Scott Grosse, PhD - PowerPoint Presentation

Slide1

Scott Grosse, PhDResearch EconomistNeonatal Health Innovation ForumMinneapolis, MNOctober 14, 2016

Newborn Screening for Congenital CMV? Opportunity for Innovation

National Center on Birth Defects and Developmental Disabilities

Office of the Director

The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy.Slide2

Outline of PresentationCriteria for public health newborn screeningCongenital CMV (cCMV) and population health

Which NBS criteria does cCMV already meet?Opportunities to collect more evidenceSlide3

Why Screen Newborns?Newborn Screening (NBS) benefits babies by detecting life-threatening diseases earlyAllows for early intervention to prevent complicationsMay reduce costs of treating complications

Criteria for selecting diseases to screen for include:Reliable screening test that is shown to be feasible, acceptable, and affordablePopulation-based pilot studiesSystem in place for

diagnostic testing, counseling, and follow-upMagnitude of

burden of disease – incidence and severityEffective treatments exist and are readily availableConsensus on who should be treatedSlide4

US Department of Health and Human ServicesRecommended Uniform Screening Panel (RUSP) In 2005, HHS Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) recommended RUSP, and it was approved

Of 29 original RUSP conditions, 28 screened by dried bloodspot test and 1 by point-of-care test--hearing loss5 conditions added to RUSP since 2010Severe combined immunodeficiency (2010)Critical congenital heart disease (2011)

Pompe disease (2015)Mucopolysaccharidosis, type I (2016)

Adrenoleukodystrophy (2016)Slide5

Process for Adding New Conditions to the RUSPSomeone nominates a conditionACHDNC reviews nomination to decide if there is sufficient evidence to proceed, including population-based pilot studiesCondition Review Workgroup amasses evidence – 6 month processSystematic review of published and unpublished evidence

Decision analysis modeling of benefits and harmsAssessment of readiness, feasibility, and cost to state public health systemsACHDNC votes whether to recommend conditionHHS Secretary decides whether to add recommended condition to RUSPSlide6

Burden of Congenital Cytomegalovirus InfectionCongenital CMV (cCMV) infection is more common than any existing newborn screening condition

Most common screened conditions are hearing loss (~1.5 per 1000) and congenital hypothyroidism (~0.5 per 1000)cCMV occurs in ~0.5% of infants according to a large US multi-center screening study using multiple methods (Boppana

et al. 2011)At least 20,000 newborns infected each year in US out of 4 million births, but few are diagnosedcCMV

is leading viral cause of birth defects and hearing loss in US

Barkai

G, Ari-Even Roth D,

Barzilai

A, et al. Universal neonatal cytomegalovirus screening using saliva - report of clinical experience. J

Clin

Virol

. 2014;60(4):

361-6.

Boppana

SB, Ross SA,

Shimamura

M, Palmer AL, Ahmed A. Saliva polymerase-chain -reaction assay for cytomegalovirus screening in newborns.

N

Engl

J Med

2011; 364: 2111–8. Slide7

Congenital CMV Symptoms and Sequelae ~10-15% of infants with cCMV are symptomatic at birth (Dreher

et al. 2014)Clinical signs: jaundice, petechiae, hepatosplenomegaly, purpura, microcephaly, seizures, and intrauterine growth retardation Non-specific signs, most affected infants are never diagnosed

Complications of symptomatic cCMV

Elevated risk of infant death – 5-10% (Cannon et al. 2013)Microcephaly, intracranial calcification, and brain

anomalies

Cerebral palsy, intellectual disability,

sensorineural hearing

loss, & eye problems are disabling conditions in about ½ of children

Dreher

AM, Arora N, Fowler KB, Novak Z, Britt WJ,

Boppana

SB, Ross SA. Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection

.

J

Pediatr

. 2014;164(4):855-9

Cannon MJ, Grosse SD, Fowler KB. Cytomegalovirus epidemiology and public health impact. In:

Cytomegaloviruses: From Molecular Pathogenesis to Intervention.

MJ

Reddehase

, ed. Norfolk, UK,

Caister

Academic Press. 2013. Volume II, pp. 26-48.

Alarcon A, Martinez-

Biarge

M, Cabanas F, et al. Clinical, biochemical, and neuroimaging findings predict long-term neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection.

J

Pediatr

. 2013;163(3):

828-34Slide8

“Asymptomatic” Congenital CMV Major sequela in asymptomatic cCMV cases is sensorineural hearing loss (SNHL)10-15% develop permanent hearing loss (Grosse et al. 2008)

About one-half of cases of SNHL can be detected through newborn hearing screening, others are late-onset or progressiveMost studies show no excess risk of intellectual disability in these childrenHowever, some children without apparent symptoms may have experienced brain damage in utero

Cannon

MJ, Grosse SD, Fowler KB. Cytomegalovirus epidemiology and public health impact. In: Cytomegaloviruses: From Molecular Pathogenesis to Intervention. MJ Reddehase

, ed. Norfolk, UK,

Caister

Academic Press. 2013. Volume II, pp. 26-48.

Grosse

SD,

Ross DS, Dollard SC. Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing

loss: A quantitative assessment.

J

Clin

Virol

.

2008; 41(1):57–62

.Slide9

Evidence of Late-Onset and Progressive SNHL:Houston Congenital CMV Longitudinal StudyDuring 1982-1992, 32,543

newborns underwent hospital-based screening by urine culture Cohort of 92 newborns with asymptomatic cCMV infection:

no CMV-related symptomsLong-term audiological

follow-up for 86 children up to age 18, median 8 evaluations (range 2-17), 95% followed to 9+ years Comparison group: 51 uninfected newborns, median 3 evaluations

SNHL ≥

25

dB in any ear

Lead investigators

Gail

Demmler

-Harrison, PI

Tatiana

Lanzieri, epidemiology and statistics

Winnie Chung, audiology Slide10

Cumulative Risk of SNHL in Houston Study (under review)Prevalence of SNHL assessed at various ages 3 months7% of case group vs. 0% of comparison group5 years

14% of case group vs. 0% of comparison group14 years23% of case group vs. 8% of comparison groupLaterality100% unilateral at age 3 months

50% unilateral age 14 yearsSlide11

Implications of FindingsChildren with asymptomatic cCMV at increased risk of developing SNHL through age 5 years

Excess risk of SNHL relative to uninfected children about 15% among children with asymptomatic cCMVUpper end of estimated range of 10-15% (Grosse et al. 2008)Many children with unilateral SNHL develop bilateral SNHL

SNHL is either late onset or progressive in up to 50% of cases among children with asymptomatic

cCMV (Fowler 2013)

Higher than reported in recent systematic review (

Goderis

et al. 2014)

UNHS may not detect ~50% of

cases of

SNHL that occur among children with

cCMV

Fowler KB. Congenital cytomegalovirus infection:

audiologic

outcome.

Clin

Infect Dis. 2013;57

Suppl

4:S182-4

.

Goderis

J, De

Leenheer

E,

Smets

K,

et al.

Hearing Loss and Congenital CMV Infection: A Systematic Review. Pediatrics. 2014;134(5):

972-82

.Slide12

cCMV and Criteria for Newborn ScreeningMagnitude of burden of disease 

Existence and availability of effective treatment?Feasibility, acceptability, accuracy, and cost of screening test?Potential harms versus benefits? Slide13

Options for Intervention Following Diagnosis Medical treatment Antiviral medicationsHearing amplification and cochlear implantsEarly intervention services Developmental services

Hearing and language interventionsMonitoring for late-onset and progressive hearing lossSlide14

Benefits of Antiviral Treatment Robust evidence of efficacy among infants with symptomatic cCMV with CNS involvement 1st RCT: 6

weeks IV ganciclovir reduced progression of hearing loss (Kimberlin

et al. 2003)21% of treated infants at 12 months vs. 68% of untreated infants

2nd RCT: 6 months vs. 6 weeks oral

valganciclovir

improved hearing & development at 24 months (

Kimberlin

et al. 2015)

Improved hearing in 77% of children in 6-month group vs. 64% in 6-week group

Significantly better language and receptive communication BSID scales (p=0.004)

Evidence lacking for other groups of infants with

cCMV

Kimberlin

DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J

Pediatr

.

2003;143:16–25

Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for

symptomatic

congenital

cytomegalovirus disease. N

Engl

J Med 2015; 372:933–943

.Slide15

Harms of Antiviral Treatment Transient neutropenia is commonGrade 3 or 4 neutropenia occurred in 21% of infants in 6-month valganciclovir trial arm Toxicity concerns lead many experts to restrict antiviral use to symptomatic infants with CNS involvement because of evidence of benefit exceeds risk of harm

Some experts recommend antivirals to infants with cCMV who do not pass hearing screening, which can be controversial because of lack of evidence

Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for symptomatic

congenital cytomegalovirus disease. N Engl J Med 2015; 372:933–943.

Hamilton ST, van

Zuylen

W,

Shand

A, et al. Prevention of congenital cytomegalovirus complications by maternal and neonatal treatments: a systematic review. Rev Med

Virol

. 2014;24(6):420-33.Slide16

Why Screen for cCMV?Potential Management OptionsIdentify infants with symptomatic cCMV, most of whom miss clinical recognition (

Sorichetti et al. 2016)Initiate antiviral treatment as soon as possibleRefer for early intervention servicesIdentify asymptomatic infants at risk of SNHL

Enable monitoring for language development, hearing lossRefer infants for early intervention therapies if SNHL is diagnosedPrescribe antiviral treatment to those

with possible SNHL? AAP: No evidence for this population (Pickering et al. 2012)

Some experts recommend this (e.g., Swanson & Schleiss 2013)

Sorichetti

B, Goshen O, Pauwels J, et al.

Symptomatic

Congenital

Cytomegalovirus

Infection Is

Underdiagnosed

in British Columbia. J

Pediatr

. 2016

Feb;169:316-7

.

Pickering

LK, Baker CJ,

Kimberlin

DW, Long SS. Red Book. 29

th

edition of the Committee on Infectious Diseases, American Academy of Pediatrics.

2012

Swanson EC,

Schleiss

MR. Congenital cytomegalovirus infection: new prospects for prevention and therapy.

Pediatr

Clin

North Am. 2013;60(2):335-49Slide17

Audiological Monitoring of Children with cCMVHow often should asymptomatic children with cCMV be assessed for hearing loss? “Children with risk indicators that are highly associated with delayed-onset hearing loss, such as having received ECMO or having CMV infection, should have more frequent audiological assessment.” (JCIH 2007)

“Frequent audiologic monitoring at 6-month intervals until age 5 years should be strongly considered, with

the possibility of more frequent monitoring every 3 months when hearing levels are changing or until the child is talking.” (Fowler 2013)Slide18

Impact of Early Diagnosis and InterventionEarly intervention (<6 months) after UNHS: Improves language development and reading comprehension (Kennedy et al. 2006; Pimperton et al. 2016)Lowers educational costs (Schroeder et al. 2006; Grosse 2007)

Fitting of cochlear implants for children with acquired severe SNHL (>70 dB) also improves outcomesChildren with late-onset SNHL who were fitted within 12 months has better speech and language outcomes (Geers 2004)

Kennedy CR, McCann DC, Campbell MJ, et al. Language ability after early detection of permanent childhood hearing impairment. N

Engl J Med. 2006;354:2131-41.Pimperton H, Blythe H, Kreppner J

, et al.

The impact of universal newborn hearing screening on long-term literacy outcomes: a prospective cohort study. Arch Dis Child.

2016;101(1

):9-15.

Schroeder

L,

Petrou

S, Kennedy C, et

al

. The economic costs of congenital bilateral permanent childhood hearing impairment.

Pediatrics

.

2006;117:1101–12.

Grosse SD. Education cost savings from early detection of hearing loss: New findings. Volta Voices. 2007;14(6): 38-40.

Geers

AE. Speech, language, and reading skills after early cochlear implantation

. Arch

Otolaryngol

Head Neck

Surg

2004;

130

:634–8.Slide19

Potential Newborn Screening Strategies for cCMVUniversal screening -- add cCMV to screening panel Screening using dried blood spot (DBS) sent to public health labCollection of saliva specimens in birth hospital and transport to laboratory for testing

Targeted screeningcCMV testing of specimens collected <21 days for infants who do not pass newborn hearing screeningTargeted screening adopted as state policy in Utah in 2013 and in Connecticut in 2015

Dollard SC, Grosse SD, Schleiss MR. Newborn screening for congenital CMV.

J Inher

Metabol

Dis.

2010; 33(

Suppl

2):S249–254.

Grosse SD, Dollard S, Ross DS, Cannon M. Newborn screening for congenital cytomegalovirus: Options for hospital-based and public health programs.

J

Clin

Virol

. 2009; 46S:S32–S36.

Gantt S, Dionne F,

Kozak

FK, et al.

Cost-effectiveness

of Universal and

Targeted

Newborn

Screening for

Congenital

Cytomegalovirus

Infection.

JAMA

Pedia

tr

. 2016

Oct

10

.Slide20

Is Newborn Screening for cCMV Cost-Effective?Advocates say yes (Demmler-Harrison 2016)Newly published article (Gantt et al. 2016) states:

However, certain assumptions about costs and effectiveness may be too optimisticExample: Assumes screening using saliva would impose no cost beyond laboratory testing, which is unrealisticEvidence using rigorous study designs is still needed

Demmler

-Harrison GJ. Congenital Cytomegalovirus Infection: The Elephant in Our Living Room

.

JAMA

Pediatr

. 2016 Oct 10.

Gantt

S, Dionne F,

Kozak

FK, et al.

Cost-effectiveness

of Universal and

Targeted

Newborn

Screening for

Congenital

Cytomegalovirus

Infection.

JAMA

Pedia

tr

. 2016

Oct

10

.Slide21

Challenges to NBS for cCMV: Opportunities to Invest in ResearchTo justify adding cCMV to RUSP evidence is needed

Testing methods for viral DNA Accuracy of DBS assays in high throughput testing needs to be testedFeasibility and cost of testing of saliva and urine specimens uncertainPopulation-based pilot studies required (ACHDNC)

Costs & benefits of audiological monitoring Who will perform audiologic assessments? Barriers to access

How often and how long should children be monitored?Modeling outcomes: How many cochlear implants will be avoided?

Agreement on who should be treated with antivirals

Outcomes of antiviral treatment in children without CNS involvement remain uncertain

RCT data needed– two trials are planned/underwaySlide22

Saliva or DBS for cCMV Screening?

Advantages of saliva:Saliva and urine currently specimens of choice to diagnose congenital CMV for select patient testing and research studies due to high viral load in these fluids

Analytical sensitivity >95%

Disadvantages of saliva:

Lack of infrastructure for saliva collection and testing presents substantial barrier

Hospital-based

testing in general presents higher cost, less standardized quality and lower rates of follow-up

Credit for following slides: Sheila Dollard, CDCSlide23

Dried Blood SpotsAdvantages of DBS:

DBS obtained on virtually all newborns

Integration of CMV screening into NBS program would reduce expense and enable high-throughput testing

DBS may have high clinical sensitivity based on associations between high viral load and severity of disease

Disadvantages of DBS:

CMV viral load in blood 2-3 logs lower than in urine or saliva

Analytical sensitivity of DBS 30-70% depending on lab

methods

Clinical sensitivity of DBS unknownSlide24

CDC / Minnesota NBS Study to Establish Clinical Sensitivity of DBS for CMV Testing

Enrollment Goal: 30,000 infants over 4 yearsSpecimen Collection

Saliva swab for identification of all infected infants

DBS; already obtained for newborn screening

Testing

Saliva swabs tested at UM lab within one week, results reported to PCP and parents

DBS specimens tested by CDC and UM labs

Follow-up for

CMV positive

infants

Annual review of medical records

through age

4 years

Hearing tested every 6 months by MN EHDI Program, assessment of program’s ability to handle influx of infants

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Thank You for ListeningScott Grosse, PhD Research Economist Office of the Director

National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention4770 Buford Highway NE, Mail Stop

E-87 Atlanta, GA 30341