Tmd175 Slide Congenital Cmv Infection

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Congenital CMVinfection

Infectious and Tropical Pediatric Division

Department of Child Health

Medical Faculty, University of Sumatera Utara



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



• 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)



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



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)



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



Symptomatic CongenitalCMV Infection

• Jaundice (67%)• Petechiae (76%)

• Microcephaly (53%)

• Chorioretinitis (20%)

• Seizure (7%)

• Fatal outcome (10%)

Boppana et al. (1999) Pediatrics 104:55



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)



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



SEQUELAE OF SYMPTOMATICCONGENITAL CMV INFECTION

• Seizures

• Chorioretinitis

• Periventricular calcifications

• Sensorineural hearing loss

• motor deficits



CHORIORETINITIS



Congenital CMV



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



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%



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



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



Advanced CMV diagnosisAdvanced CMV diagnosis

IgM confirmation by Western blot

index

Isolation of the virus from urine,

saliva and blood



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



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



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



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



Antiviral Therapy

for

Infection?



• 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



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



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



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



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



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 ??



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 !!



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



How do we communicate

this message?



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