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Treatment & Prognostic factor of Congenital CMV infection
SNUH PID Clinical & Research FellowKi-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
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
Deafness, mental retardation, cerebral palsy, convulsions and chorioretinitis
• occurs in 0.6–0.7% of all newborns
• Symptomatic disease - in 10% of all congenitally infected infants microcephaly, chorioretinitis, hepatosplenomegaly and sensorineural hearing loss, etc…
• Asymptomatic children at birth - a risk of hearing loss, with approximately 8%
Congenital CMV Infection
Journal of Clinical Virology 46S (2009) S6–S10 (by CDC)
Frequency of sequelae among children with congenital CMV infection
Permanent disabilities 무엇 ?
Perinatal CMV 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 shed-ding
70% of infants of mothers excreting CMV in the milk will be infected perinatally
• Heating the milk up to 72°C for 10 seconds inactivates the virus saving immunologic/nutritional prop-
erties
Diagnosis
Prenatal Imaging (MRI vs. US)
• 2000–2008, 38 consecutive fetuses with proved CMV infec-tion
• 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
Radiology: Volume 255: Number 2—May 2010
Number of Pathologic Findings Detected between Exami-nations
P = .0002
P = .05
P = .08
2000–2008, 38 consecutive fetuses with proved CMV in-fection
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
Total 38 Women
1st Trimester: 10
3
16
5
Singleton pregnancies with proven vertical transmission of CMV (Primary CMV infec-tion)
2nd Trimester: 19
3rd Trimester: 9
both US scans & MRI normal
5: TOP
abnormal US normal
MRI
2/3: damage to the auditory sys-tem
normal US subtle MRI
favorable with normal hear-ing and developmental out-come
hyper-intense signal in the white matter, specifically in the Temporal lobe
Ultrasound Obstet Gynecol. 2010 Apr 15.
Prenatal Imaging (MRI vs. US)
Umbilical cord blood sam-ples
• 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
Journal of Medical Virology 81:1773– 1776 (2009)
TABLE II. Results of Developmental Testing in Infants With CMV DNA-Positive Cord Blood Samples
Table 2 Clinical and virologic characteristics of CMV-posi-tive patients with bilateral sensorineural hearing loss
Eur Arch Otorhinolaryngol (2009) 266:351–355 (by Japan)
• Detection of CMV DNA in preserved umbilical cords from pa-tients with bilateral sensori-neural hearing loss (3/15)
• useful for the retrospective diagnosis of congenital CMV in-fection
Umbilical cord blood sam-ples
Neuroimaging in newborns
• In newborns with symptomatic congenital CMV infection, - the best available predictor of neurodevelopmental out-
come
Eur J Pediatr (2006) 165: 636–645
Table 2 Neuroimaging findings of 14 newborns with symptomatic congenital CMV infection
Neonatology 2008;94:183–186
Eur J Pediatr (2006) 165: 636–645
Concentrations of β2-m in CSF 14 new-borns with symptomatic congenital CMV infection
Concentrations of β2-m in serum
Beta-2 microglobulinCorrelation between CSF and neuroimaging findings in 14 newborns with symptomatic congenital CMV in-fection
Treatment
The Journal of Maternal-Fetal and Neonatal Medicine, February 2009; 22(2): 169–174
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 preven-tive HIG.
Prevention
Ganciclovir therapy
• 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 Er Ke Za Zhi. 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 treat-ment
• Denver developmental tests: 6 weeks, 6 months, and 12 months
J Clin Virol. 2009 Dec;46 Suppl 4:S22-6. Epub 2009 Sep 18.
(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 Pediatr 2010;-:---)
Summary of clinical manifestations and treatment are depicted
GCV Tx. for Chorioretinitis
J Pediatr 2010;-:---)
Reports on treatment and outcome of chorioretinitis caused by congenital cytomegalovirus infection
Long-term treatment necessary for managing congenital CMV-associ-ated chorioretinitis ?!!
Oral Valganciclovir Tx.
• Oral valganciclovir V-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
Eur J Clin Microbiol Infect Dis (2009) 28:1465–1470
Fig. 1 The figure shows the percentage of plasma and urine cytomegalovirus (CMV)-negative samples at various time-points
Oral Valganciclovir Tx.
• 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
J Trop Pediatr. 2010 Jun 24.
Brainstem evoked response audiometry (BERA) results of patient during 1-year fol-low-up
IV Ganciclovir followed by long-term oral Valganciclovir
Eur J Pediatr. 2010
Fig. 1 Study outcomes according to BSER status before treatment, total ears analysis
6-weeks' treat-ment with ganci-clovir
ganciclovir for 6 weeks followed by oral valganci-clovir to age 12 months
Prognostic Factors
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 asympto-
matic congenital infection.
Pediatr Infect Dis J. 2009 Jul;28(7):588-92.
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 (▲).
CMV shedding & delayed hearing loss
• longitudinal follow-up of children with congenital inf.
• older age at last culture-positive visit (OR = 1.6)
Pediatr Infect Dis J. 2009 Jun;28(6):515-20. (CDC)
Logistic regression modeling of the association be-tween persistent positive CMV cultures and delayed hearing loss
Neonatal cytomegalovirus blood load and risk of seque-lae
• 1997.1 ~ 2003.12, 99 newborns
Pediatrics. 2006 Jan;117(1):e76-83. Epub 2005 Dec 1.
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.
Arch Virol (2008) 153:667–674
Distribution of CMV genotypes of human cytomegalovirus strains collected from con-genitally and postnatally infected Japanese children
Arch Virol (2008) 153:667–674
Relationship between gB genotype and clinical out-come
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)
J. Perinat. Med. 37 (2009) 433–445(by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK)
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)