CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS Faye P. McCollister, EdD University of...
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Transcript of CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS Faye P. McCollister, EdD University of...
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