Presentation on theme: "CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS"— Presentation transcript:
1 CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS Faye P. McCollister, EdDUniversity of Alabama, EmeritusDiane L. Sabo, PhDChildren’s Hospital of PittsburghUniversity of PittsburghConsulting Audiologists,National Center for HearingAssessment and Management
2 CONGENITAL CYTOMEGALOVIRUS INFECTION Most common congenital infection in humansNewborn morbidity/mortality + late sequelae – hearing loss, mental retardation, cerebral palsy, impaired visionLeading cause of non-hereditary sensorineural hearing loss in childrenLeading infectious cause of brain damage in US childrenPass, 1999
3 CLINICAL IMPACT OF CONGENITAL CMV INFECTION for SX and ASX Frequency of sequelaeSymptomatic (7%) Asymptomatic (93%)Infant death %Hearing loss % –15%Mental retardation 45% –10%Cerebral palsy 35% <1%Chorioretinitis 15% –2%
4 ISSUES BEING ADDRESSED Maternal screening and prenatal diagnosisNewborn diagnosis and screeningAntiviral treatment of the newbornPrevention of maternal and congenital CMV infectionManagement of sequelae
5 ANNUAL CONGENITAL CMV INFECTION Range – .5 % to 1.5 %Average – 1 %With annual birthrate of 4 million40,000 US children born with infection annually
6 DIAGNOSISIsolation of CMV from the urine or saliva of the neonate within first three weeks of lifePresence of CMV IgM from the blood of the neonateDetection of Cytomegalic Inclusion Bodies from affected tissue (rarely used)
7 SOURCES OF INFECTION Transplacental Intrapartum Breast milk Nosocomial/transfusion
8 TYPES OF CONGENITAL CMV INFECTION Symptomatic 5-10 %Asymptomatic – %Primary – First time infectionRecurrent – Reactivation of infection, seropositive before pregnancy
9 CHARACTERISTICS OF CONGENITAL SYMPTOMATIC CMV INFECTION HepatosplenomegalyMicrocephalyThrombocytopeniaPetechiaeJaundice with conjugated hyperbilirubinemia
11 SEQUELAE OF ASYIMPTOMATIC CONGENITAL CMV INFECTION Hearing lossChorioretinitisSeizures
12 PRIMARY MATERNAL CMV INFECTION DURING PREGNANCY 95% clinically inapparent35% transmitted to fetusNo clear relationship between gestational age and transmissionFetal damage more likely in first 26 weeks, (32%) than later (15%)
13 HIGH RISK FOR PRIMARY MATERNAL AND CONGENITAL CMV INFECTION Teen mothersExposure to young children:day-care workersmothersSexual activity
14 RECURRENT CMV INFECTION Can cause symptomatic infection in infantsCan cause similar sequelae to primary infection
15 CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAE Primary maternal infectionSymptomatic congenital CMV infectionPresence of neonatal neurological abnormalitiesAbnormal head CT scanChorioretinitis in the newbornPass, 1999
21 Sudden Delayed Onset Hearing Loss at Six Years Secondary to SX CMV
22 HEARING LOSS IN CHILDREN WITH CONGENITAL CMV INFECTION Longitudinal study-- 24 yearsFirst hearing article published in 1977Ss identified 1st week of lifeAge at time of audiologic evaluation: 1 month to 19 yrs; mean age of 5 yrsAudiologic evaluations every 3 months in 1st year, every 6 months until yrs and yearly thereafterDahle et al. 2000
23 HEARING LOSS AND CMV EARLY STUDIES Texas study: 17 symptomatic children; mean age of outcome 5.5 years11/17 (64%) had hearing loss (1 unilateral)3/11 (27%) progressive hearing loss1980
24 AUDIOLOGICAL PROTOCOL ABR (chloral hydrate) : Click, TB of 500 & 4000 HZ until 9 monthAir and bone conduction if AC>25 dBnHLImmittanceVRA after 5 months until 2.5 to three yearsDahle, et al, 2000
25 PROJECT PROTOCOL CMV Isolated from urine during first 3 weeks of life Interdisciplinary assessmentAudiologyDentalLaboratoryNeurologyOptometryPediatricsPsychology
26 CMV STUDY POPULATION Dahle et al, 2000 CATEGORYNSN HLControls201ASX CMV65148SX CMV20985TOTAL860133
28 FLUCTUATING LOSSESExpect higher percentage in the asymptomatic group at 2K Hz, both groups were similar with respect to frequencies and amount of change250 and 500 Hz the least stable4000 Hz most stableNote: more hearing improvements at 250 and 500 Hz alsoDahle et al, 2000
29 AULDIOMETRIC CONFIGURATION Audiometric patternFlat (largest % in both groups)Upward sloping (symptomatic)Downward sloping (asymptomatic)Upward and downward slopingFlat losses accounted for 39% in Asymptomatic group and 56% in symptomatic groupSloping configurations in Asymptomatic group ~29% downward; symptomatic ~25% had upward slopingDahle et al, 2000
30 HEARING LOSS RESULTING FROM CONGENITAL CMV INFECTION 4 Million - Annual Birth Rate1 Percent - Average CMV Infection Rate40, Children Infected4,000 -Symptomatic CMV (40.7% with HI)36,000 -Asymptomatic CMV( 7.4 % with HI)4,292 -Children born annually with/develop HI from CMV3/1, Hearing loss in newborn population% of hearing loss due to CMVAdapted from Dahle et al, 2000
31 Treatment of Sudden onset or Progressive Hearing Loss Immunosuppressant DrugsDexamethazoneSide effects in childrenAntiviral DrugsDoes not cure virus but stops viral replicationWhen drug is stopped, virus may start replication again
32 USE OF GANCICLOVIR IN NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION Pro-Antiviral effectMight prevent death or improve newborn diseaseNo other optionsCon-Most damage done prior to birthLimited antiviral effectPotential reproductive toxicityPotential ‘rebound’ retinitis or other diseaseLack of evidence of efficacyPass, 1999
33 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/weekHigher, but not lower dose, cleared viruriaAbnormal liver and haematologic function appeared to clear faster with higher doseAlthough outcome appeared better with higher dose, CNS sequelae appeared in both groupsfrom Nigro et al, J Pediatr 1994; 124: 318
34 A PHASE II STUDY OF GANCICLOVIR IN 47 NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION Patients with CNS disease treated with 8mg/kg/d or 12mg/kg/d iv for 6 weeks19 % of participants had neutropenia requiring dose modification12 mg/kg reduced viral shedding; shedding returned when drug was discontinued3 patients had improved hearing at 6 months; 25 had abnormal hearingfrom Whitley et al, J Infect Dis, 1997; 175: 1080
35 GANCICLOVIR Kimberlin et al. 2003 Multi-center randomized, controlled trialSs: 100 symptomatic neonates6 weeks ganciclovir (6mg/kg q12h)Outcome: BSER42 Ss used in analysisUrine specimen in 1st monthEvidence of cns disease: microcephaly, intracranial calcificationsAbnormal cerebral-spinal fluid for ageChoriorentinitis and/or HLGanciclovir; 6 mg/kg q 12 hrs for 6 weeksEndpoint: BSER improvement of by one gradation i.e. moderate to mildBSER at entry, 6 wks, 6 mos, 1 yr and 2 yr1-20, 21-45, and >70 severe evaluated by best ear and by both earsRandom assignment no drug or ganciclovir
36 GANCICLOVIR Kimberlin et al. 2003 Best earTotal earGanciclovir (n=25)No treatment (n=17)Ganciclovir (n=49)No treatment (n=36)Improved6 (24%)5 (29%)11 (22%)6 (17%)No change-normal15 (60%)23 (47%)8 (22%)No change –HL4 (16%)0 (0%)15 (31%)A7 (19%)Worse7 (41%)15 (42%)Urine specimen in 1st monthEvidence of cns disease: microcephaly, intracranial calcificationsAbnormal cerebral-spinal fluid for ageChoriorentinitis and/or HLSs not used were children who did not meet entry criteria or did not have adequate BSER testing6 month data
38 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”
39 GANCICLOVIR Michaels et al. 2003 Ss: 9 childrenLong term ganciclovir treatment (10mg/kg/day, 2-4 wks; 5mg/kg/day~ 12 months)4/9 normal—normal5 no progression2 ears with improvementTreatment of 10 mg/kg/day for 2-4 weeks then IV, 5 mg.kg/d lasting median time of 12 months ,Age of time of testing was 1-7 years with median of 2 years.
40 DURATION OF CMV EXCRETION AND HEARING LOSS Noyola et al. 2000 70 children; 58 ASXSNHL and progressive SHNL were significantly more likely to occur in short duration CMV excretion regardless of symptomsExcretion< 4 year> 4 yearPSNHL15 (43%)6 (17%)0.019Pro SNHL12 (34%)3 (8.5%)0.009104 children (born ) 85 (81.7%) ACMV and 19 (18.3%) SCMV27 ACMV and 7 SCMV (34) excluded b/c not enough urine culture to document so 70 left with 58 ACMV and 12 SCMVSS divided into <4 and >4 years duration hearing loss at age 6The significant difference persisted after multiple logistic regression analysis including whether the patient had ACMV or SCMV and duration of excretion in relation to the presence or progression of SNHL Possible explanation for more SNHL in children with shorter duration CMV may be due to host immune response –decreed replication of CMV—might be associated with progressive damage to inner ear. –Studies looking at cellular immunity and development of SNHL were not being done at that time but there was a case report of improvement in hearing loss after administration of agent that alter host immune response i.e. steroids and histamines.
41 PREDICTORS OF NEURODEVELOPMENTAL OUTCOME Noyola et al. 2001 41 symptomatic children17 (41.5%) had SNHL –congenital11 (26%) had late onset of SNHLSNHL group had lower IQ/DQ score, more motor difficulties and more abnormal head CT
42 PREDICTORS Rivera et al. 2002 180 symptomatic infants enrolled and followed over 30 yr period65% referred from other health care providers outside of UAB virology screening programMedian age of last hearing test: 5.75 yrsMedian # of hearing evaluations: 8209 children –190 enrolled in prospective study, 180 followed, 6 died and 6 lost to f/u; 14/19 not enrolled died during infancySymptomatic: petechiae, jandice (defined) hepatosplenomegaly, microcepaly, seizures, chorioretinitis16 received ganciclovir but kept in the180 symptomatic children followed prospectively. Although 16 received gancyclovir, they we included since no significant statistical difference was obtained when dropped from analysis. No demographic differences between those with and those without hearing loss but there were demographic differences between those referred and those born at UAB. Referral group; born mainly to white (73%), married women (68%) with private insurance (54%) and with more symptoms as compared to the UAB born infants to mothers who were mainly black(75%), single (66%) and medicaid insurance or uninsured (83%).
43 PREDICTORS cont. Rivera 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 lossAudiological eval: q 6 months to 24 months; annually thereafter, >25 on ABR, >20 behaviorally
44 PREDICTORS cont. Rivera et al. 2002 CharacteristicIUGROR (95% CI)2.2 ( )Petechiae3.1 ( )Hepatosplenomegaly**2.0 ( )Univariate analysis**After adjusting based on regression analyses, hepatosplenomegaly wasnot shown to be an independents predictor of hearing loss.
45 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 needed180 symptomatic children followed prospectively. Although 16 received gancyclovir, they we included since no significant statistical difference was obtained when dropped from analysis. They recommend that all children with symptomatic congenital CMV infection, not just those with neurologic abnormalities at birth, be monitored closely for the development of hearing loss. The results of this study also suggest that the pathogenic mechanisms that contribute to the development of HO in children with symptomatic congenital CMV are different from those that lead to cognitive and motor deficits. That CNS disease at birth ahs no predictive value for hearing loss in the study suggests that future studies of antiviral therapy for symptomatic CMV should include children with disseminated disease regardless of whether that have CNS involvement.
46 WHAT WE KNOWLeading (nongenetic) cause of sensorineural hearing loss in childrenAccounting for approximately 1/3 of sensorineural hearing loss in young childrenFrequent late onset hearing lossFrequent progression of hearing lossFrequent fluctuating hearing lossMajority of children with congenital cmv infection never identified
47 MEDICAL MANAGEMENTPrimary 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
48 POSSIBLE FACTORS IIN CMV EAR DAMAGE WITH CHRONIC INFECTION Persistent low grade viral replication in affected organsReactivation of latent virusVasculitisImmune Complex formationCMV specific defect in cell-mediated immunityDarmstadt, Keithley and Harris, l990
49 CMV MANAGEMENT CONCERNS Frequency of viral reactivationFrequency of monitoringProtocol for medical treatmentSide effects of drugsNeed for long term treatmentLong term subject complianceEmotional needs of parent and child
50 VIGILANT SURVEILLANCE REQUIRED 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
51 MONITORING FOR BEHAVIORAL CHANGES SUGGESTING PROGRESSIVE HEARING LOSS WithdrawalActing out behaviorsUncharacteristic irritabilityInability to understand speech in noiseDifficulty localizing soundPreference for increased volume settingChanges in acoustic characteristics of speechComplaints of broken amplification
52 AUDIOLOGICAL MANAGEMENT Frequent audiological monitoringHearing aids with power and frequency response flexibilityTraining in communication methods that accommodate changing hearing levels
53 AUDIOLOGIC MONITORING OBJECTIVES Behavioral audiometric evaluationsAdjustment of amplificationPeriodic electroacoustic evaluationsListening checksCheck ear mold fitPeriodic probe mic measurementsMonitor functional development of auditory skills
54 MANAGEMENT OF INTERVENTION FOR HEARING LOSS Interdisciplinary assessment to identify any additional conditionsEarly intervention program referralTraining to empower child/parent to optimize learning opportunitiesParent training about federal legislation/state/local regulations developed to address needs of children with disabilities
55 GUIDELINES FOR EDUCATIONAL MANAGEMENT Frequent monitoring of hearing and visionFrequent monitoring of academic performanceFlexibility in placement and resource servicesIn-service training regarding CMVInfection control plan
56 WHAT WE DON’T KNOWWhat causes progressive and delayed onset hearing lossWhat is the role of newborn hearing screening in relation to detection of CMV infectionWhat causes the hearing loss and what factors predispose some infants to hearing loss.