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Detection of CMV DNA in the perilymph of a 6-year-old boy with congenital cytomegalovirus infection.

Introduction

Cytomegalovirus (CMV) is the largest and the most structurally complex member of the family of human herpesviruses. After primary infection, virus excretion can persist for several months, and even years, after infection in children and adults. (1) In a patient with a congenital infection, prolonged excretion of virus that continues for years is also possible. (1,2)

Congenital CMV (cCMV) infection has been recognized as one of the most common congenital infections in the United States and northern Europe and a leading cause of brain disease. Since the virtual elimination of circulating rubella, it has become the most common nongenetic cause of childhood hearing loss and an important cause of neurodevelopmental delay. In industrialized countries where maternal seroprevalence is relatively low, overall rates of cCMV infection range from 0.3 to 1% of live births. (3-6)

Studies have shown that prolonged excretion of the virus in children with cCMV infection and persistent viral replication represent a possible explanation for the development of sequelae. (2) Furthermore, recent reports have documented that hearing loss due to cCMV may be progressive and/or of late onset. (7) The pathogenesis of these progressive and late-onset auditory sequelae has not yet been established, but prolonged viral replication in the cochlea could be related to their development. Hearing losscanoccurasa result of a local inflammatory response leading to cochlear hair cell death or as a result of a direct cytopathic effect of the virus in the inner ear.

In this article, we describe the detection of CMV DNA in a 6-year-old patient with cCMV infection who received a cochlear implant.

Case report

Our patient was a 6-year-old boy who had been born with a symptomatic CMV infection secondary to a maternal primary CMV infection during the first trimester of pregnancy. The child was diagnosed at birth with severe bilateral sensorineural hearing loss. T2-weighted magnetic resonance imaging (MRI) of his brain demonstrated bilateral hyperintense lesions in the subependymal zone that were compatible with subependymal cysts.

The patient was treated with intravenous ganciclovir at 20 mg twice daily for 6 weeks. When the antiviral therapy did not alter his hearing thresholds, rehabilitation with bilateral hearing aids was started; the patient was 4 months of age at this point. The child exhibited no ophthalmologic problems, but he did demonstrate some slight signs of difficulties with gross motor development. He also demonstrated a particular behavior that could not be attributed solely to his hearing problem. Despite intensive training and rehabilitation, a serious language delay was documented. As a result, the option of bilateral cochlear implantation was proposed to his parents.

The parents initially refused to allow cochlear implantation. However, by the time the child had reached the age of 6 years, it was obvious that his oral communication was very poor, and the parents then granted their approval. At that time, tonal audiometry showed bilateral hearing thresholds at 90 dB HL (pure-tone average). No thresholds at 95 dB nHL were found on auditory brainstem response testing. MRI and computed tomography ruled out any inner ear malformations.

A neurologic consultation found no contraindications to cochlear implantation on the left side. Informed consent was obtained from the parents for perilymph liquid sampling for viral culture and detection of CMV DNA.

Surgery involved a standard mastoidectomy, during which a well was created for placement of the implant's receiver/stimulator. Byway of a posterior tympanotomy, a cochleostomy in the scala tympani was performed with a diamond bur at low speed inferior and slightly anterior to the round window. A Nucleus CI422 cochlear implant (Cochlear; Sydney, Australia) with straight electrodes was placed.

Before the electrodes were inserted, a sample of perilymph liquid was collected by holding a sterile swab under microscopic monitoring against the cochleostomy. The sample was placed in a universal transport medium (UTM; Copan; Brescia, Italy) for viral culture and a real-time polymerase chain reaction (PCR) assay. CMV culturing was performed on MRC-5 cells. Nucleic acid extraction was performed on an automated extraction platform (NucliSens easyMAG; bioMerieux; Marcy-l'Etoile, France) using a 200-[micro]l input volume. For amplification of CMV DNA, primers pp5549s and pp812as and probe FAM 5'-ACGTGGCACTGCGGCACGTGGT-3' TAMRA were defined in the UL83 region. (8) Real-time amplification was performed with a LightCycler 480 Instrument II (Roche Diagnostics; Risch-Rotkreuz, Switzerland). The PCR sample was tested in triplicate. A region of the human [beta]-globin gene was used as the target for internal control. (8)

The patient's postoperative period was uncomplicated. The CMV culture demonstrated no virus in the perilymph liquid, but CMV DNA was detected by real-time PCR in the three PCR assays performed on the sample (mean Cp value: 40.06).

A sample of saliva taken after surgery to control for CMV shedding was negative, and viral culture of the saliva was negative, indicating that there was no reactivation of endogenous CMV at the time of surgery.

Discussion

The implementation of cochlear implantation in children with already severe hearing loss or deafness gives us the opportunity to collect samples from the inner ear and to study the presence and persistence of CMV in the inner ear.

The presence of CMV in the inner ear of children has been reported in a few case reports and case series. (9-11) According to Teissier et al, CMV was detected in the inner ear of 6 children who died because of complications of a symptomatic cCMV infection. (9) Sugiura et al reported that CMV DNA was found in 2 children as old as 3 years who were receiving a cochlear implant because of severe hearing loss after a cCMV infection. (10) The oldest child with CMV DNA in the perilymph at the time of cochlear implantation previously reported in the literature was 54 months. (11) Ogawa et al reported the presence of CMV DNA in a boy 60 months of age who received a cochlear implant because of severe SNHL of unknown origin. (12) However, cCMV infection was not proven at birth, and for this reason, acquired CMV infection could not be ruled out.

Attempts to detect CMV in the perilymph of older children and adults with known or suspected cCMV have remained unfruitful. Rarey and Davis reported the case of a boy with known cCMV infection who died at the age of 14 years; his perilymph CMV culture was negative at autopsy. (13) In a series by de Vries et al, no CMV DNA was found in 21 adult cochlear implant recipients with prelingual deafness. (14) Although it was not known how many of these patients had deafness due to cCMV, it would be likely that at least some of them would have had a cCMV infection to explain their hearing loss.

Our patient was a 6-year-old boy who received a cochlear implant because of profound hearing loss secondary to a cCMV infection. Implantation was undertaken at an unusually late age due his parents' initial refusal to allow it. This case demonstrates that CM V DNA was still present in the perilymph of the cochlea even after 6 years. To the best of our knowledge, this is the first reported case in which CMV DNA was detected in the inner ear 6 years after diagnosis of a proven congenital infection.

In our patient, viral culture of the perilymphatic fluid remained negative while the PCR findings were positive. It is probable that only minimal amounts of virus are present in inner ear fluids, and since PCR testing is highly sensitive for the detection of CMV DNA, it is therefore superior to culture for demonstrating the virus in a small volume obtained from the cochlea.

Another possible explanation for the negative viral culture is that the DNA detected in this case was from a virus that was in a nonreplicative state. Soetens et al evaluated the specificity of the PCR assay for detecting CMV DNA on 40 dried blood spots of CMV-negative children, and they found that the specificity was 100%.8

In conclusion, we describe the detection of CMV DNA in the cochlea of a 6-year-old boy with severe hearing loss due to cCMV infection. We assume from this case that viral replication of CMV after a cCMV infection can persist for several years and that it can be responsible for progressive and/or late-onset hearing loss. In children with severe sensorineural hearing loss of no known etiology, the use of a PCR assay to detect CMV in perilymph at the time of cochlear implantation might lead to the diagnosis of cCMV at a more advanced age.

Ina Foulon, MD; Oriane Soetens, PhD; Leen Vleurinck, MA; Frans Gordts, PhD; Astrid Leus, MD; Anne Naessents, PhD

From the Department of Otolaryngology-Head and Neck Surgery (Dr. Foulon, Mrs. Vleurinck, and Dr. Gordts), the Department of Microbiology (Dr. Soetens and Dr. Naessens), and the Department of Radiology (Dr. Leus), University Hospital, Brussels, Belgium.

Corresponding author: Ina Foulon, MD, Department of Otolaryngology-Head and Neck Surgery, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Email: ina.foulon@uzbrussel.be

References

(1.) Stagno S, Reynolds DW, Tsiantos A, et al. Comparative serial virologic and serologic studies of symptomatic and subclinical congenitally and natally acquired cytomegalovirus infections. J Infect Dis 1975;132(5):568-77.

(2.) Noyola DE, Demmler GJ, Williamson WD, et al. Cytomegalovirus urinary excretion and long term outcome in children with congenital cytomegalovirus infection. Congenital CMV Longitudinal Study Group. Pediatr Infect Dis J 2000;19(6):505-10.

(3.) Ahlfors K, Ivarsson SA, Harris S. Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden. Review of prospective studies available in the literature. Scand J Infect Dis 1999;31(5):443-57.

(4.) Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17(4):253-76.

(5.) Griffiths PD, Baboonian C, Rutter D, Peckham C. Congenital and maternal cytomegalovirus infections in a London population. Br J Obstet Gynaecol 1991;98(2):135-40.

(6.) Foulon I, Naessens A, Foulon W, et al. A 10-year prospective study of sensorineural hearing loss in infants with congenital cytomegalovirus infection. J Pediatr 2008;153(l):84-8.

(7.) Foulon I, Naessens A, Faron G, et al. Hearing thresholds in children with a congenital CMV infection: A prospective study. Int J Pediatr Otorhinolaryngol 2012;76(5):712-17.

(8.) Soetens O, Vauloup-Fellous C, Foulon I, et al. Evaluation of different cytomegalovirus (CMV) DNA PCR protocols for analysis of dried blood spots from consecutive cases of neonates with congenital CMV infections. J Clin Microbiol 2008;46(3):943-6.

(9.) Teissier N, Delezoide AL, Mas AE, et al. Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol 2011;122(6):763-74.

(10.) Sugiura S, Yoshikawa T, Nishiyama Y, et al. Detection of herpesvirus DNAs in perilymph obtained from patients with sensorineural hearing loss by real-time polymerase chain reaction. Laryngoscope 2004;114(12):2235-8.

(11.) Bauer PW, Parizi-Robinson M, Roland PS, Yegappan S. Cytomegalovirus in theperilymphaticfluid. Laryngoscope 2005; 115(2):223-5.

(12.) Ogawa H, Matsui T, Baba Y, et al. Presence of cytomegalovirus in the perilymphatic fluid of patients with profound sensorineural hearing loss caused by congenital cytomegalovirus infection. Acta Otolaryngol 2016; 136(2): 132-5.

(13.) Rarey KE, Davis LE. Temporal bone histopathology 14 years after cytomegalic inclusion disease: A case study. Laryngoscope 1993;103(8):904-9.

(14.) de Vries JJ, Vesseur A, Rotteveel LJ, et al. Cytomegalovirus DNA detection in dried blood spots and perilymphatic fluids from pediatric and adult cochlear implant recipients with prelingual deafness. J Clin Virol 2013;56(2): 113-17.
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Article Details
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Title Annotation:ORIGINAL ARTICLE; cytomegalovirus DNA
Author:Foulon, Ina; Soetens, Oriane; Vleurinck, Leen; Gordts, Frans; Leus, Astrid; Naessens, Anne
Publication:Ear, Nose and Throat Journal
Article Type:Clinical report
Date:Jun 1, 2016
Words:1906
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