Congenital CMV infectionInfectious and Tropical Pediatric DivisionDepartment of Child HealthMedical Faculty, University of Sumatera Utara

Congenital CMV infectionApproximately 0.152% of live birthsLeading cause of sensorineural deafnessMajor cause of mental retardation, cerebral palsyApproximately 10% death in symptomatic newbornsLifelong habilitation for impaired survivors

Fetus: Via placenta from the motherHuman milkBlood transfusion, organ transplantationChildren and adults: Mainly via bodily fluids (esp. urine, saliva)

How is CMV transmitted?

Transmission of CMV through the placenta barrier and infection of the fetusInfected motherviraemiainfection of placenta trophoblastsInfection of fetalendothelial cellsViralreplication intarget organs(kidney)Fetal viruriaVirus inamniotic fluidInfection ofthe oropharynxFetal viraemia

PRIMARY MATERNAL CMV INFECTION DURING PREGNANCY95% clinically inapparent

35% transmitted to fetus

No clear relationship between gestational age and transmission

Fetal damage more likely in first 26 weeks, (32%) than later (15%)

MATERNAL CMV INFECTION DURING PREGNANCY Primary maternal infection leads to fetal infection in 30-50% of cases--10-15% of these have overt clinical disease

Secondary maternal infection less likely to lead to fetal infection (1-2% ) but can do so and may lead to severe disease (Boppana et al, NEJM 2001, 344: 1366)

Rates of primary CMV infection during pregnancyStudy (Location)Rate as % ofRate as % of% cong CMV, PregnanciesSeronegativesprimary mat infStern1.14.145 (London)Grant (Scotland)0.290.7138Stagno (USA,0.571.447 mid-income)Ahlfors (Sweden)0.321.443Griffiths (London)0.300.8620

Symptomatic Congenital CMV InfectionJaundice (67%)Petechiae (76%)Hepatosplenomegaly (60%)Microcephaly (53%)Chorioretinitis (20%)Seizure (7%)Fatal outcome (10%)Boppana et al. (1999) Pediatrics 104:55

Sequelae of Congenital CMV Infections Neurological sequelae are the most common, and most severe: >90% of newborns with symptomatic congenital CMV infection have visual, audiologic and/or other neurological sequelae- 5-17% of newborns with asymptomatic congenital CMV infection develop neurological sequelae (esp. hearing loss)

Sequelae of Congenital CMV Infections Cranial CT is a good predictor of sequelae in neonates with congenital CMV infectionMost common abnormality is intracerebral calcification (typically periventricular)Boppana et al (Pediatrics 99:409, 1997) reported that 90% of neonates with abnormal CT scan developed at least 1 sequelaeOnly 1/17 neonates with normal CT had IQ < 70

SEQUELAE OF SYMPTOMATIC CONGENITAL CMV INFECTIONSeizuresChorioretinitisPeriventricular calcificationsSensorineural hearing lossmotor deficits

CHORIORETINITIS

Congenital CMV

Congenital CMV

CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAEPrimary maternal infectionSymptomatic congenital CMV infectionPresence of neonatal neurological abnormalitiesAbnormal head CT scanChorioretinitis in the newborn

CLINICAL IMPACT OF CONGENITAL CMV INFECTION Frequency of sequelae Symptomatic (7%) Asymptomatic (93%)Infant death10%0Hearing loss60%715%Mental retardation45%210%Cerebral palsy35%

Diagnosis of Congenital CMV InfectionsIsolation of CMV from urine or other body fluid (CSF, blood, saliva) in the first 21 days of life is considered proof of congenital infectionSerologic tests are unreliable; IgM tests currently available have both false positive and false negative resultsPCR may be useful in selected cases

Detection: screening for maternal CMV infectionCMV IgG antibody sensitive and specific screen for past infectionCMV IgM antibody variable sensitivity and specificityAntibody avidity testing can increase accuracy of detection of primary infectionNo test for immune mothers who will transmit

Advanced CMV diagnosisIgM confirmation by Western blotDetermination of the IgG avidity indexIsolation of the virus from urine, saliva and blood

A confirmatory test for CMV-IgMNew immunoblot1)Contains both structural and nonstructural proteins2)Reactivity to vp 150 can be confirmed with recpUL323)Agrees with consensus of different ELISAs4)Is easy to standardize5)Is easy to interpretrp150rp52rp130CKSrp38PurifiednativeviralproteinsRecombinantproteinsVp28Vp65Vp82Vp150

Weeks after beginning of symptomsAvidity index (%)70060504030201005101520253035Congenital CMV infectionsLow IgG avidity is linked to primary infection

Evaluation of mothers at risk of transmitting CMV to the fetusRefer for prenatal diagnosis

Intervention: using results of maternal screening to prevent congenital CMV diseasePossible intervention Counsel regarding prevention (seroneg mother)Use prenatal diagnosis, abort infected fetusUse antivirals to prevent or treat fetal infectionProblems No proven means to prevent maternal infection~75% infected fetuses will be normal No available antiviral treatment for prenatal use

Antiviral Therapy for Congenital CMV Infection?

100 Neonates enrolled to receive 6 weeks of IV ganciclovir (6 mg/kg/dose q 12 hours)

No significant difference in mortality (6% GCV, 12% untreated)

Hearing Improvement was more likely in the GCV treated group at 6 and 12 mos (OR 4.31, 4.03)

29/46 (63%) GCV recipients experienced neutropenia, compared with 9/43 (21%) untreated control patients

Kimberlin et al, J. Pediatrics,143:17,2003Phase lll randomized trial of ganciclovir for symptomatic congenital CMV infections involving the CNS

USE OF GANCICLOVIR IN SYMPTOMATIC CONGENITAL CMV INFECTION12 newborns treated for 2 weeks with 5 mg/kg/day or 7.5 mg/kg/day + 3 months of 10 mg/day 3x/weekHigher, but not lower dose, cleared viruriaAbnormal liver and haematologic function appeared to clear faster with higher doseAlthough outcome appeared better with higher dose, CNS sequelae appeared in both groupsfrom Nigro et al, J Pediatr 1994; 124: 318

A PHASE II STUDY OF GANCICLOVIR IN 47 NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTIONPatients with CNS disease treated with 8mg/kg/d or 12mg/kg/d iv for 6 weeks19 % of participants had neutropenia requiring dose modification12 mg/kg reduced viral shedding; shedding returned when drug was discontinued3 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 effective therapy for certain CMV infections in immunocompromised hosts (e.g., retinitis or enterocolitis in HIV-infected patients)Neonatal experience with ganciclovir is limited, the toxicity of the drug is considerable (e.g., platelets, neutrophils), and oral bioavailability unreliable

Ganciclovir Therapy for Congenital CMV? 2006A six week course of IV ganciclovir may reduce the rate of long-term hearing loss in neonates with symptomatic CMV infectionHowever, this regimen is associated with significant toxicity, long-term followup data are lacking, and the optimal duration of therapy (if any) is unknownPotential benefits of antiviral therapy for asymptomatically infected neonates may be greater

Antiviral Therapy for Congenital CMV? 2006Current role for IV ganciclovir uncertain: therapy may be considered for patients with symptomatic congenital CMV disease involving the CNS (Kimberlin et al, 2003) 2006 Red Book says that it is not recommended routinely because of insufficient efficacy data ?? Treatment of neonates with worsening retinitis or hepatitis, severe pneumonia, or persistent severe thrombocytopenia ?? Duration of therapy ??

Prevention of CMV Infections?A vaccine to prevent CMV infections is desperately neededTrials of candidate vaccines are underwayCMV Vaccine development a Level One priority !!

How is congenital CMV prevented?Many different ways toprevent CMV

Our approach:

Hygiene, especially handwashing

Education about CMV and how to prevent it through hygiene

How do we communicate this message?

The End

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