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CONGENITAL CYTOMEGALOVIRUS
INFECTION AND HEARING LOSS
Faye P. McCollister, EdD
University of Alabama, Emeritus
Diane L. Sabo, PhD
Children’s Hospital of Pittsburgh
University of Pittsburgh
Consulting Audiologists,
National Center for Hearing
Assessment and Management
CONGENITAL CYTOMEGALOVIRUS
INFECTION




Most common congenital infection in humans
Newborn morbidity/mortality + late sequelae –
hearing loss, mental retardation, cerebral palsy,
impaired vision
Leading cause of non-hereditary sensorineural
hearing loss in children
Leading infectious cause of brain damage in US
children
Pass, 1999
CLINICAL IMPACT OF CONGENITAL CMV
INFECTION for SX and ASX
Frequency of sequelae
Symptomatic (7%) Asymptomatic (93%)
Infant death
10%
0
Hearing loss
60%
7–15%
Mental retardation
45%
2–10%
Cerebral palsy
35%
<1%
Chorioretinitis
15%
1–2%
ISSUES BEING ADDRESSED
Maternal screening and prenatal
diagnosis
 Newborn diagnosis and screening
 Antiviral treatment of the newborn
 Prevention of maternal and congenital
CMV infection
 Management of sequelae

ANNUAL CONGENITAL CMV
INFECTION

Range – .5 % to 1.5 %

Average – 1 %

With annual birthrate of 4 million

40,000 US children born with infection
annually
DIAGNOSIS



Isolation of CMV from the urine or saliva of the
neonate within first three weeks of life
Presence of CMV IgM from the blood of the
neonate
Detection of Cytomegalic Inclusion Bodies from
affected tissue (rarely used)
SOURCES OF INFECTION




Transplacental
Intrapartum
Breast milk
Nosocomial/transfusion
TYPES OF CONGENITAL CMV
INFECTION


Symptomatic 5-10 %
Asymptomatic – 90-95 %
 Primary – First time infection
 Recurrent – Reactivation of infection,
seropositive before pregnancy
CHARACTERISTICS OF CONGENITAL
SYMPTOMATIC CMV INFECTION





Hepatosplenomegaly
Microcephaly
Thrombocytopenia
Petechiae
Jaundice with conjugated hyperbilirubinemia
SEQUELAE OF SYMPTOMATIC
CONGENITAL CMV INFECTION




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Seizures
Chorioretinitis
Periventricular calcifications
Sensorineural hearing loss
motor deficits
SEQUELAE OF ASYIMPTOMATIC
CONGENITAL CMV INFECTION



Hearing loss
Chorioretinitis
Seizures
PRIMARY MATERNAL CMV
INFECTION DURING PREGNANCY
•
95% clinically inapparent
•
35% transmitted to fetus
•
No clear relationship between gestational
age and transmission
•
Fetal damage more likely in first 26 weeks,
(32%) than later (15%)
HIGH RISK FOR PRIMARY MATERNAL
AND CONGENITAL CMV INFECTION

Teen mothers

Exposure to young children:
day-care workers
– mothers
–

Sexual activity
RECURRENT CMV INFECTION

Can cause symptomatic infection in infants

Can cause similar sequelae to primary infection
CHARACTERISTICS ASSOCIATED WITH
INCREASED RISK OF SEQUELAE





Primary maternal infection
Symptomatic congenital CMV infection
Presence of neonatal neurological
abnormalities
Abnormal head CT scan
Chorioretinitis in the newborn
Pass, 1999
CHORIORETINITIS
DENTAL ABNORMALITIES
CMV Case Study (1)
CMV Case Study (2)
CMV Case Study (3)
Sudden Delayed Onset Hearing Loss
at Six Years Secondary to SX CMV
HEARING LOSS IN CHILDREN WITH
CONGENITAL CMV INFECTION




Longitudinal study-- 24 years
 First hearing article published in 1977
Ss identified 1st week of life
Age at time of audiologic evaluation: 1
month to 19 yrs; mean age of 5 yrs
Audiologic evaluations every 3 months in
1st year, every 6 months until 2.5-3 yrs and
yearly thereafter
Dahle et al. 2000
HEARING LOSS AND CMV
EARLY STUDIES



Texas study: 17 symptomatic children;
mean age of outcome 5.5 years
11/17 (64%) had hearing loss (1 unilateral)
3/11 (27%) progressive hearing loss
AUDIOLOGICAL PROTOCOL




ABR (chloral hydrate) : Click, TB of 500 &
4000 HZ until 9 month
Air and bone conduction if AC>25 dBnHL
Immittance
VRA after 5 months until 2.5 to three years
Dahle, et al, 2000
PROJECT PROTOCOL


CMV Isolated from urine during first 3 weeks of life
Interdisciplinary assessment
 Audiology
 Dental
 Laboratory
 Neurology
 Optometry
 Pediatrics
 Psychology
CMV STUDY POPULATION
Dahle et al, 2000
CATEGORY
N
SN HL
Controls
201
0
ASX CMV
651
48
SX CMV
209
85
TOTAL
860
133
Asymptomatic
Symptomatic
Subjects
651
209
Subjects HI
48(7.4%)
85(40.7%)
Unilateral Loss
25(52.1%)
28(32.9%)
Bilateral Loss
23(47.9%)
57(67.!%)
High Frequency
18(37.5%)
11(12.9%)
Delayed Onset
18(37.5%)
23(27.1%)
Age Range
Progressive
Age Range
Fluctuating
Dahle et al, 2000
24-182 mo
26(54.2%)
3-186 mo
25(47.9%)
6-197 mo
46(54.1%)
2-209 mo
5(29.4%)
FLUCTUATING LOSSES




Expect higher percentage in the
asymptomatic group at 2K Hz, both
groups were similar with respect to
frequencies and amount of change
250 and 500 Hz the least stable
4000 Hz most stable
Note: more hearing improvements at 250
and 500 Hz also
Dahle et al, 2000
AULDIOMETRIC CONFIGURATION

Audiometric pattern
 Flat (largest % in both groups)
 Upward sloping (symptomatic)
 Downward sloping (asymptomatic)
 Upward and downward sloping
Dahle et al, 2000
HEARING LOSS RESULTING FROM
CONGENITAL CMV INFECTION





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
4 Million
1 Percent
40,000
4,000
36,000
4,292
3/1,000
35.76
- Annual Birth Rate
- Average CMV Infection Rate
- Children Infected
-Symptomatic CMV (40.7% with HI)
-Asymptomatic CMV( 7.4 % with HI)
-Children born annually with/develop
HI from CMV
- Hearing loss in newborn population
- % of hearing loss due to CMV
Adapted from Dahle et al, 2000
Treatment of Sudden onset or
Progressive Hearing Loss


Immunosuppressant Drugs
 Dexamethazone
 Side effects in children
Antiviral Drugs
 Does not cure virus but stops viral replication
 When drug is stopped, virus may start
replication again
USE OF GANCICLOVIR IN NEWBORNS
WITH SYMPTOMATIC CONGENITAL CMV
INFECTION
Pro Antiviral effect
 Might prevent death or
improve newborn disease
 No other options
Pass, 1999
Con Most damage done prior to
birth
 Limited antiviral effect
 Potential reproductive
toxicity
 Potential ‘rebound’ retinitis
or other disease
 Lack of evidence of efficacy
USE OF GANCICLOVIR IN SYMPTOMATIC
CONGENITAL CMV INFECTION




12 newborns treated for 2 weeks with 5 mg/kg/day or 7.5
mg/kg/day + 3 months of 10 mg/day 3x/week
Higher, but not lower dose, cleared viruria
Abnormal liver and haematologic function appeared to
clear faster with higher dose
Although outcome appeared better with higher dose, CNS
sequelae appeared in both groups
from Nigro et al, J Pediatr 1994; 124: 318
A PHASE II STUDY OF GANCICLOVIR IN 47
NEWBORNS WITH SYMPTOMATIC CONGENITAL
CMV INFECTION

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Patients with CNS disease treated with 8mg/kg/d
or 12mg/kg/d iv for 6 weeks
19 % of participants had neutropenia requiring
dose modification
12 mg/kg reduced viral shedding; shedding
returned when drug was discontinued
3 patients had improved hearing at 6 months; 25
had abnormal hearing
from Whitley et al, J Infect Dis, 1997; 175: 1080
GANCICLOVIR Kimberlin et al. 2003
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Multi-center randomized, controlled trial
Ss: 100 symptomatic neonates
6 weeks ganciclovir (6mg/kg q12h)
Outcome: BSER
42 Ss used in analysis
GANCICLOVIR Kimberlin et al. 2003
Best ear
Total ear
Ganciclovir
(n=25)
No
treatment
(n=17)
Ganciclovir
(n=49)
No
treatment
(n=36)
Improved
6 (24%)
5 (29%)
11 (22%)
6 (17%)
No changenormal
15 (60%)
5 (29%)
23 (47%)
8 (22%)
No change –HL
4 (16%)
0 (0%)
15 (31%)A
7 (19%)
Worse
0 (0%)
7 (41%)
0 (0%)
15 (42%)
6 month data
GANCICLOVIR Kimberlin et al. 2003
Best ear
Total ear
Ganciclovir
(n=24)
No treat
(n=19)
Ganciclovir
(n=48)
No treat
(n=36)
Improved
4 (17%)
0 (0%)
12 (25%)
0 (0%)
No change
normal
8 (33%)
5 (26%)
11 (23%)
8 (22%)
No change
HL
7 (29%)
1 (5%)
15 (31%)
6 (17%)
Worse
5 (21%)
13 (68%)
10 (21%)
22 (61%)
12 month data
GANCICLOVIR

Kimberlin et al. 2003
Conclusion: “Six weeks of intravenous
ganciclovir therapy prevents best-ear
hearing deterioration at 6 months….and
may prevent …deterioration at or beyond
1 year”
GANCICLOVIR


Michaels et al. 2003
Ss: 9 children
Long term ganciclovir treatment (10mg/kg/day, 24 wks; 5mg/kg/day~ 12 months)
 4/9 normal—normal
 5 no progression
 2 ears with improvement
DURATION OF CMV EXCRETION AND
HEARING LOSS Noyola et al. 2000


70 children; 58 ASX
SNHL and progressive SHNL were significantly more likely to occur
in short duration CMV excretion regardless of symptoms
Excretion
< 4 year
Excretion
> 4 year
P
SNHL
15 (43%)
6 (17%)
0.019
Pro SNHL
12 (34%)
3 (8.5%)
0.009
PREDICTORS OF
NEURODEVELOPMENTAL OUTCOME
Noyola et al. 2001



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41 symptomatic children
17 (41.5%) had SNHL –congenital
11 (26%) had late onset of SNHL
SNHL group had lower IQ/DQ score, more
motor difficulties and more abnormal head
CT
PREDICTORS Rivera et al. 2002




180 symptomatic infants enrolled and followed
over 30 yr period
65% referred from other health care providers
outside of UAB virology screening program
Median age of last hearing test: 5.75 yrs
Median # of hearing evaluations: 8
PREDICTORS cont.
Rivera et al. 2002

87/180 (48%) had hearing loss at follow up
 61/87
(70%) had hearing loss at birth
 26/87 (30%) had delayed onset
 55/87 (63%) had progression of
hearing loss
PREDICTORS cont.
Rivera et al. 2002
Characteristic
OR (95% CI)
IUGR
2.2 (1.1-4.1)
Petechiae
3.1 (1.5-6.3)
Hepatosplenomegaly**
2.0 (1.1-3.9)
**After adjusting based on regression analyses, hepatosplenomegaly was
not shown to be an independents predictor of hearing loss.
PREDICTORS cont.
Rivera et al. 2002


“Symptomatic infants with disseminated CMV
at birth—as evidenced by the presence of
IUGR, petechiae, hepatitis or
thrombocytopenia with or without neurologic
abnormalities-are at increased risk for
developing hearing loss.
Recommendation: vigilance in follow-up for
hearing is needed
WHAT WE KNOW






Leading (nongenetic) cause of sensorineural
hearing loss in children
Accounting for approximately 1/3 of
sensorineural hearing loss in young children
Frequent late onset hearing loss
Frequent progression of hearing loss
Frequent fluctuating hearing loss
Majority of children with congenital cmv infection
never identified
MEDICAL MANAGEMENT

Primary Infection - consider termination of pregnancy.

40% chance of the fetus being infected.

10% chance that congenitally infected baby will be
symptomatic at birth or develop sequelae later in life.

Therefore in case of primary infection, there is a 4% chance
(1 in 25) of giving birth to an infant with CMV problems.

Recurrent Infection - termination not recommended as risk
of transmission to the fetus is much lower.

Antenatal Screening – impractical.

Vaccination - may become available in the near future.
Pass, 1999
POSSIBLE FACTORS IIN CMV EAR
DAMAGE WITH CHRONIC INFECTION





Persistent low grade viral replication in affected
organs
Reactivation of latent virus
Vasculitis
Immune Complex formation
CMV specific defect in cell-mediated immunity
Darmstadt, Keithley and Harris, l990
CMV MANAGEMENT CONCERNS







Frequency of viral reactivation
Frequency of monitoring
Protocol for medical treatment
Side effects of drugs
Need for long term treatment
Long term subject compliance
Emotional needs of parent and child
VIGILANT SURVEILLANCE REQUIRED

Estimated that about 16 % of childhood hearing loss
in US is delayed in onset
 Educate parents
 Educate medical care providers
 Provide information on normal auditory
development
 Provide information of signs and symptoms of
hearing loss
MONITORING FOR BEHAVIORAL
CHANGES SUGGESTING PROGRESSIVE
HEARING LOSS

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Withdrawal
Acting out behaviors
Uncharacteristic irritability
Inability to understand speech in noise
Difficulty localizing sound
Preference for increased volume setting
Changes in acoustic characteristics of speech
Complaints of broken amplification
AUDIOLOGICAL MANAGEMENT



Frequent audiological monitoring
Hearing aids with power and frequency response
flexibility
Training in communication methods that
accommodate changing hearing levels
AUDIOLOGIC MONITORING
OBJECTIVES







Behavioral audiometric evaluations
Adjustment of amplification
Periodic electroacoustic evaluations
Listening checks
Check ear mold fit
Periodic probe mic measurements
Monitor functional development of auditory skills
MANAGEMENT OF INTERVENTION
FOR HEARING LOSS




Interdisciplinary assessment to identify any additional
conditions
Early intervention program referral
Training to empower child/parent to optimize learning
opportunities
Parent training about federal legislation/state/local
regulations developed to address needs of children
with disabilities
GUIDELINES FOR EDUCATIONAL
MANAGEMENT





Frequent monitoring of hearing and vision
Frequent monitoring of academic performance
Flexibility in placement and resource services
In-service training regarding CMV
Infection control plan
WHAT WE DON’T KNOW



What causes progressive and delayed onset
hearing loss
What is the role of newborn hearing screening
in relation to detection of CMV infection
What causes the hearing loss and what factors
predispose some infants to hearing loss.
The End