Progressive hearing loss following acquired cytomegalovirus infection in

an immunocompromised child
Ken Kato, MD
a,

, Hironao Otake, MD, PhD

a
, Mitsuhiko Tagaya, MD, PhD
a
,
Yoshiyuki Takahashi, MD, PhD
b
, Yoshinori Ito, MD, PhD
b
, Asahito Hama, MD, PhD
b
,
Hideki Muramatsu, MD, PhD
b
, Seiji Kojima, MD, PhD
b
, Shinji Naganawa, MD, PhD
c
,
Tsutomu Nakashima, MD, PhD
a
a
Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Japan
b
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
c
Department of Radiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Received 23 August 2012
Abstract We report a rare case of progressive hearing loss after acquired CMV infection in a child with
Langerhans cell histiocytosis (LCH). A 5-month-old female was diagnosed as having LCH. When
she was 14months old, she received an unrelated donor umbilical cord blood transfusion for the
treatment of intractable LCH. CMV infection was confirmed after the blood transfusion. Because her
own umbilical cord had no CMV, the CMV infection was not congenital. When she was 7years old,
mixed hearing loss was noted with bilateral otitis media with effusion. After that time, the
sensorineural hearing loss progressed to bilateral profound hearing loss over 3years. Three-
dimensional fluid-attenuated inversion recovery magnetic resonance imaging with gadolinium
contrast enhancement revealed a high intensity area in the inner ear that suggested bilateral
labyrinthitis. This case demonstrates the possibility that, under the immunodeficiency, the acquired
CMV infection causes progressive sensorineural hearing loss.
2013 Elsevier Inc. All rights reserved.
1. Introduction
Cytomegalovirus (CMV) is a DNA-containing herpes
virus. Its scientific name is human herpes virus 5 and it
causes a range of symptoms after the first infection or after
reactivation. CMV is well known as the cause of congenital
sensorineural hearing loss or the opportunistic pathogen.
Congenital CMV infection, which is caused by transplacen-
tal infection, also has various symptoms including low birth
weight, microcephaly, hepatosplenomegaly, meningitis, and
sensorineural hearing loss. Congenital CMV infection is the
most widespread cause of sensorineural hearing loss other
than inherited disease [16]. However, few reports have
described sensorineural hearing loss caused by acquired
CMV infection. We report progressive sensorineural hearing
loss caused by acquired CMV infection in an immunocom-
promised child.
2. Case report
A 5-month-old female was referred to the Department of
Pediatrics at Nagoya University Hospital because of fever,
lymphadenopathy and purpura. Based on histological examination
of neck lymph nodes, she was diagnosed with disseminate
Langerhans cell histiocytosis (LCH). Then she received chemo-
therapy. First, one course of DAL-HX 83 study group protocol
(etoposide (VP-16)+vinblastine (VBL)+prednisolone (PDN)) as
initial chemotherapy and secondly, one course of next chemother-
apy (VP-16+VBL+cyclophosphamide (CPA)) were performed.
But the LCH did not response completely. When she was 9months
old, her splenomegaly became worse and caused C-reactive protein
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American Journal of OtolaryngologyHead and Neck Medicine and Surgery 34 (2013) 8992
www.elsevier.com/locate/amjoto

Corresponding author. Department of Otorhinolaryngology, Nagoya

University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku,
Nagoya 466-8550, Japan. Tel.: +82 52 744 2323; fax: +82 52 744 2325.
E-mail address: katoken@med.nagoya-u.ac.jp (K. Kato).
0196-0709/$ see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.amjoto.2012.09.006
(CRP) elevation and anemia had progressed. Although she was
given blood transfusions many times, her anemia did not improve.
Finally, splenectomy was performed. After the operation, two
courses of CHOP therapy (CPA+VP-16+vincristine (VCR)+PDN)
and then, one course of next chemotherapy (CPA+VP-16+VCR)
were performed but her symptom such as fever elevation, anemia,
thrombocytopenia, and liver dysfunction became worse.
When she was 14months old, finally, a cord stem cell transplant
from an unrelated donor was performed and her LCH improved.
However, CMV infection that was recognized before the cord stem
cell transplantation was continuing. Because CMV antigen was not
detected in her own cord blood, it was considered that the CMV
infection was not congenital infection but acquired during treatment
of the LCH. Due to her immunodeficiency with few CD4+ T cells
(b 100/l400/l), CMV infection continued including retinitis.
CMV retinitis started when she was 18months old. She was
administered the antiviral drugs ganciclovir and foscarnet. During
treatment, CMV antigen became negative, but when the antiviral
drugs were discontinued, it became positive again, and she under-
went repeated hospitalization and discharge. The retinitis did not
become worse during this period. Fig. 1 shows changes of CMV-
DNA amount that was investigated from the age of seven. When
she was 7years old, CMV DNA increased to 3913 copies/ml, and
then decreased to zero or hundreds of copies/ml. When she was
9years old, CMV DNA increased to 8705 copies/ml, but again
decreased to zero or hundreds of copies/ml. Together with antiviral
drug therapy, she was transfused with activated CD4+ T cells. Her
blood CD4+ T cells increased to within the range of 500900/l,
but her immunodeficiency did not improve. Her CMV antigen
periodically became positive, at which times it was necessary to
administer foscarnet.
When she was 6years old, she consulted the Department of
Otorhinolaryngology in our hospital because of suspicion of otitis
media. At that time her mother did not notice her hearing impair-
ment. However, three months after her first visit to the Department
of Otorhinolaryngology, mixed hearing impairment with otitis
media (OME) with effusion was recognized bilaterally (first
audiogram in Fig. 2). A half year later, bilateral tympanostomy
and ventilation tube insertion were performed because OME did not
improve. Her bone-conduction hearing levels deteriorated to
profound hearing loss (Fig. 2). When she was 8years old, she
complained of dizziness transiently. Three-dimensional fluid-
attenuated inversion recovery (3D-FLAIR) MRI before and after
enhancement showed a high intensity lesion in the internal auditory
canal and in the cochlea without inner ear malformation. When
she was 11years old, 3D-FLAIR MRI after enhancement was
performed again. The signal intensity of internal auditory canal was
much stronger than that taken when she was 8years old (Fig. 3).
These findings suggested the exacerbation of meningitis close to the
inner ear. When she was 11years old, she had inflammation of the
ventricles of the brain and a large amount of CMV-DNA was
detected from her cerebrospinal fluid.
Fig. 1. The upper panel shows the changes in CMV DNA numbers from when she was 7years old through when she was 11years old. The lower panel shows
the frequency of foscarnet administration during this period.
90 K. Kato et al. / American Journal of OtolaryngologyHead and Neck Medicine and Surgery 34 (2013) 8992
Fig. 2. From January 2007 to the present, the patient's hearing level has deteriorated. In particular, her bony conductive hearing level became worse. This showed
that her sensorineural hearing loss was progressing.
Fig. 3. 3D-FLAIR MRI after intervenous gadolinium administration. A was taken when she was 8years old, and B was when she was 11years old. The
gadolinium enhancement of the internal auditory canal indicated by arrows was stronger in B than in A.
91 K. Kato et al. / American Journal of OtolaryngologyHead and Neck Medicine and Surgery 34 (2013) 8992
3. Comments
Because congenital CMV infection is transplacental
infection, CMV is detected from the dried umbilical cord.
On the contrary, in acquired CMV infection, CMV is not
detected from the umbilical cord [7,8]. We diagnosed this
case as acquired CMV infection since CMV was not detected
from dried umbilical cord blood, we diagnosed that it was
acquired CMV infection. There were few papers that de-
scribed progressive sensorineural hearing loss in patients
with acquired CMV infection except for the two cases
reported by Meynard et al. [9]. These patients were also
infected with human immunodeficiency virus (HIV) and
were immunodeficient. Our patient is also suffering from
immunodeficiency because of her allogeneic cord stem cell
transplantation. Thus, her condition is similar to these cases
where it was presumed that sensorineural hearing loss was
caused by opportunistic infection.
In animal studies, CMV-infected cells have been detected
in the perilymph area and spinal ganglion, but not in the
endolymph area or hair cells [4,10,11]. Katano et al. [4] and
Schraff et al. [11] injected CMV into the inner ear of guinea
pigs and observed severe inflammation and bleeding in the
scala tympani and spiral ganglion with progressive hearing
loss. Virally encoded macrophage inflammatory proteins
play the important role of inflammation in the scala tympani
and CMV-related hearing loss [11]. Sugiura et al. [12] and
Nardo et al. [13] succeeded in detecting CMV DNA in the
inner ear fluid of congenitally or acquired CMV-infected
patients who received cochlear implants. In these patients,
CMV DNA was not detected in peripheral blood mononu-
clear cell. These articles are indirect evidence of CMV
affinity and activity in the inner ear. In the temporal bone of
patients congenitally infected with CMV, many pathologic
findings such as endolabyrinthitis, endolymphatic hydrops,
loss of cochlear hair cells and CMV infecting many parts of
the cochlea and the vestibular system are observed [5,6].
Bachor et al. [14] reported their findings in the temporal bone
of patients with acquired CMV infection. In our patient, the
existence of asymptomatic meningitis and labyrinthitis was
recognized by 3D-FLAIR MRI.
4. Conclusion
We experienced a case with progressive sensorineural
hearing loss following acquired CMV infection in an immu-
compromised child with Langerhans cell histiocytosis (LCH).
To detect labyrinthitis, 3D-FLAIR MRI was very useful.
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