Congenital cytomegalovirus: a treatable cause of sensorineural

hearing loss

Dr Simone WalterConsultant Audiovestibular Physician

Cytomegalovirus (CMV)

Herpes virus, may reactivateTransmitted via body fluids

Children and adults:• Flu, cold or asymptomatic

Fetus: • congenital infection

spectrum: asymptomatic symptomatic severe disease

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Cytomegalovirus (CMV)Cytomegalovirus (CMV)

Definitions

• Congenital CMV (cCMV)CMV infection before birth, diagnosed by testing body fluid samples taken prior to Day 21

…may cause childhood sensorineural hearing loss (SNHL)

• Perinatal CMV • Acquired CMV

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Classification

1. ‘Primary’ or ‘Secondary/recurrent’(common) (rare)

2. ‘Symptomatic’ or ‘Asymptomatic’ at birth

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N.B fetus infected in only approx 40% of maternal infections

Symptom and Signs at Birth• Intrauterine

growth retardation• Microcephaly• Jaundice• Hepatosplenomegaly• Thrombocytopenia• Petechial rash• Seizures• SNHL• Chorioretinitis

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Burden of Disease

• Congenital CMV: 3-5/1000 live births in UK0.2-2% live births worldwide

• Causes 10-20% of childhood SNHL Peckham 1987, Pass 2005, Barbi 2003

• Important cause of neuro-disability (7% cerebral palsy) and vestibular dysfunction

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How common is hearing loss in cCMV?

2/3 of children with CMV-related SNHL are ‘asymptomatic’ at birth

When does the hearing loss occur?

• 50% congenital

• 50% post newborn hearing screen

• most by age 4years

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Pass 2005Pass 2005

cCMV-related SNHL Epidemiology (England)

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Characteristics of CMV-related SNHL

• Progressive >50%

• Unilateral 30-50%• Fluctuates 30%• Improvement at one or more

frequencies 20-40%• High Frequency 20-30%

Dahle 2000, Williamson 1992, Fowler 1997Dahle 2000, Williamson 1992, Fowler 1997

age 4 months

age 15 months

age 32 months

Pathogenesis of CMV-related hearing loss

• Cell damage and death

• Inflammation

• Reactivation

• ‘CMV immune escape mechanisms’

• Genetic factors

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Large CMV infected cells in the Organ of Corti, courtesy of Prof Leslie Michaels

Nystad 2007, Schraff 2007

Non-specific findings in cCMV

• Antenatal illness/fever• Premature birth• Intrauterine growth retardation• Gastro-oesophageal reflux?• Prolonged jaundice• Microcephaly• Hypotonia• Delayed motor milestones• Developmental delay• Cerebral palsy

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ImagingCranial ultrasound CT: intracranial calcifications

MRI: Static white matter changes Parietal lobe Anterior temporal lobe Polymicrogyra Multifocal lesions and cysts

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Van der knaap 2004, Manara 2011

Investigation for CMV: antibodies

Guidelines for cCMV investigation

Test maternal antibody (IgG): if negative, exclude cCMV < 1 yr urine/saliva x 2 occasions>1yr IgG antibody

If either are positive: request DBS for CMV testing

dried blood spot (DBS) (Guthrie card),taken in first week of life

Saliva testing

• Bottle fed babies-any time• Breast fed babies-1 hour

after feed• Leave swab in baby’s

mouth for 1 min

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Testing ‘Guthrie’ cards for CMV DNA

Sensitivity: 71-100%Specificity: 99-100%(Barbi 2006)

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Nucleic acid extracted

PCR using primers specific for CMV gene sequences to amplify a specific area of CMV genome.

1/2 Dried Blood Spot cut from card

Testing ‘older’ Guthrie cards

Guthrie cards received - age of children andproportion testing positive

<1 year 1-2 2-5 5-10 >100

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50

75

100+ve-ve

23.2%

22.2% 25.7% 26.3%

22.7%

Age (yrs)

No

. o

f ca

rds

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Management of cCMV-related SNHL

• Infants: refer to Paediatric infectious diseases ASAP

• Regular review• Hearing aids• Early referral for cochlear

implantation• Check vestibular function and vision• Precautions• Information: CMV Action, NDCS

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Cochlear implant

Kadambari et al 2011

CMV and the Vestibular SystemPappas 1983• Hypofunction/failure in 6/11• Unilateral/bilateral• Independent of SNHL

Zagolski 2007• Vestibular dysfunction more

common than SNHL

• Gross motor delay

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Visual complications

• Symptomatic group • mod/severe VI 22% • optic atrophy 37%• macular scars 13%• cortical VI 50%• squint 29%

• Asymptomatic group• mild unilateral VI 1% • macular scar• squint 1.2%

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Coats 2000

CMV

retinitis

Precautions

• Handwashing/gloves • Wash toys, eating and drinking

utensils, dummies• Avoid kissing mouth-mouth• Condoms• Take care re immuno-compromised

e.g. transplant patients• Wait one year before conceiving

again

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Adler et al 2004, Stowell 2014

Treatment: Rationale

Risk factors for SNHL:

• Central nervous system involvement, petechiae, IUGRWilliamson 1992, Rivera 2002

• ViraemiaBradford 2005

• Viral loadRivera 2002, Boppana 2005, Walter 2007, Arav-Boger 2007

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Boppana 2005Boppana 2005

Antiviral Therapy

• IV ganciclovir or oral valganciclovir• Prevents CMV replication• Side effects:

platelets and/or white cells, anaemia, kidney functionValganciclovir: vomiting and diarrhoea

Randomised Controlled Trial, Kimberlin 2003:‘Ganciclovir prevents hearing deterioration at 6 months

and may prevent hearing deterioration at > or =1 year’ (CNS affected symptomatic neonates)

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ganciclovir

Duration of therapy Randomised controlled trial CASG 112

All symptomatic neonates:6 weeks v 6 months valganciclovir

Abstract:6 months of oral VGCV treatment of infants with symptomatic

congenital CMV disease improves audiologic and neurodevelopmental outcomes to at least 2 years of age.

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Can we diagnose CMV-related SNHL in time for treatment?

• Integrating CMV screening with newborn hearing screen• CMVBEST study 1: CMV tests offered for ‘referred’ children• Testing kits and questionnaires posted to parents

• Outcomes: parental anxiety, comparison of diagnostic tests

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Newborn Hearing Screening Programme (NHSP)

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CMV BEST 1 Results

Saliva is more feasible than urine Parental anxiety scores not significantly different All cCMV infections detected within 28 days

6/411 referred babies (1.5%) positive for congenital CMV 3/24 (12.5%) infants with SNHL had cCMV All 3 had unilateral SNHL and parents accepted oral

valganciclovir

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Williams et al 2014

CMVBEST2: Enhancing Clinical Integration with the Newborn Hearing Screening Programme

• Screeners take saliva samples at the point of referral• Aims: 1. Recruit >90% eligible infants

2. Complete cCMV screening, return result to family and GP and commence treatment, as necessary, by 28 days of life

3. Assess feasibility of screeners performing CMV swab (Education package; designed with CMV Action)

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Future studies:

• CMVBEST 3: can targeted screening for cCMV be integrated into the NHSP in 5 regions in England?

• CASG 403: ‘Toddler Valgan’Children age 1 month-4 years with congenital CMV and SNHL 6 weeks valganciclovir v 6 weeks placebo

• Vaccines• Antenatal therapy• Avoidance

Conclusions

CMV causes 10-20% of childhood hearing loss (SNHL) SNHL: any pattern, progresses in 50%

Antiviral treatment is available for neonates

CMV-related hearing loss is treatable…if diagnosed in time

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Useful Websites• newborn screening laboratory address:

www.newbornscreening.org/laboratories.asp • cmvaction.org.uk• www.ndcs.org• www.ecci.ac.uk

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Acknowledgements

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Thank you for your attentionThank you for your attention

Professor Paul Griffiths

Prof Mike Sharland

Prof Adrian Davies

Dr Sue Luck

Dr Seilesh Kadambari

Ms Claire Atkinson

Dr Eleri Williams

Mrs Carmen Burton

CMV Action (Proceeds to Royal Free Charity)

ReferencesPeckham CS (1987) Stark O, Dudgeon JA, Martin JA, Hawkins G. Congenital

cytomegalovirus infection: a cause of sensorineural hearing loss. Arch Dis Child. Dec;62(12):1233-7

Pass RF (2005) Congenital Cytomegalovirus Infection and Hearing Loss. Herpes Oct; 12(2): 50-5

Williamson WD (1992) Demmler GJ, Percy AK, Catlin FI. Progressive hearing loss in infants with asymptomatic congenital cytomegalovirus infection. Pediatrics. Dec;90(6):862-6

Dahle AJ (2000) Fowler, KB Wright JD et al Longitudinal investigation of hearing disoders in children wih congenital cytomegalovirus. J Am Acad Audiol; 11:283-290

Rivera LB (2002) Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics. Oct;110(4):762-7

Zagólski O (2007) Vestibular-evoked myogenic potentials and caloric stimulation in infants with congenital cytomegalovirus infection.J Laryngol Otol. Sep 21;:1-6

Kadambari S (2011), Luck, S, Griffiths, P, Sharland, M, Evidence based management guidelines for the detection and treatment of congenital CMV, Early Human Development 87 (2011) 723–728

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ReferencesHicks T (1993) Fowler K, Richardson M, Dahle A, Adams L, Pass R Congenital

cytomegalovirus infection and neonatal auditory screening. J Pediatr. Nov;123(5):779-82

Fowler KB (1997) McCollister FP, Dahle AJ, Boppana S, Britt WJ, Pass RF. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus J Pediatr. Apr;130(4):624-30

Fowler KB (1999), Dahle AJ, Boppana SB, Pass RF J Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed? Pediatr. Jul;135(1):60-4

Lee DJ, Lustig L, Sampson M, Chinnici J, Niparko JK (2005) Effects of cytomegalovirus (CMV) related deafness on pediatric cochlear implant outcomes Otolaryngol Head Neck Surg. Dec;133(6):900-5.

Kimberlin DW et al (2008) Pharmacokinetic and Pharmacodynamic Assessment of Oral Valganciclovir in the Treatment of Symptomatic Congenital Cytomegalovirus Disease.J Infect Dis. Feb 15

Eleri J Williams, Kadambari S, Berrington JE, Luck S, Atkinson C, Walter S, Embleton ND, James P, Griffiths P, Davis A, Sharland M, Clark JE. Feasibility and acceptability of targeted screening for congenital CMV-related hearing loss, Arch Dis Child Fetal Neonatal Ed 2014;0:F1–F7

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ReferencesKimberlin DW et al (2003) Effect of ganciclovir therapy on hearing in

symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial J Pediatr. Jul;143(1):16-25.

Boppana SB (2005) Fowler, KB, Pass RF, Rivera LB, Bradford RD, Lakeman FD, Britt WJ Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss. J Pediatr. Jun;146(6):817-23

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