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CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS

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Presentation on theme: "CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS"— Presentation transcript:

1 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

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 death % Hearing loss % –15% Mental retardation 45% –10% Cerebral palsy 35% <1% Chorioretinitis 15% –2%

4 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 Transplacental Intrapartum Breast milk
Nosocomial/transfusion

8 TYPES OF CONGENITAL CMV INFECTION
Symptomatic 5-10 % Asymptomatic – % 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

11 SEQUELAE OF ASYIMPTOMATIC CONGENITAL CMV INFECTION
Hearing loss Chorioretinitis Seizures

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
Primary maternal infection Symptomatic congenital CMV infection Presence of neonatal neurological abnormalities Abnormal head CT scan Chorioretinitis in the newborn Pass, 1999

16 CHORIORETINITIS

17 DENTAL ABNORMALITIES

18 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 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 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 1980

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
CATEGORY N SN HL Controls 201 ASX CMV 651 48 SX CMV 209 85 TOTAL 860 133

27 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 23(27.1%) Age Range mo 6-197 mo Progressive 26(54.2%) 46(54.1%) 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 Flat losses accounted for 39% in Asymptomatic group and 56% in symptomatic group Sloping configurations in Asymptomatic group ~29% downward; symptomatic ~25% had upward sloping Dahle et al, 2000

30 HEARING LOSS RESULTING FROM CONGENITAL CMV INFECTION
4 Million - Annual Birth Rate 1 Percent - Average CMV Infection Rate 40, 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, Hearing loss in newborn population % 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 Urine specimen in 1st month Evidence of cns disease: microcephaly, intracranial calcifications Abnormal cerebral-spinal fluid for age Choriorentinitis and/or HL Ganciclovir; 6 mg/kg q 12 hrs for 6 weeks Endpoint: BSER improvement of by one gradation i.e. moderate to mild BSER at entry, 6 wks, 6 mos, 1 yr and 2 yr 1-20, 21-45, and >70 severe evaluated by best ear and by both ears Random assignment no drug or ganciclovir

36 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 change-normal 15 (60%) 23 (47%) 8 (22%) No change –HL 4 (16%) 0 (0%) 15 (31%)A 7 (19%) Worse 7 (41%) 15 (42%) Urine specimen in 1st month Evidence of cns disease: microcephaly, intracranial calcifications Abnormal cerebral-spinal fluid for age Choriorentinitis and/or HL Ss not used were children who did not meet entry criteria or did not have adequate BSER testing 6 month data

37 GANCICLOVIR Kimberlin et al. 2003
Best ear Total ear Ganciclovir (n=24) No treat (n=19) Ganciclovir (n=48) (n=36) Improved 4 (17%) 0 (0%) 12 (25%) 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

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 normal—normal 5 no progression 2 ears with improvement Treatment 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 ASX SNHL and progressive SHNL were significantly more likely to occur in short duration CMV excretion regardless of symptoms Excretion < 4 year > 4 year P SNHL 15 (43%) 6 (17%) 0.019 Pro SNHL 12 (34%) 3 (8.5%) 0.009 104 children (born ) 85 (81.7%) ACMV and 19 (18.3%) SCMV 27 ACMV and 7 SCMV (34) excluded b/c not enough urine culture to document so 70 left with 58 ACMV and 12 SCMV SS divided into <4 and >4 years duration hearing loss at age 6 The 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 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 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: 8 209 children –190 enrolled in prospective study, 180 followed, 6 died and 6 lost to f/u; 14/19 not enrolled died during infancy Symptomatic: petechiae, jandice (defined) hepatosplenomegaly, microcepaly, seizures, chorioretinitis 16 received ganciclovir but kept in the 180 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 up 61/87 (70%) had hearing loss at birth 26/87 (30%) had delayed onset 55/87 (63%) had progression of hearing loss Audiological eval: q 6 months to 24 months; annually thereafter, >25 on ABR, >20 behaviorally

44 PREDICTORS cont. Rivera et al. 2002
Characteristic IUGR OR (95% CI) 2.2 ( ) Petechiae 3.1 ( ) Hepatosplenomegaly** 2.0 ( ) Univariate analysis **After adjusting based on regression analyses, hepatosplenomegaly was not 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 needed 180 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 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 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.

57 The End


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