CHIMES STUDY: CONGENITAL CYTOMEGALOVIRUS INFECTION AND HEARING MULTICENTER SCREENING STUDY Karen Fowler, DrPH University of Alabama in Birmingham Faye.

CHIMES STUDY: CONGENITAL CHIMES STUDY: CONGENITAL CYTOMEGALOVIRUS INFECTION AND CYTOMEGALOVIRUS INFECTION AND HEARING MULTICENTER SCREENING HEARING MULTICENTER SCREENING

STUDYSTUDY

Karen Fowler, DrPHUniversity of Alabama in Birmingham

Faye P. McCollister, EdDUniversity of Alabama, Emeritus

Diane Sabo, PhDUniversity of Pittsburgh

Confusion Regarding Congenital Confusion Regarding Congenital CMV Infection & Hearing LossCMV 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

•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

Review of Congenital CMV Review of Congenital CMV InfectionInfection

Review of Congenital CMV and Review of Congenital CMV and Hearing Loss ResearchHearing 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

The Natural History of CMV-Related Hearing Loss and the Feasibility of

CMV Screening as Adjunct to Hearing in the Newborn

NIH/NIDCD ContractNIH/NIDCD Contract

CHIMES StudyCHIMES Study

NIDCD CMV Grant, UABNIDCD 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

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)

Project DesignProject Design

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 newbornin the prediction of hearing impairment with onset during infancy or in the early years of life

ObjectivesObjectives

Project StaffProject 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

Site AudiologistsSite 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

Birmingham, ALUniversity Hospital & Cooper Green Hospital

Jackson, MSUniversity of Mississippi Medical Center

New Brunswick, NJSaint Peters University Hospital

Charlotte, NCCarolinas Medical Center

Cincinnati, OHGood Samaritan Hospital

Pittsburgh, PAMagee Women’s Hospital

Dallas, TXParkland Memorial Hospital

Participating Hospitals

38% Caucasian, Non Hispanic

34% Caucasian, Hispanic

24% African American

4% Asian

Selected Hospital PopulationsSelected Hospital Populations

Challenges to the CHIMES Challenges to the CHIMES Study (1)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

Challenges to the CHIMES Challenges to the CHIMES Study (2)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

Challenges to the CHIMES Challenges to the CHIMES Study (3)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

Addressing the ChallengesAddressing the Challenges to the CHIMES Study 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

Addressing the Challenges to the Addressing the Challenges to the CHIMES StudyCHIMES Study

Subject VariablesSubject Variables

Additional Disabilities (symptomatic infection)Vision

Can not see visual reinforcersCan not process visual instructionsNeed glasses for assessment, if prescribed

Seizure disorderFlicker stimulation with lighted reinforcerAbsence, petit mal, and grand mal seizures

Cultural DiversityCultural 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

Cultural DiversityCultural 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.

CHIMES STUDY CHIMES STUDY

Audiological Assessment Protocol

Diane Sabo, PhDUniversity of Pittsburgh

Components of Study Components of Study Audiological AssessmentAudiological 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 assessmentVRAPlay

Screening Data ObtainedScreening Data Obtained

Physiologic dataABRAutomated-ABROAEsAutomated OAEsCombinations of the tests

Objective Hearing Diagnostic Objective Hearing Diagnostic MethodsMethods

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)

Entry or Baseline DataEntry or Baseline Data

Physiologic tests ABR

Tone bursts at .5, 1, 2 and 4k HzBone conduction if air conduction

abnormal (>25) DPOAEs

2-8k Hz60/45Signal and noise levels recorded

Physiologic Assessment with Physiologic Assessment with ABR and EOAEsABR and EOAEs

• Advantages• “Objective”• Reliable• Correlate well with hearing• Age not a factor (but sometimes an issue)

Physiologic Assessment Physiologic Assessment with ABR and EOAEswith ABR and EOAEs

LimitationsNot completely “objective”Not tests of hearingNot always good at predicting

thresholdNot independent of infant’s

behavior, state, or other factors

Click SpectrumClick Spectrum

Frequency

FrequencyFrequency

Comparison of Frequency Range for Comparison of Frequency Range for ABR Clicks and Tone BurstsABR Clicks and Tone Bursts

What We Know About ABR ClicksWhat We Know About ABR Clicks

Click commonly used, but……can give misleading informationClick has energy at all frequencies transduced

by earphoneWithin 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

Progressive HL Secondary to SX Progressive HL Secondary to SX CMV in Six Month PeriodCMV in Six Month Period

ABR Assessment at Enrollment ABR Assessment at Enrollment Visit 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 reportOtoscopic inspectionDPOAE

Medical referral if testing deferred because of otologic problems

Physiologic Assessment with Physiologic Assessment with ABR and EOAEsABR and EOAEs

• Advantages• “Objective”• Reliable• Correlate well with hearing• Age not a factor (but sometimes an issue)

Optimal Goal for ABR Assessment at Optimal Goal for ABR Assessment at Enrollment Visit (3-6 Weeks)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

Minimal Goal for ABR Assessment Minimal Goal for ABR Assessment at Enrollment Visit at 3-6 Weeks at Enrollment Visit at 3-6 Weeks

of Ageof 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

ABR ProtocolABR Protocol

Order for tone bursts: 2000, 4000, 500 and 1000

Use 2-0-2 for 500 Hz Use 4-0-4 for Rate 27-29 Filter setting of 30-3000 Two replications <1000 sweeps for 2.0 and 4.0 No less than 2000 sweeps for 0.5 and 1.0

kHz

ABR ParametersABR 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

Entry DataEntry Data

Acoustic Immittance Data Tympanometry

High frequency tymps (1k) < 7 months

Acoustic reflex thresholdsIPSI reflexes @ 1k only, if necessary

Use Insert EarphonesUse 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

CHIMES STUDYCHIMES STUDY

Faye P. McCollister, EdDUniversity of Alabama, Emeritus

Behavioral AudiologicalAssessment Protocols

Request Parental Help in Preparing for Request Parental Help in Preparing for Behavioral Diagnostic AssessmentBehavioral Diagnostic Assessment

Try to have child rested and feed,

comfortable and attentive for test Schedule appointment away from nap time

Bring diapers for diaper changeBring bottle for comfortingBring pacifier, if usedBring familiar car seat for test

Manage Baby/Mom/Diagnostic Manage Baby/Mom/Diagnostic EnvironmentEnvironment

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

Child/Parent Handling IssuesChild/Parent Handling Issues Child State

Activity levelComfort level

Infection controlClinic protocol

Gloves, disposables, cross contamination Parent inclusion

Pre-test information sharingTime during testingTime spent informing about procedureInforming about the results

Visual Reinforcement AudiometryVisual 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

Schedule for Behavioral Schedule for Behavioral Audiological AssessmentAudiological 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

VRA Assessment InformationVRA Assessment Information

Beginning stimulus type warble tone, speech

Beginning transducerearphone, speaker# beginning conditioning trials# reconditioning trials# stimulus trials# control trials, if greater than 0, #

correct

VRA VRA AssessmentAssessment Information 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

Visual Reinforcement Visual Reinforcement AudiometryAudiometry

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

VRA at Follow Up Visits at VRA at Follow Up Visits at 8, 12, 18, and 24 Months of Age8, 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

Visual Reinforcement Visual Reinforcement AudiometryAudiometry

Optional, 8000 hz and speech awareness threshold, record if obtained

Bc not required, leave field blank

VRA Protocol (Widen)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

Ensuring Stimulus Control For Ensuring Stimulus Control For Behavioral ResponsesBehavioral 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

When Child Does Not When Child Does Not ConditionCondition

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

Play Audiometry Data FormPlay 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 555Was not tested, enter 999Was tested, no response , enter 888

Play Audiometry Data Form Play Audiometry Data Form (2)(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

Looks Good, But…….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

Contact the CHIMES StudyContact the CHIMES Study

www.uab.edu/chimesstudy

Karen Fowler [email protected]