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)