Congenital cmv infection


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Congenital cmv infection

  1. 1. Congenital CMVinfection Siriporn phongjitsiri,MD Pediatric Infectious DivisionQueen Sirikit National Institute of Child Health July 27,2007
  2. 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. 3. How is CMV transmitted?• Fetus: Via placenta from the mother• Human milk• Blood transfusion, organ transplantation• Children and adults: Mainly via bodily fluids (esp. urine, saliva)
  4. 4. Who transmits CMV?• Duration of viral shedding following primary infection: • 2-3 weeks for adults • Months to years for young children• Therefore, CMV is most often transmitted by young children
  5. 5. Transmission of CMV through the placentabarrier and infection of the fetusInfected mother viraemia infection of placenta trophoblasts Infection of the oropharynx Infection of fetal Virus in endothelial cells amniotic fluid Fetal viraemia Fetal viruria Viral replication in target organs (kidney)
  6. 6. PRIMARY MATERNAL CMVINFECTION 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%)
  7. 7. MATERNAL CMV INFECTIONDURING 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)
  8. 8. Rates of primary CMV infectionduring pregnancy Study (Location) Rate as % of Rate as % of % cong CMV, PregnanciesSeronegativesprimary mat inf Stern 1.1 4.1 45 (London) Grant (Scotland) 0.29 0.71 38 Stagno (USA, 0.57 1.4 47 mid-income) Ahlfors (Sweden) 0.32 1.4 43 Griffiths (London) 0.30 0.86 20
  9. 9. Symptomatic CongenitalCMV Infection• Jaundice (67%)• Petechiae (76%)• Hepatosplenomegaly (60%)• Microcephaly (53%)• Chorioretinitis (20%)• Seizure (7%)• Fatal outcome (10%) Boppana et al. (1999) Pediatrics 104:55
  10. 10. Sequelae of CongenitalCMV 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. 11. Sequelae of CongenitalCMV 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. 12. SEQUELAE OF SYMPTOMATICCONGENITAL CMV INFECTION • Seizures • Chorioretinitis • Periventricular calcifications • Sensorineural hearing loss • motor deficits
  14. 14. Congenital CMV
  15. 15. Congenital CMV
  16. 16. CHARACTERISTICS ASSOCIATED WITHINCREASED RISK OF SEQUELAE • Primary maternal infection • Symptomatic congenital CMV infection • Presence of neonatal neurological abnormalities • Abnormal head CT scan • Chorioretinitis in the newborn
  17. 17. CLINICAL IMPACT OFCONGENITAL CMV INFECTION Frequency of sequelae Symptomatic (7%) Asymptomatic (93%)Infant death 10% 0Hearing loss 60% 7–15%Mental retardation 45% 2–10%Cerebral palsy 35% <1%Chorioretinitis 15% 1–2%
  18. 18. Diagnosis of CongenitalCMV 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
  19. 19. Detection: screening for maternalCMV 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
  20. 20. Advanced CMV diagnosis IgM confirmation by Western blot Determination of the IgG avidity index Isolation of the virus from urine, saliva and blood
  21. 21. A confirmatory test for CMV-IgMNew immunoblot µ1) Contains both structural Vp150 Purified Vp82 and nonstructural proteins native Vp65 viral2) Reactivity to vp 150 can Vp28 proteins be confirmed with rp150 recpUL32 rp52 Recombinant3) Agrees with consensus of rp130 proteins different ELISAs rp384) Is easy to standardize5) Is easy to interpret CKS
  22. 22. Congenital CMV infectionsLow IgG avidity is linked to primary infection 70 60Avidity index (%) 50 40 30 20 10 0 0 5 10 15 20 25 30 35 Weeks after beginning of symptoms
  23. 23. Evaluation of mothers at risk oftransmitting CMV to the fetus T e s t fo r I g G a n t ib o d y a t fir s t p r e n a t a l v is it P o s it iv e N e g a t iv e T e s t fo r I g M A n t ib o d y R e t e s t la t e r N e g a t iv e , P o s it iv e = I g G P o s it iv e = N e g a t iv e , n o fu r t h e r t e s t in g p r im a r y in fe c t io n S e r o c o n v e r s io n n o fu r th e r te s ts Refer for prenatal diagnosis
  24. 24. Intervention: using results of maternalscreening to prevent congenital CMVdiseasePossible intervention Problems• Counsel regarding • No proven means to prevention (seroneg prevent maternal mother) infection• Use prenatal diagnosis, • ~75% infected fetuses abort infected fetus will be normal• Use antivirals to prevent or treat fetal infection • No available antiviral treatment for prenatal use
  25. 25. Case Report: “Oral ganciclovirfor thetreatment of intrauterine cytomegalovirusinfection• Nulligravid cmv seronegative pt. received renal allograft from seropositive donor• Pt. became pregnant 3 months following acute CMV infection• AF CMV DNA+(80 copies) at 21 wks.• Oral CGV administered at 22 wks.• AF CMV DNA-at 26 weeks (8 copies)• Vigorous female delivered at birth• Newborn urine and blood CMV DNA-• Normal development @ 3 years of age Puliyandaet al. (2005)Transplant Infectious Disease 7:71-7
  26. 26. Antiviral Therapy forCongenital CMVInfection?
  27. 27. Phase lll randomized trial of ganciclovir forsymptomatic congenital CMV infectionsinvolving the CNS • 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
  28. 28. USE OF GANCICLOVIR IN SYMPTOMATICCONGENITAL 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 etal J Pediat 1 994; 1 24: 31 8 , r
  29. 29. A PHASE II STUDY OF GANCICLOVIR IN 47NEWBORNS WITH SYMPTOMATIC CONGENITALCMV 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 etal J InfectDis, 1 997; 1 75: 1 080 ,
  30. 30. Antiviral Therapy forCongenital 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
  31. 31. Ganciclovir Therapy forCongenital 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
  32. 32. Antiviral Therapy forCongenital 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 ??
  33. 33. Prevention of CMVInfections?• A vaccine to prevent CMV infections is desperately needed• Trials of candidate vaccines are underway• CMV Vaccine development a “Level One” priority !!
  34. 34. How is congenital CMVprevented? • Many different ways to prevent CMV • Our approach:• Hygiene, especially handwashing• Education about CMV and how to prevent it through hygiene
  35. 35. How do we communicatethis message?
  36. 36. The End