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CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS Faye P. McCollister, EdD University of Alabama, Emeritus Diane L. Sabo, PhD Childrens Hospital of.

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Presentation on theme: "CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS Faye P. McCollister, EdD University of Alabama, Emeritus Diane L. Sabo, PhD Childrens Hospital of."— Presentation transcript:

1 CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS Faye P. McCollister, EdD University of Alabama, Emeritus Diane L. Sabo, PhD Childrens Hospital of Pittsburgh University of Pittsburgh Consulting Audiologists, National Center for Hearing Assessment and Management

2 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

3 CLINICAL IMPACT OF CONGENITAL CMV INFECTION for SX and ASX Frequency of sequelae Symptomatic (7%)Asymptomatic (93%) Infant death10%0 Hearing loss60%7 – 15% Mental retardation45%2 – 10% Cerebral palsy35%<1% Chorioretinitis15% 1 – 2%

4 ISSUES BEING ADDRESSED 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

5 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

6 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)

7 SOURCES OF INFECTION SOURCES OF INFECTION Transplacental Intrapartum Breast milk Nosocomial/transfusion

8 TYPES OF CONGENITAL CMV INFECTION Symptomatic 5-10 % Asymptomatic – 90-95 % Primary – First time infection Recurrent – Reactivation of infection, seropositive before pregnancy

9 CHARACTERISTICS OF CONGENITAL SYMPTOMATIC CMV INFECTION Hepatosplenomegaly Microcephaly Thrombocytopenia Petechiae Jaundice with conjugated hyperbilirubinemia

10 SEQUELAE OF SYMPTOMATIC CONGENITAL CMV INFECTION Seizures Chorioretinitis Periventricular calcifications Sensorineural hearing loss motor deficits


12 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%)

13 HIGH RISK FOR PRIMARY MATERNAL AND CONGENITAL CMV INFECTION Teen mothers Exposure to young children: – day-care workers – mothers Sexual activity

14 RECURRENT CMV INFECTION Can cause symptomatic infection in infants Can cause similar sequelae to primary infection

15 CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAE 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



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

19 CMV Case Study (2)

20 CMV Case Study (3)

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 years First hearing article published in 1977 Ss identified 1 st 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 1 st year, every 6 months until 2.5-3 yrs and yearly thereafter Dahle et al. 2000

23 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

24 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

25 PROJECT PROTOCOL CMV Isolated from urine during first 3 weeks of life Interdisciplinary assessment Audiology Dental Laboratory Neurology Optometry Pediatrics Psychology

26 CMV STUDY POPULATION Dahle et al, 2000 CATEGORYNSN HL Controls2010 ASX CMV65148 SX CMV20985 TOTAL860133

27 AsymptomaticSymptomatic 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 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

28 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

29 AULDIOMETRIC CONFIGURATION Audiometric pattern Flat (largest % in both groups) Upward sloping (symptomatic) Downward sloping (asymptomatic) Upward and downward sloping Dahle et al, 2000

30 HEARING LOSS RESULTING FROM CONGENITAL CMV INFECTION HEARING LOSS RESULTING FROM CONGENITAL CMV INFECTION 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

31 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

32 USE OF GANCICLOVIR IN NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV 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

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/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

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 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

35 GANCICLOVIR Kimberlin 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

36 GANCICLOVIR Kimberlin et al. 2003 Best earTotal ear Ganciclovir (n=25) No treatment (n=17) Ganciclovir (n=49) No treatment (n=36) Improved6 (24%)5 (29%)11 (22%)6 (17%) No change- normal 15 (60%)5 (29%)23 (47%)8 (22%) No change –HL4 (16%)0 (0%)15 (31%)A7 (19%) Worse0 (0%)7 (41%)0 (0%)15 (42%) 6 month data

37 GANCICLOVIR Kimberlin et al. 2003 Best earTotal ear Ganciclovir (n=24) No treat (n=19) Ganciclovir (n=48) No treat (n=36) Improved4 (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%) Worse5 (21%)13 (68%)10 (21%)22 (61%) 12 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 children Long term ganciclovir treatment (10mg/kg/day, 2- 4 wks; 5mg/kg/day~ 12 months) 4/9 normalnormal 5 no progression 2 ears with improvement

40 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 SNHL15 (43%)6 (17%)0.019 Pro SNHL12 (34%)3 (8.5%)0.009

41 PREDICTORS OF NEURODEVELOPMENTAL OUTCOME Noyola 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

42 180 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 Rivera et al. 2002

43 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

44 Characteristic IUGR OR (95% CI) 2.2 (1.1-4.1) Petechiae3.1 (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.

45 Symptomatic infants with disseminated CMV at birthas 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. Rivera et al. 2002

46 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

47 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

48 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

49 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

50 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

51 MONITORING FOR BEHAVIORAL CHANGES SUGGESTING PROGRESSIVE 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

52 AUDIOLOGICAL MANAGEMENT Frequent audiological monitoring Hearing aids with power and frequency response flexibility Training in communication methods that accommodate changing hearing levels

53 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

54 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

55 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

56 WHAT WE DONT 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.

57 The End

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