1. CHIMES STUDY: CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING MULTICENTER SCREENING STUDY
Karen Fowler, DrPH
University of Alabama
in Birmingham
Faye P. McCollister, EdD
University of Alabama, Emeritus
Diane Sabo, PhD
University of Pittsburgh

2. Confusion Regarding Congenital CMV Infection & Hearing Loss
Studies/Reports of etiology of pediatric hearing loss seldom include routine screening for congenital CMV infection
Most congenital CMV infection is asymptomatic (90%)
No profile for audiometric configuration is available
Hearing may be normal; loss may be unilateral or bilateral; present at birth or delayed in onset; may be fluctuating and/or may be progressive

3. Review of Congenital CMV Infection
Common virus although not easily spread person to person
Diagnosis needs to be made in the first 3 weeks of life
Clinical observation of infection in the newborn period identifies < 5% of all infants with congenital CMV infection
Delayed onset sequelae may occur over a long period with sensorineural hearing loss being the most common

4. Review of Congenital CMV and Hearing Loss Research
1960s - CID/symptomatic CMV infection and hearing loss first reported. Medearis, l964; McCracken, et al. 1969
1970s - inapparent / asymptomatic CMV infection and HL was first reported. Reynolds, et al. 1974; Dahle, et al. 1974; Hanshaw, et al. 1976; Stagno, et al. 1977
1970s & 1980s, progression and delayed onset HL first described. Dahle, et al, 1979; Williamson et al. 1982
3.9% at birth will have hearing loss; 8.3% at 6 yrs
Symptomatic infection – 16.5% HL at birth; 36.4% at 6 yrs
Asymptomatic infection – 2.9% HL at birth; 11.3% at 6 yrs

5. NIH/NIDCD Contract
The Natural History of CMV-Related Hearing Loss and the Feasibility of CMV Screening as Adjunct to Hearing in the Newborn

6. CHIMES Study

7. NIDCD CMV Grant, UAB Multi-site investigation, 7 sites
100,000 newborns to be screened for congenital CMV infection
Link newborn hearing results
Evaluate methods for CMV screening
Saliva vs. dried blood spots (DBS)
Audiological follow up of CMV positive infants for 4 years

8. Project Design
Screen at least 100,000 newborns for CMV infection who currently undergo newborn hearing screening
Audiological follow-up of all CMV positive infants
Compare the accuracy of two diagnostic methods for CMV screening (traditional rapid saliva cell culture vs. real time PCR on DBS)

9. Objectives
Define the long-term audiologic/otologic outcome in children with congenital CMV infection
Determine the clinical validity and utility of CMV screening:
in the detection of hearing impairment in the newborn
in the prediction of hearing impairment with onset during infancy or in the early years of life

10. Project Staff
The project is directed by Drs. Suresh Bopanna & Karen Fowler
Each site will have a person designated as a co-principal investigator
Site audiologists direct audiological assessments
Project consultants: Faye McCollister, Judy Gravel, Karl White

11. Site Audiologists Julie Woodruff Birmingham, AL
Belinda Blackstone Birmingham, AL
William Mustain Jackson, MS
Marci Schwab New Brunswick, NJ
Edie Cox Charlotte, NC
David Brown Cincinnati, OH
Dan Choo Cincinnati, OH
John Greinwald Cincinnati, OH
Diane Sabo Pittsburgh, PA
Angela Shoup Dallas, TX
Kris Owen Dallas, TX

12. Participating Hospitals
Birmingham, AL
University Hospital & Cooper Green Hospital
Jackson, MS
University of Mississippi Medical Center
New Brunswick, NJ
Saint Peters University Hospital
Charlotte, NC
Carolinas Medical Center
Cincinnati, OH
Good Samaritan Hospital
Pittsburgh, PA
Magee Women’s Hospital
Dallas, TX
Parkland Memorial Hospital

13. Selected Hospital Populations
38% Caucasian, Non Hispanic
34% Caucasian, Hispanic
24% African American
4% Asian

14. Challenges to the CHIMES Study (1)
Establishing consistency in protocols across 7 sites, getting everyone on the same page
Challenges inherent in longitudinal investigation: 6 year period of study, equipment changes, staff changes, protocol changes
Age of subjects, birth through age 4 years, more difficult to evaluate audiologically
Multiple disabilities, including developmental, vision, and motor for children with symptomatic infection

15. Challenges to the CHIMES Study (2)
Variability of hearing loss: progression, delay in onset, and fluctuation
Subject ethnic background with language differences, cultural differences, social differences
Otitis media resulting in conductive overlay for sn hearing loss, delay in getting assessment data
Subject compliance with study protocol
Subject retention

16. Challenges to the CHIMES Study (3)
Specified protocol modified to accommodate clinical needs with rapidly progressive hearing loss
Accuracy/consistency in data collection, recording, transfer, and storage
Interpretation of data and clinical judgment
Ensuring client confidentiality

17. Addressing the Challenges to the CHIMES Study
Standardized collection of data: developed data forms using barcoded labels with unique study identifier for all data sent from 7 sites (scanned and processed)
Developed detailed Manual of Procedures (MOP) for study policies and procedures
Developed audiology protocols establishing optimal and minimal goals for audiology data at visits
Site Visits and Review of protocols
Detailed retention plan with computerized database at each site and data forms (Visit Forms & Missed Visit Forms) to collect information on amount of contact each site had with a study participant during the intervals between visits

18. Addressing the Challenges to the CHIMES Study

20. Subject Variables Additional Disabilities (symptomatic infection)
Vision
Can not see visual reinforcers
Can not process visual instructions
Need glasses for assessment, if prescribed
Seizure disorder
Flicker stimulation with lighted reinforcer
Absence, petit mal, and grand mal seizures

21. Cultural Diversity
Racial, cultural, socioeconomic differences exist among individuals from same country
Interpreters may have difficulty explaining medical / technical information
May be difficult for family to understand
will not qualify for public assistance medical and technical services (hearing aids)
finding financial assistance challenging, at best

22. Cultural Diversity
Project informational materials will be provided in English and Spanish for parents and at understandable reading levels.
Communication options chosen by families for their child will be respected and supported.

23. CHIMES STUDY Audiological Assessment Protocol Diane Sabo, PhD
University of Pittsburgh

24. Components of Study Audiological Assessment
ABR tone bursts, bone conduction,
Otoacoustic emissions, (DPs)
Immittance with high frequency probe for subjects less than 7 months of age, only when conductive involvement needs greater definition
Behavioral assessment
VRA
Play

25. Screening Data Obtained
Physiologic data
ABR
Automated-ABR
OAEs
Automated OAEs
Combinations of the tests

26. Objective Hearing Diagnostic Methods
Auditory Brainstem Response (ABR)
Tone Bursts –air and bone conduction
Auditory Steady State Response (ASSR) not required, optional
Acoustic Immittance
Evoked Otoacoustic Emissions (EOAEs)
Distortion Product OAEs (DPOAEs)

27. Entry or Baseline Data Physiologic tests ABR
Tone bursts at .5, 1, 2 and 4k Hz
Bone conduction if air conduction abnormal (>25)
DPOAEs
2-8k Hz
60/45
Signal and noise levels recorded

28. Physiologic Assessment with ABR and EOAEs
Advantages
“Objective”
Reliable
Correlate well with hearing
Age not a factor (but sometimes an issue)

29. Physiologic Assessment with ABR and EOAEs
Limitations
Not completely “objective”
Not tests of hearing
Not always good at predicting threshold
Not independent of infant’s behavior, state, or other factors

30. Click Spectrum
Frequency
Frequency

31. Comparison of Frequency Range for ABR Clicks and Tone Bursts

33. What We Know About ABR Clicks
Click commonly used, but……can give misleading information
Click has energy at all frequencies transduced by earphone
Within limits, regions of normal hearing will generate ABR, even with regions of hearing loss
ABR tests avoid problems associated with reverse middle ear transmission, but potential still exists for missing hearing loss with click-evoked ABR

34. Progressive HL Secondary to SX CMV in Six Month Period

35. ABR Assessment at Enrollment Visit
Enrollment visit at 3-6 weeks of age
Objective is to obtain valid/accurate estimates of ear specific, frequency specific hearing thresholds for each ear and to characterize the type of any permanent loss present as baseline information
Case history/parent observation report
Otoscopic inspection
DPOAE
Medical referral if testing deferred because of otologic problems

36. Physiologic Assessment with ABR and EOAEs
Advantages
“Objective”
Reliable
Correlate well with hearing
Age not a factor (but sometimes an issue)

37. Optimal Goal for ABR Assessment at Enrollment Visit (3-6 Weeks)
ABR minimum response levels at .5, 1.0, 2.0, and 4.0 kHz for each ear
DPOAE information at five frequency bands centered at 2,3,4,6, and 8
Bone conduction, tympanometry, and ipsilateral reflexes may be required if loss suspected
Record on ABR data form CF107
Record on OAE data form
Record on immittance data form CF110

38. Minimal Goal for ABR Assessment at Enrollment Visit at 3-6 Weeks of Age
Due to the importance of obtaining baseline information that is a clear and accurate reflection of infant’s hearing level a minimum goal was set:
Obtain MRL at 0.5, 2.0, and 4.0 kHz for each ear
Bone conduction, tympanometry, and ipsilateral acoustic reflexes may be necessary if loss is suspected
If additional assessment apt necessary, use sequence system of 1,2, and 3 on forms for enrollment visit
Prolonged delays between assessments avoided if possible

39. ABR Protocol Order for tone bursts: 2000, 4000, 500 and 1000
Use for 500 Hz
Use for
Rate 27-29
Filter setting of
Two replications
<1000 sweeps for 2.0 and 4.0
No less than 2000 sweeps for 0.5 and 1.0 kHz

40. ABR Parameters 15-20 msec window
At least two replications at no response level and next level up, using a 10dB step above the last response level; threshold determination is midpoint between these two levels
Electrode configuration of high forehead to earlobe, with low forehead as ground; assuming a two channel recording
Insert earphones

41. Entry Data Acoustic Immittance Data Tympanometry
High frequency tymps (1k) < 7 months
Acoustic reflex thresholds
IPSI 1k only, if necessary

42. Use Insert Earphones
Separation of stimulus artifact from the onset of the response makes wave I more visible
Prevent ear canal collapse
Increase interaural attenuation
Provide greater comfort for long periods of time
Can attenuate surrounding environmental noise more efficiently
Absolute latencies delayed by 0.9ms
Affect amplitude of wave I, lower

43. CHIMES STUDY Faye P. McCollister, EdD University of Alabama, Emeritus
Behavioral Audiological
Assessment Protocols

44. Request Parental Help in Preparing for Behavioral Diagnostic Assessment
Try to have child rested and feed, comfortable and attentive for test
Schedule appointment away from nap time
Bring diapers for diaper change
Bring bottle for comforting
Bring pacifier, if used
Bring familiar car seat for test

45. Manage Baby/Mom/Diagnostic Environment
Quietest environment possible, no talking, no noisy toys
Reduce undesirable visual, auditory, tactile distractions
calm, alert child preferred, but not after heavy feeding, will fall asleep
Do not separate child from parent and create crying, agitated child
Wait for child to calm prior to initiating test

46. Child/Parent Handling Issues
Child State
Activity level
Comfort level
Infection control
Clinic protocol
Gloves, disposables, cross contamination
Parent inclusion
Pre-test information sharing
Time during testing
Time spent informing about procedure
Informing about the results

47. Visual Reinforcement Audiometry
Developmentally appropriate technique that gives valid estimate of hearing
Gives ear specific, frequency specific information
Reliable method for early years
Practical for repeat use

48. Schedule for Behavioral Audiological Assessment
Visual Reinforcement Audiometry scheduled at 7,12, 18, and 24 month follow-up visits
Play Audiometry scheduled
at 24, 30, 36, 42, and 42 month follow-up visit

49. VRA Assessment Information
Beginning stimulus type
warble tone, speech
Beginning transducer
earphone, speaker
# beginning conditioning trials
# reconditioning trials
# stimulus trials
# control trials, if greater than 0, # correct

50. VRA Assessment Information
Test time
Number of breaks taken
DPs completed, 2,3,4,6,and 8
Acoustic Immittance Measures Done?
Acoustic reflex threshold
tympanometry
Follow up/ reschedule, no, yes- mark reason
Fussy scared, wax occluding canal, time, refused earphones/inserts, habituated, test reliability poor, failed to condition, mrl > 20, cnd if sn loss present, other- specify
Medical Follow-up Recommended- yes, no- mark reason
Conductive component, tymps abnormal, ab gap, draining ear, hearing aid clearance

51. Visual Reinforcement Audiometry
Affix study id label, site initials, al, ms, nj, nc, oh, pa, tx
Record ideal visit month according to protocol
Record sequence number, 1 for first test in ideal month sequence, sequence number of repeat assessments required to obtain complete assessment data
Was VRA testing done
Date of assessment
Minimal threshold level for each frequency
Lowest threshold level
999 frequency not tested
555 could not determine
888 tested, but no response

52. VRA at Follow Up Visits at 8, 12, 18, and 24 Months of Age
Optimal goal: obtain pure tone minimum response level of 15 dB HL at 0.5, 1.0, 2.0, and 4.0 kHz
If MRLs elevated above 20 dB HL, tymps and/or bc will be needed to distinguish between sn, cond. Or mixed loss
Record VRA data on CF108
If immittance is administered, record data on CF110
Minimal goal: Obtain MRLs at 0.5, 2.0, and 4.0 kHz
If MRLs elevated above 20 dB HL, administer tymps and/or bc
If MRLs for Minimal goal can not be obtained, schedule up to 3 additional visits and report any valid data collected using sequenced numbered data forms: visit 1, 2, or 3, for 8 month data

53. Visual Reinforcement Audiometry
Optional, 8000 hz and speech awareness threshold, record if obtained
Bc not required, leave field blank

54. VRA Protocol (Widen) Pulsed, FM Tones, 1-2 sec. Duration, LV speech
at 35 dB unconditioned, 2 responses naturally go to test protocol
35 dB no response, go to 55 dB
If no response, go to conditioning at higher level
Training - pair the reinforcer with stimulus at 55 dB, 2 chances then go to probe with reinforcement presented with correct head turn response, do second correct probe trial, then TEST
If training does not work at 55 dB, go to 75 dB and repeat process
Use down 20 dB, up 10 dB in TEST mode in first reversal, then down 10 up 5 thereafter
Next frequency, begin at level of previous response
MRL – lowest level with 2 responses out of 3

55. Ensuring Stimulus Control For Behavioral Responses
Control trials - observation intervals in which no stimulus was present, but examiner notes head turn behavior and no reinforcement provided to ensure head turn linked to stimulus presentation (inserted at a rate of 25%) >30%, test validity ???
Probe trials - stimulus presentations at suprathreshold levels used to confirm conditioning at beginning and throughout session

56. When Child Does Not Condition
Change ear
Change stimulus type- another frequency or speech
Mode of presentation change – sound field
Change reinforcer, strength of video reinforcer not strong enough
Take a 10 minute break

57. Play Audiometry Data Form
Complete at 24, 30, 36, 42, and 48 month follow up visits
Complete Header
Affix study id label, complete site id with state initials
Was testing done- yes, no give reason,
Parental refusal, late for apt, missed slot, uncooperative, would not participate
Date of audiology evaluation – mm/dd/yy
Minimal threshold level, enter lowest threshold for each freq. for each ear.
Could not test, enter 555
Was not tested, enter 999
Was tested, no response , enter 888

58. Play Audiometry Data Form (2)
Optional – if 12 kHz or speech recognition threshold (SRT) were obtained, enter otherwise, leave blank
Primary Language of household
Dps completed
Acoustic immittance measures completed
Follow up/reschedule, specify reason
Medical follow up recommended, specify reason

59. Looks Good, But…….
Visual alerting by examiner can give normal audiogram for child who is deaf
Results may look confusing,
but be accurate, evaluate carefully
Hearing is dynamic, does not
necessarily stay the same, be
alert to progression
Use all sources of information

62. Contact the CHIMES Study
Karen Fowler