Congenital cytomegalovirus:
a treatable cause of sensorineural
hearing loss
Dr Simone Walter
Consultant Audiovestibular Physician
Cytomegalovirus (CMV)
Herpes virus, may reactivate
Transmitted via body fluids
Children and adults:
• Flu, cold or asymptomatic
Fetus:
• congenital infection
spectrum: asymptomatic
Cytomegalovirus (CMV)
symptomatic
severe disease
2
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
3
Classification
1.
‘Primary’ or
(common)
‘Secondary/recurrent’
(rare)
N.B fetus infected in only approx 40% of maternal infections
2. ‘Symptomatic’ or ‘Asymptomatic’ at birth
4
Symptom and Signs at Birth
• Intrauterine
growth retardation
• Microcephaly
• Jaundice
• Hepatosplenomegaly
• Thrombocytopenia
• Petechial rash
• Seizures
• SNHL
• Chorioretinitis
5
Burden of Disease
• Congenital CMV: 3-5/1000 live births in UK
0.2-2% 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
6
How common is hearing loss in cCMV?
2/3 of children with CMV-related SNHL are ‘asymptomatic’ at birth
7
When does the hearing loss occur?
• 50% congenital
• 50% post newborn
hearing screen
• most by age 4years
Pass 2005
8
cCMV-related SNHL Epidemiology (England)
Characteristics of CMV-related SNHL
• Progressive >50%
• Unilateral 30-50%
• Fluctuates 30%
• Improvement at one or more
frequencies 20-40%
• High Frequency 20-30%
age 4 months
age 15 months
age 32 months
Dahle 2000, Williamson 1992, Fowler 1997
10
Pathogenesis of CMV-related
hearing loss
• Cell damage and death
• Inflammation
• Reactivation
• ‘CMV immune escape
mechanisms’
• Genetic factors
Large CMV infected cells in the Organ of Corti,
courtesy of Prof Leslie Michaels
Nystad 2007, Schraff 2007
11
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
12
Imaging
Cranial ultrasound
CT: intracranial calcifications
MRI:
 Static white matter changes
 Parietal lobe
 Anterior temporal lobe
 Polymicrogyra
 Multifocal lesions and cysts
Van der knaap 2004, Manara 2011
13
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
16
Testing ‘Guthrie’ cards for CMV DNA
1/2 Dried Blood
Spot cut from card
Nucleic acid extracted
Sensitivity: 71-100%
Specificity: 99-100%
(Barbi 2006)
PCR using primers specific for
CMV gene sequences to
amplify a specific area of CMV
genome.
17
Testing ‘older’ Guthrie cards
Guthrie cards received - age of children and
proportion testing positive
100
23.2%
+ve
-ve
No. of cards
22.2% 25.7% 26.3%
75
22.7%
50
25
0
<1 year
1-2
2-5
5-10
>10
Age (yrs)
18
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
Cochlear
implant
Kadambari et al 2011
19
CMV and the Vestibular System
Pappas 1983
• Hypofunction/failure in 6/11
• Unilateral/bilateral
• Independent of SNHL
Zagolski 2007
• Vestibular dysfunction more
common than SNHL
• Gross motor delay
20
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%
CMV
Coats 2000
retinitis
21
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
Adler et al 2004,
Stowell 2014
22
Treatment: Rationale
Risk factors for SNHL:
• Central nervous system involvement, petechiae, IUGR
Williamson 1992, Rivera 2002
• Viraemia
Bradford 2005
• Viral load
Rivera 2002, Boppana 2005,
Walter 2007, Arav-Boger 2007
Boppana 2005
23
Antiviral Therapy
• IV ganciclovir or oral valganciclovir
• Prevents CMV replication
ganciclovir
• Side effects:
platelets and/or white cells, anaemia, kidney function
Valganciclovir: 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)
24
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.
25
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
26
Newborn Hearing Screening
Programme (NHSP)
27
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
Williams et al 2014
28
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)
29
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
31
Useful Websites
•
•
•
•
newborn screening laboratory address:
www.newbornscreening.org/laboratories.asp
cmvaction.org.uk
www.ndcs.org
www.ecci.ac.uk
32
Acknowledgements
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)
Thank you for your attention
33
References
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cytomegalovirus infection: a cause of sensorineural hearing loss. Arch Dis Child.
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Pass RF (2005) Congenital Cytomegalovirus Infection and Hearing Loss. Herpes Oct;
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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
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hearing loss in children with symptomatic congenital cytomegalovirus infection.
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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
34
References
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