1. Hearing-targeted testing for early diagnosis of congenital CMV
Sunil K. Sood MD
Courtesy nationalcmv.org

2. Disclosures
Funding from NIH-CASG (via University of Alabama) to support participation in multicenter CMV studies
“Off label” use of valganciclovir

3. Goals for Today
Understand congenital CMV: epidemiology, disease spectrum and the estimated burden of sensorineural hearing loss (SNHL)
Explain rationale for hearing-targeted screening for CMV
Increase awareness and advocacy
Early intervention & neuro followup
Hearing intervention
Vanganciclovir

4. What is Cytomegalovirus
A beta-herpes DNA virus “HHV-5”
Ribbert: Owl’s eye cells in
kidneys of stillborn with syphilis
Lowenstein: Children parotid glands “salivary gland viruses”
Renamed cytomegalovirus by Weller

5. Seropositive mothers Seronegative mothers Virus in milk 30-70%
50% of nursing infants acquire infection
Shed virus for years
Source for other kids, and care providers

6. Worldwide 0.2 - 2.2% of live births
Worldwide CMV seroprevalence rates among women of reproductive age, and birth prevalence of congenital CMV infection
Worldwide CMV seroprevalence rates among women of reproductive age and birth prevalence of congenital CMV infection. For CMV seroprevalences (shaded), percentages were obtained by adding the number of seropositive women from all studies within a given country and dividing that number by the total number of women tested. Reproductive age was generally defined as between 12 and 49 years of age. To reduce sampling variability, only countries that had at least 500 women tested were included. Studies were from Australia, Belgium, Brazil, Canada, Chile, England, Finland, France, Germany, Ghana, India, Israel, Italy, Japan, Scotland, South Africa, Spain, Sweden, Taiwan, Turkey, and the United States (26). For congenital CMV birth prevalences (circles), percentages were obtained from studies with a representative sample size (at least 1,000 newborns). To reduce detection bias, only studies using PCR or culture on saliva or urine were included, with the exception of Netherlands and Portugal, which tested DBS samples by PCR. When more than one representative study was available, percentages were obtained by adding the number of congenitally infected newborns from all studies within a given country and dividing that number by the total number of newborns tested. Countries for which maternal seroprevalence rates and birth prevalence of congenital CMV infection data were available are Brazil, Canada, England, India, Israel, Italy, Japan, Sweden, and the United States. (Adapted from reference 26.)‏
Worldwide % of live births
Sheetal Manicklal et al. Clin. Microbiol. Rev. 2013;26:86-102

7. Hygiene precautions and behavioural interventions that could prevent CMV infection in pregnant women
Do not share food, drinks, or utensils with young children
Do not put a child’s pacifier in your mouth
Avoid contact with saliva when kissing a child
Thoroughly wash hands with soap and water for 15–20 seconds, especially after changing diapers, feeding a young child, or wiping a young child’s nose or saliva
Less evidence for:
cleaning toys, countertops, and other surfaces that come into contact with children’s urine or saliva
not sharing a toothbrush with a young child
Rawlinson, et al Consensus statement
Lancet Infect Dis 2017

8. Estimated annual number of congenital infections in the United States.
Estimated annual number of congenital infections in the United States. The most common cause of congenital infection wordwide.
Zika 1+ case

9. Percentage of women who had heard of these diseases
Women’s awareness of conditions affecting infants and
children [58].

10. Textbook Cytomegalovirus Infection
Red Book Online Visual Library, Image 039_07.
Copyright ©2009 American Academy of Pediatrics

11. Maternal serology Pre-pregnancy
CMV+
CMV-
“non-primary infection”
re-activation or re-infection
primary infection
Compared with a maternal nonprimary infection (ie, reinfection
or reactivation), a maternal primary infection is more
likely to transmit CMV from mother to fetus (1% vs
32%) and is also more likely to result in severe, longterm
sequelae in children born with congenital CMV
1440 • CID 2010:50 (1 June) • Bate et al
infection [6, 8, 9].
Congenital CMV
about 1%
Congenital CMV
about 33%
Similar rate of symptomatic, rate of SNHL, & severity

12. Maternal serology Pre-pregnancy
1000
CMV+
CMV-
600
400
“non-primary infection”
re-activation or re-infection
primary 1- 4%
Compared with a maternal nonprimary infection (ie, reinfection
or reactivation), a maternal primary infection is more
likely to transmit CMV from mother to fetus (1% vs
32%) and is also more likely to result in severe, longterm
sequelae in children born with congenital CMV
1440 • CID 2010:50 (1 June) • Bate et al
infection [6, 8, 9].
New: 4-16% primary inf X 33% = 1-5
Congenital CMV
about 1%
Congenital CMV
about 33% 6
1-5
Similar rate of symptomatic, rate of SNHL, & severity

13. 4 million births  up to 30,000 congenital infections
Congenital CMV in U.S.
4 million births  up to 30,000 congenital infections

14. Congenital CMV spectrum
3000 symptomatic
Brain imaging abnormal in 50%–70%: could be minor such as punctate calcifications, periventricular leucomalacia, mild hydrocephaly
About half develop permanent sequelae: sensorineural hearing loss (SNHL) being the most common, followed by cognitive impairment with IQs <70, microcephaly, chorioretinitis, and cerebral palsy
Demmler-Harrison, Boppana CID (2013), Fowler

15. Congenital CMV spectrum
27000 “Asymptomatic”
10-15% develop SNHL:
- much higher than 0.1%–0.4% in general population
often bilateral and/or profound and/or progressive and/or delayed onset, requiring ongoing audiologic evaluation
5% develop microcephaly and motor defects
2% chorioretinitis
Boppana CID (2013)

16. Hearing loss in ~ 1 in 10 babies with CMV
Congenital CMV in U.S.
Hearing loss in ~ 1 in 10 babies with CMV

17. CMV in the Inner Ear -an ongoing endolabyrinthitis Semicircular canals
Vestibule
Semicircular canals
Utricle
Vestibule
Saccule
Cochlea
Utricle
Cochlea
Saccule

18. The NIDCD CMV & Hearing Multicenter Screening Study (CHIMES Study)
Table 1. Study Characteristics of 43,557 infants enrolled in the CHIMES Study, March 2007 – March 2009
The NIDCD CMV & Hearing Multicenter Screening Study (CHIMES Study)
Determine the relative contribution of CMV-related hearing loss to overall hearing loss in children
-Screen at least 100,000 newborns for congenital CMV infection and link their newborn hearing screening results
-Audiometric follow-up of all CMV positive infants
(3-5 wks, 7, 12, 18, 24, 30, 36, months).
CHIMES Study Co-PIs: Suresh Boppana & Karen Fowler Courtesy Karen Fowler May 2016
Congenital cytomegalovirus (CMV) infection remains the most common congenital infection in the United States (US), and a leading cause of hearing loss in children. Precise regional and national estimates of the prevalence of congenital CMV infection according to race & ethnicity and socioeconomic status are needed for developing strategies to identify and develop interventions for CMV-related hearing loss in children.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.
To determine the prevalence of congenital CMV infection in newborns at seven medical centers in the US.

19. CHIMES Study 99,945 newborns
congenital CMV
449 (0.4%)
Newborn Hearing Screen referral rate at birth = 7%
31 (22 NBN 9 NICU)
Additional 15 who passed
NHS had SNHL by ABR
At 3 to 8 weeks of life
20 confirmed to
have SNHL by ABR
CHIMES 100,333 newborns screened for CMV
0.5% had congenital CMV
89% asymptomatic
35 SNHL of 443 CMV positive = 8% or 1 in 13
Fowler et al 2017 & unpublished data

20. CHIMES study: Newborn Hearing Screen (NHS)
The NHS referral (did not pass) rate
for the study population was 1.0%
However, 7.0% of CMV-positive infants did not
pass their NHS compared with 0.9% of CMV- negative infants who did not pass their NHS
Of ~ 1000 who failed NHS, 20 turned out to have CMV-related SNHL (2% = ~ 1 in 50)
An additional 15 CMV-positive infants who passed NHS had SNHL confirmed by a diagnostic hearing evaluation in the first 3 to 8 weeks of life

22. Hearing-targeted screening – Why?
Early Intervention
Provides parents and providers reason for the hearing loss
Ancillary effect -- more hearing screens done in NICU
Antiviral treatment
EARLY HEARING DETECTION & INTERVENTION

23. March 5, 2015 23

24. (CNS involvement not required)
6 months vs 6 weeks of oral valganciclovir for symptomatic congenital CMV disease
(CNS involvement not required)
109 babies ≤ 30 day old, enrolled
Hearing assessed at baseline, 6, 12, 24 months
Neurodevelopment assessed at 12 and 24 months by Bayley-III
Safety labs and viral load followed

25. 6 months vs 6 weeks of oral valganciclovir
Conclusions
6 months of oral valganciclovir in symptomatic congenital CMV disease provides moderately favorable audiologic and neurodevelopmental outcomes to at least 2 years age
Less neutropenia is seen during the first 6 weeks of valganciclovir (19%) than was seen in earlier study of IV ganciclovir (63%)
No excess neutropenia with continuation of valganciclovir treatment from 6 weeks to 6 months compared with placebo

26. Importance of Timing of Diagnosis
After 3 weeks of age, congenital CMV cannot be reliably diagnosed as the etiology for infants with SNHL
After 4 weeks of age, symptomatic babies are not eligible for treatment per current recommendations

27. Screening programs Universal – by state Hearing Targeted – by hospital
Other hospitals esp. Dallas
Northwell program
Intent & numbers
Hurdles

28. Northwell procedure for Hearing-targeted Testing
OAE fail
 screening ABR fail
 notify nurse manager
 notify MD to order CMV urine or saliva PCR
 schedule diagnostic ABR in Hearing & Speech by 3 weeks of age
CMV comes back positive
 notify ID
 schedule outpatient ID consult by 3 weeks of age
 arrange Neuro and EI

30. Northwell ID protocols
Symptomatic: discuss 6 months of valganciclovir with parent
Asymptomatic and Hearing- impaired: placebo-controlled study of valganciclovir
Asymptomatic
Re-evaluate hearing periodically
arrange Neuro and EI

31. 1 in every 150 babies 1 in 5 disability rate 1 in 10 hearing loss rate
Disabilities from cCMV infection are more common in children in the U.S. than other more recognized diseases such as Down syndrome, FAS, or spina bifida.
18% disability rate
10% hearing loss rate
Julie Goderis, Pediatrics October 2014

34. Hearing Screen Referral Rates, % (95% CI)
Newborn Hearing Screen Referral Rates for Infants by CMV Status, Overall and by Nursery
CMV Screen
No. Screened
No. Referred
Hearing Screen Referral Rates, % (95% CI) P
 CMV positive
443 31
7.0% (4.8%–9.8%)
<.0001
 CMV negative
99 502
930
0.9% (0.8%–1.0%)
Well-Infant Nursery
400 22
5.5% (3.5%–8.2%)
96 336
768
0.8% (0.7%–0.9%)
NICU 43 9
20.9% (10.0%–36.0%)
<.001
3166
162
5.1% (4.4%–5.9%)

35. Hearing loss rate At birth or late onset
Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL.
In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy.
NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period.