CONGENITAL CYTOMEGALOVIRUS CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSSINFECTION AND HEARING LOSS

Faye P. McCollister, EdDUniversity of Alabama, Emeritus

Diane L. Sabo, PhDChildren’s Hospital of PittsburghUniversity of Pittsburgh

Consulting Audiologists,National Center for HearingAssessment and Management

CONGENITAL CYTOMEGALOVIRUS CONGENITAL CYTOMEGALOVIRUS INFECTIONINFECTION

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 CLINICAL IMPACT OF CONGENITAL CMV INFECTION for SX and ASXCMV INFECTION for SX and ASX

Frequency of sequelaeSymptomatic (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 ADDRESSEDISSUES BEING ADDRESSED

Maternal screening and prenatal diagnosisNewborn diagnosis and screeningAntiviral treatment of the newbornPrevention of maternal and congenital

CMV infectionManagement of sequelae

ANNUAL CONGENITAL CMV ANNUAL CONGENITAL CMV INFECTION INFECTION

Range – .5 % to 1.5 %

Average – 1 %

With annual birthrate of 4 million

40,000 US children born with infection annually

DIAGNOSISDIAGNOSIS

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 INFECTIONSOURCES OF INFECTION

Transplacental Intrapartum Breast milk Nosocomial/transfusion

TYPES OF CONGENITAL CMV TYPES OF CONGENITAL CMV INFECTIONINFECTION

Symptomatic 5-10 % Asymptomatic – 90-95 %

Primary – First time infectionRecurrent – Reactivation of infection,

seropositive before pregnancy

CHARACTERISTICS OF CONGENITAL CHARACTERISTICS OF CONGENITAL SYMPTOMATIC CMV INFECTIONSYMPTOMATIC CMV INFECTION

Hepatosplenomegaly Microcephaly Thrombocytopenia Petechiae Jaundice with conjugated

hyperbilirubinemia

SEQUELAE OF SYMPTOMATIC SEQUELAE OF SYMPTOMATIC CONGENITAL CMV INFECTIONCONGENITAL CMV INFECTION

Seizures Chorioretinitis Periventricular calcifications Sensorineural hearing loss motor deficits

SEQUELAE OF ASYIMPTOMATIC SEQUELAE OF ASYIMPTOMATIC CONGENITAL CMV INFECTIONCONGENITAL CMV INFECTION

Hearing loss Chorioretinitis Seizures

PRIMARY MATERNAL CMV PRIMARY MATERNAL CMV INFECTION DURING INFECTION DURING

PREGNANCYPREGNANCY

• 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 HIGH RISK FOR PRIMARY MATERNAL AND CONGENITAL MATERNAL AND CONGENITAL

CMV INFECTIONCMV INFECTION

Teen mothers

Exposure to young children:– day-care workers– mothers

Sexual activity

RECURRENT CMV INFECTIONRECURRENT CMV INFECTION

Can cause symptomatic infection in infants

Can cause similar sequelae to primary infection

CHARACTERISTICS ASSOCIATED WITH CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAEINCREASED 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

CHORIORETINITISCHORIORETINITIS

DENTAL ABNORMALITIESDENTAL ABNORMALITIES

CMV Case Study (1)CMV Case Study (1)

CMV Case Study (2)CMV Case Study (2)

CMV Case Study (3)CMV Case Study (3)

Sudden Delayed Onset Hearing Sudden Delayed Onset Hearing Loss at Six Years Secondary to Loss at Six Years Secondary to

SX CMV SX CMV

HEARING LOSS IN CHILDREN HEARING LOSS IN CHILDREN WITH CONGENITAL CMV WITH CONGENITAL CMV

INFECTIONINFECTION

Longitudinal study-- 24 yearsFirst 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. 2000Dahle et al. 2000

HEARING LOSS AND CMVHEARING LOSS AND CMVEARLY STUDIESEARLY 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 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 PROTOCOLPROJECT PROTOCOL

CMV Isolated from urine during first 3 weeks of life Interdisciplinary assessment

Audiology Dental Laboratory Neurology Optometry Pediatrics Psychology

CMV STUDY POPULATIONCMV STUDY POPULATION Dahle et al, 2000 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 209Subjects 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 24-182 mo 6-197 mo

Progressive 26(54.2%) 46(54.1%)

Age Range 3-186 mo 2-209 mo

Fluctuating 25(47.9%) 5(29.4%)

Dahle et al, 2000

FLUCTUATING LOSSESFLUCTUATING 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 AULDIOMETRIC CONFIGURATIONCONFIGURATION

Audiometric patternFlat (largest % in both groups)Upward sloping (symptomatic)Downward sloping

(asymptomatic)Upward and downward sloping

Dahle et al, 2000Dahle et al, 2000

HEARING LOSS RESULTING HEARING LOSS RESULTING FROM CONGENITAL CMV FROM CONGENITAL CMV

INFECTIONINFECTION 4 Million - Annual Birth Rate 1 Percent - Average CMV Infection Rate 40,000 - Children Infected 4,000 -Symptomatic CMV (40.7% with HI) 36,000 -Asymptomatic CMV( 7.4 % with HI) 4,292 -Children born annually with/develop

HI from CMV 3/1,000 - Hearing loss in newborn population 35.76 - % of hearing loss due to CMV

Adapted from Dahle et al, 2000

Treatment of Sudden onset or Treatment of Sudden onset or Progressive Hearing LossProgressive 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 USE OF GANCICLOVIR IN NEWBORNS WITH SYMPTOMATIC CONGENITAL WITH SYMPTOMATIC CONGENITAL

CMV INFECTIONCMV INFECTION

Pro- Antiviral effect Might prevent death

or improve newborn disease

No other options

Con- Most damage done prior

to birth Limited antiviral effect Potential reproductive

toxicity Potential ‘rebound’

retinitis or other disease Lack of evidence of

efficacy

Pass, 1999

USE OF GANCICLOVIR IN USE OF GANCICLOVIR IN SYMPTOMATIC CONGENITAL CMV SYMPTOMATIC CONGENITAL CMV

INFECTIONINFECTION

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 A PHASE II STUDY OF GANCICLOVIR IN 47 NEWBORNS WITH SYMPTOMATIC NEWBORNS WITH SYMPTOMATIC

CONGENITAL CMV INFECTIONCONGENITAL CMV INFECTION

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 GANCICLOVIR Kimberlin et al. 2003Kimberlin et al. 2003

Multi-center randomized, controlled trial

Ss: 100 symptomatic neonates 6 weeks ganciclovir (6mg/kg q12h) Outcome: BSER 42 Ss used in analysis

GANCICLOVIR GANCICLOVIR Kimberlin et al. 2003Kimberlin 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 change-normal

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 GANCICLOVIR Kimberlin et al. 2003Kimberlin 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

GANCICLOVIRGANCICLOVIR Kimberlin et al. 2003Kimberlin 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 GANCICLOVIR Michaels et al. 2003Michaels et al. 2003

Ss: 9 children Long term ganciclovir treatment

(10mg/kg/day, 2-4 wks; 5mg/kg/day~ 12 months) 4/9 normal—normal 5 no progression 2 ears with improvement

DURATION OF CMV EXCRETION DURATION OF CMV EXCRETION AND HEARING LOSS AND HEARING LOSS Noyola et al. 2000Noyola 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 PREDICTORS OF NEURODEVELOPMENTAL NEURODEVELOPMENTAL

OUTCOMEOUTCOME Noyola et al. 2001Noyola et al. 2001

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

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

PREDICTORSPREDICTORS Rivera et al. 2002Rivera et al. 2002

87/180 (48%) had hearing loss at follow up61/87 (70%) had hearing loss at

birth26/87 (30%) had delayed onset55/87 (63%) had progression of

hearing loss

PREDICTORS contPREDICTORS cont.. Rivera et al. 2002Rivera et al. 2002

PREDICTORS cont.PREDICTORS cont. Rivera et al. 2002Rivera et al. 2002

Characteristic

IUGR

OR (95% CI)

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 wasnot shown to be an independents predictor of hearing loss.

“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

PREDICTORS cont.PREDICTORS cont. Rivera et al. 2002Rivera et al. 2002

WHAT WE KNOWWHAT 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 MANAGEMENTMEDICAL 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 POSSIBLE FACTORS IIN CMV EAR DAMAGE WITH CHRONIC DAMAGE WITH CHRONIC

INFECTIONINFECTION

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 CMV MANAGEMENT CONCERNSCONCERNS

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 VIGILANT SURVEILLANCE REQUIREDREQUIRED

Estimated that about 16 % of childhood hearing loss in US is delayed in onsetEducate parentsEducate medical care providersProvide information on normal auditory

developmentProvide information of signs and

symptoms of hearing loss

MONITORING FOR BEHAVIORAL MONITORING FOR BEHAVIORAL CHANGES SUGGESTING CHANGES SUGGESTING

PROGRESSIVE HEARING LOSSPROGRESSIVE HEARING LOSS 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 AUDIOLOGICAL MANAGEMENTMANAGEMENT

Frequent audiological monitoring Hearing aids with power and frequency

response flexibility Training in communication methods that

accommodate changing hearing levels

AUDIOLOGIC MONITORING AUDIOLOGIC MONITORING OBJECTIVESOBJECTIVES

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 MANAGEMENT OF INTERVENTION FOR HEARING INTERVENTION FOR HEARING

LOSSLOSS

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 GUIDELINES FOR EDUCATIONAL MANAGEMENTMANAGEMENT

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 KNOWWHAT 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 EndThe End