Transcript Screening for congenital CMV - CT-AAP

Screening for congenital
CMV
Nicholas Bennett MBBChir, PhD FAAP
Medical director of infectious diseases and immunology
Connecticut Childrens Medical Center
Disclosures
Dr Bennett has no relevant conflicts of interest to
disclose
Dr Bennett will be discussing off-label use of
valganciclovir.
Background
1% of all births
90% asymptomatic
Most common cause of nongenetic sensorineural hearing
loss
Effects are progressive in some
Prior research
IV ganciclovir effective against CMV
Approved for retinitis in AIDS
Approved for prevention and treatment of
transplant complications
CASG 102
6 weeks of intravenous ganciclovir for neonate
with symptomatic congenital CMV
Compared to placebo had improved hearing and
developmental outcomes at 1 and 2 years
Neutropenia noted in about two thirds of patients
Outcomes from CASG102
Hearing loss
100
75
50
Treated
25
0
6 months
12 months
Remember this was a 6 week treatment with
effects seen 1 year later…
Untreated
CASG 112
Pharmacokinetics - 16mg/kg BID of oral
valganciclovir equivalent to 6mg/kg BID of IV
ganciclovir
6 weeks versus 6 months of oral valganciclovir
6 months of therapy had improved outcomes at 1
and 2 years of age with hearing and development
Neutropenia similar to placebo group in historical
study cohort (20% or so)
Outcomes from
CASG112
6mo therapy resulted in approx 8 point higher
Bayley Composite scores for language, motor
skills, at 12 and 24 months than 6 weeks of
therapy
No apparently difference in hearing outcomes
between 6 months and 6 weeks of therapy
But remember that 6 weeks was a huge
improvement over no treatment at all
Summary of findings
Treatment of symptomatic congenital CMV for 6
weeks dramatically reduces hearing loss
PO valganciclovir is as effective as IV ganciclovir
but with much less neutropenia
6 months of therapy has improved
developmental outcomes over 6 weeks of
therapy - similar hearing outcomes
2015 Red Book
Prior situation
Child would fail hearing screens
Referral to ENT/Audiology
CMV testing
Diagnosis aged 6+ weeks
?Treatment?
Preferred situation
Child fails hearing screens
CMV testing
Diagnosis aged 3-4 weeks
Referral to ENT/Audiology/ID as needed
?Treatment?
Why still a question?
Hearing-loss only WAS eligible for enrollment in
CASG112
No child in CASG112 had only hearing loss
Ongoing studies addressing precisely this
question
No guidance yet from international CMV group
Smaller Studies
Lackner et al J Laryngol Otol. 2009
Apr;123(4):391-6
3 weeks of ganciclovir, 23 children, 18
followed for 4-11 years
2 untreated children with CMV (out of 9)
developed hearing loss years later
0 of 9 treated children had hearing loss
Smaller Studies
Amir, Wolff and Levy European Journal of
Pediatrics, September 2010, Volume
169, Issue 9, pp 1061-1067 (1 year of
valganciclovir after IV)
Advantages
Potential improved hearing and
neurodevelopment if treated
Therapy is oral, can be done at home
Side effects appear minimal in the short term
Disadvantages
Prolonged (6 month) course
Need for monitoring for drug toxicity
Potential for carcinogenic/mutagenic activity
according to animal studies
Ongoing research to investigate this in children
from prior studies
When to test
Test for CMV after SECOND failed screen in
either ear.
Typically still done in the hospital prior to
discharge (i.e. not a PCP responsibility!)
80% of first screen failures pass the second
screen
Do NOT wait for formal audiology referral
Limitations
Won't pick up late-onset hearing loss
But universal CMV screening may be overkill
No data in this specific population
Will miss home-births, hospitals where hearing
screening isn't complete prior to discharge
Proposal
Early identification by testing neonates who fail
hearing screens (at-risk population)
Early referral to ID for discussion with the family
regarding options
May include additional workup
Cranial US, hematology, biochemistries
Treatment offered if indicated
Testing
Performed at birth hospitals prior to discharge
Saliva can be tested at Yale labs by PCR
DO NOT send to State labs!
Collect at least 30 minutes after breastfeeding
Positives need confirmation by urine PCR/Shell vial culture
Can start with CMV urine testing - performed by many
commercial labs
PCR or shell vial results take a few days
Referrals
Both Yale and CT Children's ID divisions will see
patients and families for evaluation
Make sure consult request CLEARLY states
reason for referral, may prefer to call ahead
Goal is early identification of children who should
be treated - routine "next available" appointment
may be too late
Impact of CMV screening
Approx 2500 children fail their hearing tests
Approx 2000 of those pass on the repeat test
Approx 500 will require CMV testing
Estimate ~50 a year will be CMV-positive
Cost approx $100 per child
Will probably reduce the need for genetic testing
Reduced hearing loss - significant savings to society
If hearing impairment cut by ⅔, number needed to screen is 25
Prevention
No vaccine
CMV very common (over 50% of adults may be infected)
At-risk women - pregnant, CMV-negative
Daycare setting (high titers shed in urine)
No proven role for treatment of pregnant women
Remember that ganciclovir teratogenic/oncogenic in animal
models
Cytogam (hyperimmune globulin), reduced congenital CMV by
more than 90% in several small open-label studies in Europe
Prevention
Avoiding high-risk activities if you’re an at-risk person
Hand-washing!
Diaper changing, feeding, wiping noses
Do not share food, drinks, or pacifiers!
Do not share toothbrushes with a young child.
Try to avoid saliva from a young child.
Summary
Good data exists to support treatment of symptomatic congenital CMV to
reduce hearing loss and improve neurodevelopmental outcomes.
Some data to support the use of antiviral therapy in less-affected neonates
New State law mandates screening for CMV in infants with two failed
hearing screens
Goal is early identification for referral to ID specialists for possible treatment
Send testing to Yale (saliva or urine PCR) or commercial lab (urine
PCR/shell vial culture)
Request urgent appointment with ID at Yale or Connecticut Children’s
Education of pregnant women to help with prevention important