1. Congenital CMV infection Infectious and Tropical Pediatric Division Department of Child Health Medical Faculty, University of Sumatera Utara

2. Congenital 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

3. Fetus: Via placenta from the mother Human milk Blood transfusion, organ transplantation Children and adults: Mainly via bodily fluids (esp. urine, saliva) How is CMV transmitted?

4. Transmission of CMV through the placenta barrier and infection of the fetus Infected motherviraemiainfection of placenta trophoblasts Infection of fetal endothelial cells Viral replication in target organs (kidney) Fetal viruria Virus in amniotic fluid Infection of the oropharynx Fetal viraemia

5. PRIMARY MATERNAL CMV INFECTION DURING PREGNANCY 95% 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%)

6. 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 )

7. Rates of primary CMV infection during pregnancy Study (Location)Rate as % ofRate as % of% cong CMV, PregnanciesSeronegativesprimary mat inf Stern1.14.145 (London) Grant (Scotland)0.290.7138 Stagno (USA,0.571.447 mid-income) Ahlfors (Sweden)0.321.443 Griffiths (London)0.300.8620

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

10. 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)

11. Sequelae of Congenital CMV Infections Cranial CT is a good predictor of sequelae in neonates with congenital CMV infection Most 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 sequelae Only 1/17 neonates with normal CT had IQ < 70

12. SEQUELAE OF SYMPTOMATIC CONGENITAL CMV INFECTION Seizures Chorioretinitis Periventricular calcifications Sensorineural hearing loss motor deficits

13. CHORIORETINITIS

14. Congenital CMV

17. CHARACTERISTICS ASSOCIATED WITH INCREASED RISK OF SEQUELAE Primary maternal infection Symptomatic congenital CMV infection Presence of neonatal neurological abnormalities Abnormal head CT scan Chorioretinitis in the newborn

18. CLINICAL IMPACT OF CONGENITAL CMV INFECTION F requency of sequelae Symptomatic (7%) Asymptomatic (93%) Infant death10%0 Hearing loss60%7 – 15% Mental retardation45%2 – 10% Cerebral palsy35%<1% Chorioretinitis15% 1 – 2%

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

20. Detection: screening for maternal CMV infection CMV IgG antibody – sensitive and specific screen for past infection CMV IgM antibody – variable sensitivity and specificity Antibody avidity testing can increase accuracy of detection of primary infection No test for immune mothers who will transmit

22. Advanced CMV diagnosis  IgM confirmation by Western blot  Determination of the IgG avidity index  Isolation of the virus from urine, saliva and blood

23. A confirmatory test for CMV-IgM New immunoblot 1)Contains both structural and nonstructural proteins 2)Reactivity to vp 150 can be confirmed with recpUL32 3)Agrees with consensus of different ELISAs 4)Is easy to standardize 5)Is easy to interpret rp150 rp52 rp130 CKS rp38 Purified native viral proteins Recombinant proteins Vp28 Vp65 Vp82 Vp150 

24. Weeks after beginning of symptoms Avidity index (%) 70 0 60 50 40 30 20 10 0 5 1520253035 Congenital CMV infections Low IgG avidity is linked to primary infection

25. Evaluation of mothers at risk of transmitting CMV to the fetus Refer for prenatal diagnosis

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

27. Antiviral Therapy for Congenital CMV Infection ?

28. 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,143:17,2003 Phase lll randomized trial of ganciclovir for symptomatic congenital CMV infections involving the CNS

29. USE OF GANCICLOVIR IN SYMPTOMATIC CONGENITAL CMV INFECTION 12 newborns treated for 2 weeks with 5 mg/kg/day or 7.5 mg/kg/day + 3 months of 10 mg/day 3x/week Higher, but not lower dose, cleared viruria Abnormal liver and haematologic function appeared to clear faster with higher dose Although outcome appeared better with higher dose, CNS sequelae appeared in both groups from Nigro et al, J Pediatr 1994; 124: 318

30. A PHASE II STUDY OF GANCICLOVIR IN 47 NEWBORNS WITH SYMPTOMATIC CONGENITAL CMV INFECTION Patients with CNS disease treated with 8mg/kg/d or 12mg/kg/d iv for 6 weeks 19 % of participants had neutropenia requiring dose modification 12 mg/kg reduced viral shedding; shedding returned 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

31. 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

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

33. Antiviral Therapy for Congenital CMV? 2006 Current 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 ??

34. Prevention of CMV Infections? A vaccine to prevent CMV infections is desperately needed Trials of candidate vaccines are underway CMV Vaccine development a “Level One” priority !!

35. How is congenital CMV prevented? Many different ways to prevent CMV Our approach: Hygiene, especially handwashing Education about CMV and how to prevent it through hygiene

36. How do we communicate this message?

37. The End