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CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS

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.

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CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING LOSS

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  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 10% 0 Hearing loss 60% 7–15% Mental retardation 45% 2–10% Cerebral palsy 35% <1% Chorioretinitis 15% 1–2%

  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 – 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

  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 2.5-3 yrs and yearly thereafter Dahle et al. 2000

  23. HEARING LOSS AND CMVEARLY 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

  27. 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 • 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. 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 USE OF GANCICLOVIR IN NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION 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,JPediatr 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,JInfect 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 6 month data

  37. GANCICLOVIR Kimberlin et al. 2003 12 month data

  38. GANCICLOVIRKimberlin 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

  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

  41. PREDICTORS OF NEURODEVELOPMENTAL OUTCOMENoyola 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. PREDICTORSRivera 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

  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

  44. PREDICTORS cont.Rivera et al. 2002 **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

  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

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