical Microbiology, December 2001, p. 4585-4587, Vol. 39, No. 12
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.12.4585-4587.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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