Treatment & Prognostic factor of Congenital CMV infection SNUH PID Clinical & Research Fellow Ki-Wook, YUN 2010. 07. 07
Congenital CMV Infection a lifelong latent infection following primary infection periodically reactivate with shedding of infectious virus in utero transmission to the fetus: 1.4% New maternal CMV infection - in 0.7 ~ 4.1% of pregnancies - Fetal transmission in 30–60% much more likely to cause fetal damage 1/3: have disease at birth or develop severe sequelae
Deafness, mental retardation, cerebral palsy, convulsions and chorioretinitis Prevalence of congenital neurological manifestations related to the gestational age, in which primary CMV infection occurred. The Journal of Maternal-Fetal and Neonatal Medicine, February 2009; 22(2): 169–174
occurs in 0.6–0.7% of all newborns Symptomatic disease - in 10% of all congenitally infected infants microcephaly, chorioretinitis, hepatosplenomegaly and sensorineuralhearing loss, etc… Asymptomatic children at birth - a risk of hearing loss, with approximately 8% Congenital CMV Infection
Permanent disabilities 무엇? Frequency of sequelae among children with congenital CMV infection Journal of Clinical Virology 46S (2009) S6–S10 (by CDC)
PerinatalCMV infection Intrapartum and immediately postnatal transmission - 10–15% of infants acquiring CMV in the first 4–8 weeks of life 50% of the infants born to mothers with cervical CMV shedding 70% of infants of mothers excreting CMV in the milk will be infected perinatally Heating the milk up to 72°Cfor 10 seconds inactivates the virus saving immunologic/nutritional properties
Prenatal Imaging (MRI vs. US) 2000–2008, 38 consecutive fetuses with proved CMV infection Targeted ultrasound: every 3-4 weeks, until delivery MR 1st - at around 30 WG for 1st and 2nd trimester infections 2nd - later on (upon diagnosis) for third trimester infection Radiology: Volume 255: Number 2—May 2010
Number of Pathologic Findings Detected between Examinations 2000–2008, 38 consecutive fetuses with proved CMV infection P = .0002 P = .05 P = .08 Radiology: Volume 255: Number 2—May 2010
Type of Pathologic Findings Detected at US and First Fetal MR Imaging Efficiency of US and First Fetal MR Imaging Examinations in Predicting CMV Infection–related Postnatal Symptoms Radiology: Volume 255: Number 2—May 2010
Singleton pregnancies with proven vertical transmission of CMV (Primary CMV infection) Total 38 Women 1st Trimester: 10 2nd Trimester: 19 3rd Trimester: 9 16 5: TOP both US scans & MRI normal 3 5 abnormal US normal MRI normal US subtle MRI favorable with normal hearing and developmental outcome hyper-intense signal in the white matter, specifically in the Temporal lobe 2/3: damage to the auditory system Ultrasound Obstet Gynecol. 2010 Apr 15. Prenatal Imaging (MRI vs. US)
Umbilical cord blood samples 1,010 neonates, Yonaha Clinic (Japan), 2005. 7~ 2007. 3 Umbilical cord blood was collected at birth 2 cases (0.2%): CMV DNA was detected TABLE II. Results of Developmental Testing in Infants With CMV DNA-Positive Cord Blood Samples Journal of Medical Virology 81:1773– 1776 (2009)
Umbilical cord blood samples Detection of CMV DNA in preserved umbilical cords from patients with bilateral sensori-neural hearing loss (3/15) useful for the retrospective diagnosis of congenital CMV infection Table 2 Clinical and virologic characteristics of CMV-positive patients with bilateral sensorineural hearing loss Eur Arch Otorhinolaryngol (2009) 266:351–355 (by Japan)
Neuroimaging in newborns In newborns with symptomatic congenital CMV infection, - the best available predictor of neurodevelopmentaloutcome Table 2 Neuroimaging findings of 14 newborns with symptomatic congenital CMV infection Eur J Pediatr (2006) 165: 636–645
Beta-2 microglobulin Neonatology 2008;94:183–186 Correlation between CSF and neuroimaging findings in 14 newborns with symptomatic congenital CMV infection Concentrations of β2-m in CSF 14 newborns with symptomatic congenital CMV infection Concentrations of β2-m in serum Eur J Pediatr (2006) 165: 636–645
Prevention Prevalence of congenital CMV disease in CMV-infected infants from 15 hyperimmunoglobulin (HIG)-treated pregnant women with fetal abnormalities or from six women who had received preventive HIG. The Journal of Maternal-Fetal and Neonatal Medicine, February 2009; 22(2): 169–174
Ganciclovirtherapy a meta analysis of 10 papers compared with the non-ganciclovir therapy control group ↑improvement rate (91.4% vs 34.0%; p<0.01) CMV infection indexes to become negative in more patients (87.6% vs 15.3%; p<0.01) ↓incidence of hearing disturbance (4.7% vs 37.2%; p<0.01) The incidence of the ganciclovir-therapy-related S/E: low Zhongguo Dang Dai ErKeZaZhi. 2010 Vol 12:1;39-9
GCV & Neurodevelopmental outcomes 100 neonates, symptomatic congenital CMV involving the CNS, randomized to either 6 weeks of IV ganciclovir or no treatment Denver developmental tests: 6 weeks, 6 months, and 12 months (A) Total delays, including Personal/Social, Fine Motor, Language, and Gross Motor components of the Denver II developmental test (mean±SE). (B) excluding the Language component. J ClinVirol. 2009 Dec;46 Suppl 4:S22-6. Epub 2009 Sep 18.
Summary of clinical manifestations and treatment are depicted J Pediatr 2010;-:---) GCV Tx. for Chorioretinitis
Reports on treatment and outcome of chorioretinitis caused by congenital cytomegalovirus infection Long-term treatment necessary for managing congenital CMV-associated chorioretinitis ?!! J Pediatr 2010;-:---)
Oral ValganciclovirTx. Oral valganciclovirV-GCV, 15 mg/kg bid for 6 weeks to 13 neonates with symptomatic congenital CMV infection paucity of adverse events, stability of drug plasma concentrations Fig. 1 The figure shows the percentage of plasma and urine cytomegalovirus (CMV)-negative samples at various time-points Eur J Clin Microbiol Infect Dis (2009) 28:1465–1470
Oral ValganciclovirTx. A newborn with asymptomatic congenital CMV with bilateral SNHL Oral treatment with valganciclovir - progressive improvement of SNHL, - effectively reduced the CMV viral load - well tolerated without apparent A/Es Brainstem evoked response audiometry (BERA) results of patient during 1-year follow-up J TropPediatr. 2010 Jun 24.
IV Ganciclovirfollowed by long-term oral Valganciclovir 6-weeks' treatment with ganciclovir ganciclovir for 6 weeks followed by oral valganciclovir to age 12 months Fig. 1 Study outcomes according to BSER status before treatment, total ears analysis Eur J Pediatr. 2010
CMV viral load & Hearing loss 135 children with congenital CMV infection Peripheral blood viral load is not associated with hearing loss However, a viral load of <3500 ge/mL - lower risk of hearing loss in children born with asymptomatic congenital infection. FIGURE 1. Results of tests measuring levels of CMV DNA in PB at 3 different age ranges from children enrolled in the study with congenital CMV infection with asymptomatic (A) and symptomatic (B) infection at birth that had hearing loss (○) and normal hearing (▲). Pediatr Infect Dis J. 2009 Jul;28(7):588-92.
CMV shedding & delayed hearing loss longitudinal follow-up of children with congenital inf. older age at last culture-positive visit (OR = 1.6) Logistic regression modeling of the association between persistent positive CMV cultures and delayed hearing loss Pediatr Infect Dis J. 2009 Jun;28(6):515-20. (CDC)
Neonatal cytomegalovirus blood load and risk of sequelae 1997.1 ~ 2003.12, 99 newborns The proportion of children who developed sequelae at 12 months according to the neonatal CMV blood load. Pediatrics. 2006 Jan;117(1):e76-83. Epub 2005 Dec 1.
Sensitivity, Specificity, PPV, and NPV of Neonatal pp65 Antigenemia and DNAemia (Cutoff Point 103 Copies per 105 PMNLs) With Regard to the Presence or Absence of CMV Sequelae at 12 Months of Life a Fisher’s exact test. Pediatrics. 2006 Jan;117(1):e76-83. Epub 2005 Dec 1.
Distribution of CMV genotypes of human cytomegalovirus strains collected from congenitally and postnatally infected Japanese children Arch Virol (2008) 153:667–674
Relationship between gB genotype and clinical outcome Arch Virol (2008) 153:667–674
Guidelines (1) J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK)
J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK) Guidelines (2)
Guidelines (3) J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK)
Guidelines (4) J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK)
Guidelines (5) J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK)