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

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

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

What is Cytomegalovirus A beta-herpes DNA virus “HHV-5” 1904 Ribbert: Owl’s eye cells in kidneys of stillborn with syphilis 1907 Lowenstein: Children parotid glands “salivary gland viruses” Renamed cytomegalovirus by Weller

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

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 0.2 - 2.2% of live births Sheetal Manicklal et al. Clin. Microbiol. Rev. 2013;26:86-102

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

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

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

Textbook Cytomegalovirus Infection Red Book Online Visual Library, 2009. Image 039_07. http://aapredbook.aappublications.org/visual. Copyright ©2009 American Academy of Pediatrics

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

Maternal serology Pre-pregnancy 1000 CMV+ CMV- 600 400 “non-primary infection” re-activation or re-infection primary infection @ 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

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

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

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)

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

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

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, 42-48 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.

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

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

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

March 5, 2015 23

(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 2008 - 2011 Hearing assessed at baseline, 6, 12, 24 months Neurodevelopment assessed at 12 and 24 months by Bayley-III Safety labs and viral load followed

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

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

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

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

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

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

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%)

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.