tmd175 slide congenital cmv infection
TRANSCRIPT
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 1/37
Congenital CMVinfection
Infectious and Tropical Pediatric Division
Department of Child Health
Medical Faculty, University of Sumatera Utara
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 2/37
Congenital CMV infectionCongenital CMV infection
• Approximately 0.15–2% of live births• Leading cause of sensorineural deafness
• Major cause of mental retardation, cerebral
palsy
• Approximately 10% death in symptomatic
newborns
• Lifelong habilitation for impaired survivors
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 3/37
• Fetus: Via placenta from the mother • Human milk
• Blood transfusion or an
How is CMV transmitted?
transplantation
• Children and adults: Mainly via bodily
fluids (esp. urine, saliva)(esp. urine, saliva)(esp. urine, saliva)(esp. urine, saliva)
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 4/37
Transmission of CMV through the placenta
barrier and infection of the fetus
Transmission of CMV through the placenta
barrier and infection of the fetus
Infected mother viraemia infection of placenta trophoblasts
Infection of fetal
Infection ofthe oropharynx
endothelial cells
Viralreplication intarget organs
(kidney)
Fetal viruria
rus namniotic fluid
Fetal viraemia
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 5/37
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 6/37
MATERNAL CMV INFECTIONDURING PREGNANCY
• Primary maternal infection leads tofetal infection in 30-50% of cases--10-15% of these have overt clinical
• Secondary maternal infection lesslikely to lead to fetal infection (1-2% )
but can do so and may lead to severedisease (Boppana et al, NEJM 2001, 344:
1366)
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 7/37
Rates of primary CMV infection
during pregnancy
Rates of primary CMV infection
during pregnancy
Study (Location)Study (Location)Study (Location)Study (Location) Rate as % of Rate as % of Rate as % of Rate as % of Rate as % of Rate as % of Rate as % of Rate as % of % cong CMV,% cong CMV,% cong CMV,% cong CMV,
PregnanciesPregnanciesPregnanciesPregnancies SeronegativesSeronegativesSeronegativesSeronegatives primary mat inf primary mat inf primary mat inf primary mat inf
Stern 1.1 4.1 45
(London)
rant cot an . .
Stagno (USA, 0.57 1.4 47
mid-income)
Ahlfors (Sweden) 0.32 1.4 43
Griffiths (London) 0.30 0.86 20
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 8/37
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 9/37
Symptomatic CongenitalCMV Infection
• Jaundice (67%)• Petechiae (76%)
• Microcephaly (53%)
• Chorioretinitis (20%)
• Seizure (7%)
• Fatal outcome (10%)
Boppana et al. (1999) Pediatrics 104:55
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 10/37
Sequelae of CongenitalCMV Infections
• Neurological sequelae are the mostcommon, and most severe:• >90% of newborns with symptomatic
con enital CMV infection have visual
audiologic and/or other neurologicalsequelae
• - 5-17% of newborns withasymptomatic congenital CMVinfection develop neurologicalsequelae (esp. hearing loss)
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 11/37
Sequelae of CongenitalCMV Infections
• Cranial CT is a good predictor ofsequelae in neonates with congenitalCMV infection
• Most common abnormalit is
intracerebral calcification (typicallyperiventricular)
• Boppana et al (Pediatrics 99:409,1997) reported that 90% of neonates
with abnormal CT scan developed atleast 1 sequelae
• Only 1/17 neonates with normal CThad IQ < 70
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 12/37
SEQUELAE OF SYMPTOMATICCONGENITAL CMV INFECTION
• Seizures
• Chorioretinitis
• Periventricular calcifications
• Sensorineural hearing loss
• motor deficits
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 13/37
CHORIORETINITIS
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 14/37
Congenital CMV
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 15/37
Congenital CMV
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 16/37
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 17/37
CHARACTERISTICS ASSOCIATED WITH
INCREASED RISK OF SEQUELAE
• Primary maternal infection
• Symptomatic congenital CMV
• Presence of neonatal neurological
abnormalities
• Abnormal head CT scan
• Chorioretinitis in the newborn
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 18/37
CLINICAL IMPACT OF
CONGENITAL CMV INFECTION
Frequency of sequelae
Symptomatic (7%) Asymptomatic (93%)
Infant death 10% 0
Hearing loss 60% 7 –15%Mental retardation 45% 2 –10%
Cerebral palsy 35% <1%
Chorioretinitis 15% 1 –2%
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 19/37
Diagnosis of CongenitalCMV Infections
• Isolation of CMV from urine or otherbody fluid (CSF, blood, saliva) in thefirst 21 days of life is considered
• Serologic tests are unreliable; IgMtests currently available have bothfalse positive and false negative
results• PCR may be useful in selected cases
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 20/37
Detection: screening for maternal
CMV infection
Detection: screening for maternal
CMV infection
• CMV IgG antibody – sensitive and specific
screen for past infection
–
specificity
• Antibody avidity testing can increase accuracy
of detection of primary infection
• No test for immune mothers who will transmit
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 21/37
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 22/37
Advanced CMV diagnosisAdvanced CMV diagnosis
IgM confirmation by Western blot
index
Isolation of the virus from urine,
saliva and blood
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 23/37
A confirmatory test for CMV-IgMA confirmatory test for CMV-IgM
New immunoblotNew immunoblotNew immunoblotNew immunoblot
1) Contains both structural
and nonstructural proteins
Purified
native
viral
roteinsVp65
Vp82
Vp150
µµµµ
be confirmed withrecpUL32
3) Agrees with consensus of
different ELISAs4) Is easy to standardize
5) Is easy to interpret
rp150
rp52
rp130
CKS
rp38
Recombinant
proteins
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 24/37
x ( % )
70
60
50
Congenital CMV infectionsCongenital CMV infectionsLow IgG avidity is linked to primaryLow IgG avidity is linked to primaryLow IgG avidity is linked to primaryLow IgG avidity is linked to primary
infectioninfectioninfectioninfection
Weeks after beginning of symptoms
A v i d i t y i n
d
0
30
20
10
0
5 10 15 20 25 30 35
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 25/37
Evaluation of mothers at risk of
transmitting CMV to the fetus
Evaluation of mothers at risk of
transmitting CMV to the fetus
Positive Negative
Test for IgG antibodyat first prenatal visit
Negative,
no further testing
Positive =
primary infection
Test for IgM Antibody
IgG Positive =
Seroconversion
Negative,
no further tests
Retest later
Refer for prenatal diagnosis
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 26/37
Intervention: using results of maternal
screening to prevent congenital CMVdisease
Intervention: using results of maternal
screening to prevent congenital CMVdisease
Possible interventionPossible interventionPossible interventionPossible intervention• Counsel regarding
prevention (seroneg
ProblemsProblemsProblemsProblems• No proven means to
prevent maternal
• Use prenatal diagnosis,
abort infected fetus
• Use antivirals to prevent
or treat fetal infection
n ec on
• ~75% infected fetuses
will be normal
• No available antiviraltreatment for prenatal
use
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 27/37
Antiviral Therapy
for
Infection?
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 28/37
• 100 Neonates enrolled to receive 6 weeks of IVganciclovir (6 mg/kg/dose q 12 hours)
Phase lll randomized trial of ganciclovir for
symptomatic congenital CMV infectionsinvolving the CNS
,
untreated)
• Hearing Improvement was more likely in the GCVtreated group at 6 and 12 mos (OR 4.31, 4.03)
• 29/46 (63%) GCV recipients experiencedneutropenia, compared with 9/43 (21%) untreatedcontrol patients
Kimberlin et al, J. Pediatrics,143:17,2003
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 29/37
USE OF GANCICLOVIR IN SYMPTOMATICCONGENITAL CMV INFECTION
• 12 newborns treated for 2 weeks with 5mg/kg/day or 7.5 mg/kg/day + 3 months of 10
mg/day 3x/week
, ,
• Abnormal liver and haematologic function
appeared to clear faster with higher dose
• Although outcome appeared better with
higher dose, CNS sequelae appeared in bothgroups
from Nigro et al, J Pediatr 1994; 124: 318
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 30/37
A PHASE II STUDY OF GANCICLOVIR IN 47
NEWBORNS WITH SYMPTOMATIC CONGENITAL
CMV INFECTION
• Patients with CNS disease treated with8mg/kg/d or 12mg/kg/d iv for 6 weeks
• 19 % of participants had neutropenia
• 12 mg/kg reduced viral shedding; sheddingreturned when drug was discontinued
• 3 patients had improved hearing at 6
months; 25 had abnormal hearing
from Whitley et al, J Infect Dis, 1997; 175: 1080
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 31/37
Antiviral Therapy for
Congenital CMV Infection?
• Ganciclovir has been shown to be effectivetherapy for certain CMV infections in
immunocompromised hosts (e.g., retinitis
or enterocolitis in HIV-infected atients
• Neonatal experience with ganciclovir islimited, the toxicity of the drug is
considerable (e.g., platelets, neutrophils),
and oral bioavailability unreliable
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 32/37
Ganciclovir Therapy for
Congenital CMV? 2006
• A six week course of IV ganciclovir mayreduce the rate of long-term hearing loss inneonates with symptomatic CMV infection
• However, this regimen is associated withsignificant toxicity, long-term followupdata are lacking, and the optimal durationof therapy (if any) is unknown
• Potential benefits of antiviral therapy for
asymptomatically infected neonates maybe greater
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 33/37
Antiviral Therapy for
Congenital CMV? 2006
• Current role for IV ganciclovir uncertain:therapy “may be considered for patientswith symptomatic congenital CMV diseaseinvolving the CNS” (Kimberlin et al, 2003)
• 2006 Red Book says that it “is notrecommended routinely because ofinsufficient efficacy data”
• ?? Treatment of neonates with worsening
retinitis or hepatitis, severe pneumonia, orpersistent severe thrombocytopenia ??Duration of therapy ??
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 34/37
Prevention of CMV
Infections?
• A vaccine to prevent CMV infections
is desperately needed
• Trials of candidate vaccines areunderway
• CMV Vaccine development a “Level
One” priority !!
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 35/37
How is congenital CMV
prevented?
• Many different ways to
prevent CMV
• Our approach:
• Hygiene, especiallyHygiene, especiallyHygiene, especiallyHygiene, especiallyhandwashing handwashing handwashing handwashing
• Education about CMVEducation about CMVEducation about CMVEducation about CMV
and how to prevent itand how to prevent itand how to prevent itand how to prevent it
through hygiene through hygiene through hygiene through hygiene
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 36/37
How do we communicate
this message?
7/26/2019 Tmd175 Slide Congenital Cmv Infection
http://slidepdf.com/reader/full/tmd175-slide-congenital-cmv-infection 37/37
The End