Congenital CMV 101: From Prevention to Treatment...2018/01/26 · Congenital toxoplasmosis (toxo)...
Transcript of Congenital CMV 101: From Prevention to Treatment...2018/01/26 · Congenital toxoplasmosis (toxo)...
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NCHAM Webinar Series
Congenital CMV 101: From Prevention to Treatment
Presented by: Dr. Michael Cannon
Epidemiologist Centers for Disease Control and Prevention
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Possible Outcomes of Congenital CMV Infection
Transient outcomes Permanent outcomes Hepatomegaly Hearing loss Splenomegaly Intellectual disability Jaundice Vision loss Petechia and purpura Microcephaly Seizures Motor disabilities Fetal growth retardation
Seizures
Pneumonitis Death
Adapted from Stagno, 2001
Infant with microcephaly
Child with cerebral palsy, hearing loss, and mental retardation
Child with spastic quadraplegic cerebral palsy, vision loss, microcephaly, intracranial calcifications, and epilepsy
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US Estimated Annual Congenital CMV Disease Burden
•! 30,000 congenital CMV infections
•! 3,500 symptomatic infections •! 140 deaths •! ! 5500 children with
permanent sequelae
Dollard, Grosse, & Ross, Rev Med Virol, 2007
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Long-term sequelae
Annual Number of U.S. Children with Long-Term Sequelae
0 1000 2000 3000 4000 5000 6000
Congenital rubella syndrome
Invasive Hib
Pediatric HIV/AIDS
Spina bifida/anencephaly
Down syndrome
Fetal alcohol syndrome
Congenital CMV disease
Relative Burden of Congenital CMV
Adapted from Cannon & Davis, BMC Public Health, 2005
Costs > $1 billion in direct medical care each year
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Congenital CMV is an Invisible Disease
•! Mothers do not know when they are infected
•! Many infected babies are asymptomatic at birth
•! When babies have symptoms, they are often non-specific
•! Congenital CMV usually cannot be diagnosed retrospectively
% of women who had heard of the condition
0 20 40 60 80 100
Down syndrome
HIV/AIDS
Sudden infant death syndrome (SIDS)
Autism
Spina bifida
Fetal alcohol syndrome
Parvovirus B19 (Fifth disease)
Beta strep (Group B strep)
Congenital toxoplasmosis (toxo)
Congenital rubella syndrome
Congenital cytomegalovirus (CMV)
15
29
13
16
42
80
83
93
96
96
97
Cannon, Prev Med, 2012
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The Laboratory Vocabulary Measurement Labelled Detects Test format
Ever been infected Seropositive Antibody ELISA
At risk for transmission
Shedding or excreting Virus or viral DNA PCR or culture
Primary infection Latency Reactivation
Reinfection
Recurrent or secondary infection
CMV Natural History
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1999-2004 CMV Seroprevalence in the US
Bate, CID, 2010
Seroprevalence is higher among: •! Older people •! Females •! Mexican-Americans •! Non-Hispanic Blacks
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Demographic Risk Factors for Seroconversion •! In the U.S., rates of new CMV infections in susceptibles
are much higher in disadvantaged populations such as racial/ethnic minorities and persons of low SES
CMV Force of Infection by Race/Ethnicity, SES, and Region
Race/ethnicity
NH-W
hite
NH-B
lack
Mex
ican
Low
Mid
dle
High
North
east
Mid
west
Sout
h
Wes
t
CM
V in
fect
ions
per
100
sus
cept
ible
s pe
r yea
r
0
1
2
3
4
5
6
7
Socioeconomic status Region
Adapted from Colugnati, 2007, BMC Infect Dis
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Household Transmission Risk
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CMV seroprevalence differences
•! Seroprevalences among family members of seropositive children are 30-50 percentage points higher than among family members of seronegative children
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Summary CMV Annual Seroconversion Rates
*Annual infection rate of less 25% in this high risk group suggests that CMV is not easily transmitted.
Risk group Summary annual
seroconversion rate (%)
95% confidence interval (%)
Pregnant women 2.2 2.1 - 2.4 Parents with child not shedding CMV 2.1 0.3 - 6.8
Healthcare workers 2.7 2.3 - 3.2 Day care providers 8.5 6.1 - 11.6 Women attending STD clinics 13 10 - 17
Parents with child shedding CMV* 24 18 - 30
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Comparison of Models of Contagiousness
Study Design Force of
infection (100 p-y)
Basic reproductive
rate
Age of infection (years)
Measles Mumps Rubella
Review Ages 11-17
20 12 10
Varicella Convenience Ages !10 6
CMV Griffiths (2001)
Hospital-based Ages 16-40 3.1 and 3.5 2.4 and 2.7 29 and 32
(median)
CMV Colugnati (2007)
Pop.-based Ages 12-49 1.8 1.7 28.7 (mean)
HSV-2 Pop.-based Ages !12 0.84
Hepatitis A Pop.-based Ages !10 0.2-1.0
Hepatitis B Pop.-based Ages 6-39 0.15
Adapted from Colugnati, BMC Infect Dis, 2007
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CMV Shedding Prevalences by Risk Group
Cannon, Rev Med Virol, 2011
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Among children, shedding prevalence
peaks at ages 1-2 years
These are the ages at which children are
putting the most fluids into the environment
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
20
40
60
80
100
Years
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
%Shedding
CMV
0
20
40
60
80
100
Children born with congenital CMV
Healthy children in day care centers(U. Alabama at Birmingham studies)
Healthy children in day care centers(non-U. Alabama at Birmingham studies)
Healthy children not in day care centers
Children with medical conditions
%Shedding
CMV
%Shedding
CMV
%Shedding
CMV
%Shedding
CMV A
B
C
D
E
Cannon, Rev Med Virol, 2011
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CMV Viral Load Data
P<0.001
Viral loads higher in: •! Saliva than in urine •! Children than in adults •! Younger children than
in older children
Cannon et al., unpublished data
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Summary of CMV Transmission
•! CMV is transmitted through direct contact with body fluids
•! CMV is not transmitted easily •! Saliva and urine are important
fluids for transmission •! Saliva has higher viral loads
than urine •! Young children are a major
source of infection •! CMV can be transmitted
through intimate adult contact
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Cannon, Rev Med Virol, 2014
Note: About 30% of HL is bilateral moderate to profound About 70% of HL is unilateral or mild bilateral
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Timing of Hearing Loss
Fowler, J Peds, 1999
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Bilateral Moderate to Profound Hearing Loss Attributable to Congenital CMV
82% Other Causes
18% Congenital
CMV
Adapted from Grosse, J Clin Virol, 2008
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Takeaway Points for Congenital CMV Infection and Outcomes
!! Non-primary maternal infection is a major source of congenital infection
!! Congenital infection occurs in 0.5%-1% of newborns in the U.S.
!! Disabilities occur or develop in 15%-20% of infected newborns
!! Congenital CMV is a major cause of childhood hearing loss
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Potential Clinical and Public Health Interventions for Congenital CMV
Vaccination
Pre-conception screening Treatment to prevent
fetal disease
Newborn screening
(NBS) Early detection and intervention
Treatment to prevent fetal infection
Currently, none of these interventions is routine in the U.S.
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Utility of Newborn CMV Screening
Probably satisfies •! Important health problem •! Recognizable latent or
early symptomatic stage •! Natural history adequately
understood
May not yet satisfy •! Suitable test available •! Test acceptable to
population •! Agreed on policy on whom
to treat •! Facilities for diagnosis and
treatment available •! Cost-effective
Grosse, J Clin Virol, 2009
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Laboratory Approaches to Newborn CMV Screening
Specimen Method Advantages Disadvantages Dried blood spot PCR from DBS NBS program
already in place CMV viral load lower in blood, less available specimen
Saliva PCR from cheek swab
CMV viral load higher in saliva
Not part of existing NBS program
Urine PCR from bagged urine or diaper insert
CMV viral load higher in urine
Not part of existing NBS program
Dollard, J Inherit Metabol Dis, 2010
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Pharmaceutical Treatment of Infants with Congenital CMV
•! 42 symptomatic infants with central nervous system (CNS) deficits were evaluated for hearing loss.
•! 6 weeks IV ganciclovir vs. no treatment •! Ganciclovir recipients were significantly less likely to
experience worsening in hearing. •! Two thirds of treated infants had significant neutropenia
during therapy.
•! Current multi-site trial underway with oral valganciclovir •! Infants need not have CNS deficits to be enrolled
Kimberlin, J Ped, 2003; Kimberlin, J Infect Dis, 2008
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Cannon, Rev Med Virol, 2014
Note: About 30% of HL is bilateral moderate to profound About 70% of HL is unilateral or mild bilateral
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Proportion of Respondents who Somewhat/Strongly Agreed by CMV Statement
Din, Pediatrics, 2011
33
85 87 86
44
0 10 20 30 40 50 60 70 80 90
100 P
erce
nt (%
)
Would want to have baby
tested for CMV even if doctor/hospital didn’t do it routinely,
N=3,832
I think CMV problems
are too rare to worry about,
N=3,785
Would want to know if child has
CMV even if he/she never
develops problems, N=3,820
Willing to pay $20 to have baby tested
for CMV, N=3,811
Would worry that CMV test would lead to
unneeded doctor visits
and expenses, N=3,803
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Future Directions for Newborn CMV Screening
!! Further assessments of DBS assays !! Development of point-of-care assays for saliva and urine !! Evaluation of saliva or urine collection on filter paper
cards !! Assessments of psychosocial impacts of screening !! Develop protocols for monitoring and treatment of
children who screen positive for CMV at birth !! Pilot studies for feasibility of universal screening !! Pilot studies of targeted CMV screening (e.g., infants
who fail hearing screen)
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Selected Additional References !! Vaccines
•! Griffiths et al., Vaccine, Vol. 31, p. B197-B203 (2013) •! Krause et al., Vaccine, Vol. 32, p. 4-10 (2013)
!! Prenatal screening/prenatal diagnosis •! Lazzarotto, Clin Microbiol Newsletter, Vol. 32, p. 9-15 (2010)
!! Behavioral intervention •! Vauloup-Fellous, J Clin Virol, Vol. 46, p. S49-S53 (2009)
!! Prenatal treatment •! Nigro, N Engl J Med, Vol. 353, p. 1350-1362 (2005) •! Revello, N Engl J Med, Vol. 370, p. 1316-1326 (2014) •! Jacquemard, BJOC, Vol. 114, p. 1113-1121 (2007)
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Go to cmv.usu.edu to register for the conference, view the conference agenda, and learn more about cmv.
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Questions?
Michael J. Cannon, PhD [email protected]
For more information about CMV please visit www.cdc.gov/cmv 1600 Clifton Road NE, Atlanta, GA 30333 Telephone: 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348 Visit: www.cdc.gov | Contact CDC at: 1-800-CDC-INFO or www.cdc.gov/info The findings and conclusions in this report are those of the author and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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