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  • Figure 1. Prevalence of congenital neurological manifestations related to the gestational age, in which primary CMV infection occurred.
    Multi-system disease included deafness, mental retardation, cerebral palsy, convulsions and chorioretinitis. WG: weeks’ gestation. Modified from Pass RF, et al. J Clin Virol 2006;35:216–220.
  • Symptomatic disease occurs in 10% of all congenitally infected infants, resulting in a spectrum of clinical manifestations that include microcephaly, chorioretinitis, hepatosplenomegaly and sensorineural hearing loss, among others.
    Even those children who are asymptomatic at birth have a risk of hearing loss, with approximately 8% experiencing this sequela.
    Overall, congenital CMV infection accounts for one-third of all cases of sensorineural hearing loss.
    The economic burden of disease exceeds $2 billion annually in the USA.

    Therefore, this infection has been the target for antiviral therapy.
    Studies performed by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (CASG) have evaluated ganciclovir for the treatment of symptomatic congenital CMV infection with central nervous system involvement.
    In a randomized, controlled clinical trial of ganciclovir treatment (6 mg/kg iv every 12 h for 6 weeks) brainstem-evoked responses were utilized as the primary endpoint and demonstrated stabilization of hearing both at 6 months and >1 year.
    Treatment was associated with neutropenia in over 60% of treated patients.
    Since ganciclovir must be given intravenously, studies with its prodrug, valganciclovir, have been performed to assess pharmacokinetics and pharmacodynamics.
    Currently, a clinical trial of 6 weeks versus 6 months of valganciclovir is being performed by the CASG.
    Notably, only intravenous ganciclovir and orally administered valganciclovir have been used to treat congenital CMV infection.
    Hopefully, other drugs such as maribavir will be available for evaluation in this population.
  • Fig. 2. Frequency of sequelae among children with congenital CMV infection (adapted from Dollard et al.3).
    Highlighted boxes show children who develop permanent disabilities. Data are from a literature review, with varying collection periods spanning multiple years.3
  • Thirty-eight fetuses with CMV infection, examined by using serial level II US, underwent fetal MR imaging (mean gestational age, 25 weeks; age range at first fetal MR examination, 20-34 weeks).
    The frequency of pathologic findings at US (29 cases with transabdominal examination and nine cases with both transabdominal and transvaginal examination) and MR imaging was calculated, and a comparison between techniques by considering number (paired Student t test) and type (McNemar test) of finding was made.
    A comparison (paired Student t test) in cases of repeated fetal (nine of 38) and/or postnatal (14 of 38) MR imaging was obtained.
    Diagnostic and prognostic sensitivity was calculated for both techniques.

    RESULTS: US and MR imaging findings were both normal in 47% of cases (18 of 38). Abnormal studies were reported in 26% (10 of 38) of US and 53% (20 of 38) of MR imaging cases.
    In 47% of cases (18 of 38), MR imaging provided additional information (P = .0002).
    MR imaging had better results than US in detecting polar temporal lesions (P = .0001), microencephaly (P = .03), and cortical anomalies (P = .06).
    In 44.5% of cases (four of nine), the second fetal MR examination results showed new findings (P = .05).
    In 79% of cases, postnatal MR imaging results confirmed prenatal findings (P = .08).
    MR imaging had higher sensitivity than US in detecting brain anomalies (92% vs 38%) and in predicting symptomatic infection (83% vs 33%).
    US and MR imaging revealed low positive predictive values (29% vs 36%).

    CONCLUSION: Fetal MR imaging results can show abnormalities in the fetal brain after CMV infection, even when US results are normal. The early detection of some brain abnormalities, such as microencephaly and cortical anomalies, may substantially influence the prognosis of fetal infection.
  • Table 1
    Number of Pathologic Findings Detected between Examinations
    * P = .0002 for US versus first MR examination (Student t test for paired data).
    † P = .05 for fi rst versus second MR examination (Student t test for paired data).
    ‡ P = .08 for fetal MR imaging (fi rst or second MR examination, when present) versus postnatal MR imaging (Student t test for
    paired data).

    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
  • Table 2
    Type of Pathologic Findings Detected at US and First Fetal MR Imaging
    Note.—Data are numbers of fi ndings, with percentages in parentheses.
    * McNemar test.
  • We report the clinical course of two neonates with congenital CMV infection confirmed by real-time polymerase chain reaction (PCR) for CMV DNA in umbilical cord blood.
    A total of 1,010 neonates born at Yonaha Clinic from July 2005 to March 2007 were investigated.
    Umbilical cord blood was collected at birth, and DNA was extracted to screen for CMV DNA by real-time PCR.
    Head MRI and a developmental test were conducted for two cases (0.2%) in which CMV DNA was detected.
    Neither case showed clear abnormalities at birth, and head CT conducted at 1 month after birth revealed no abnormalities.
    Auditory brainstem responses were normal at both 1 and 12 months after birth in both cases.
    Head MRI at 12 months showed abnormalities in both cases.
    For both cases, development tests conducted at 12 months revealed mild developmental delays, particularly in posture and movement areas, which might have been caused by congenital CMV infection.
  • Table 1 Clinical characteristics of each group with SNHL
    SNHL sensorineural hearing loss, EVAs enlarged vestibular aqueducts

    Table 2 Clinical and virologic characteristics of CMV-positive patients with bilateral sensorineural hearing loss
    CMV cytomegalovirus, CT computed tomography, MRI magnetic resonance imaging
  • Table 2 Neuroimaging findings of 14 newborns with symptomatic congenital CMV infection
    - no; + mild; ++ moderate; +++ severe
    periventricular (PV)
    Hyperechogenic areas in the thalamus and basal ganglia (HTBG)
    neuronal migration disorders (NMDs)
  • Fig. 5 Correlation between CSF and neuroimaging findings in 14 newborns with symptomatic congenital CMV infection.
    a Correlation between neuroimaging scores and CSF β2-m (rs =.753).
    b β2-m concentrations in six newborns with neuroimaging scores of 2–3 (median 12.83 mg/L, range 3.5–20.00 mg/L) vs. eight newborns with neuroimaging scores of 0–1 (median 5.52 mg/L, range .65–9.15 mg/L).
    c Correlation between neuroimaging scores and CSF NSE (rs =.620).
    d NSE concentrations in six newborns with neuroimaging scores of 2–3 (median 19.9 ng/ml, range 7.60–98.40 ng/ml) vs. eight newborns with neuroimaging scores of 0–1 (median 9.45 ng/ml, range 2.90–15.90 ng/ml)
  • Figure 2. 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. Controls were seven women with fetal abnormalities and 19 women who did not accept preventive HIG infusions.
  • following electronic databases: PubMed (January 1988 to January 2009), EMbase (January 1988 to January 2009), the Cochrane library (Issue 3, 2003 and Issue 1, 2009), the Chinese Journals Full-text Database (January 1994 to January 2009), the Chinese Biological Medical Disc (January 1994 to January 2009) and the Chinese Medical Current Contents (January 1994 to January 2009).
  • BACKGROUND: Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS).

    OBJECTIVES: To assess the neurodevelopmental impact of ganciclovir therapy in this population.

    STUDY DESIGN: 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment.
    Denver developmental tests were performed at 6 weeks, 6 months, and 12 months.
    For each age, developmental milestones that > or =90% of normal children would be expected to have achieved were identified.
    The numbers of milestones not met ("delays") were determined for each subject.
    The average number of delays per subject was compared for each treatment group.

    RESULTS: At 6 months, the average number of delays was 4.46 and 7.51, respectively, for ganciclovir recipients and "no treatment" subjects (p=0.02).
    At 12 months, the average number of delays was 10.06 and 17.14, respectively (p=0.007).
    In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 months (p=0.007).

    CONCLUSIONS: Infants with symptomatic congenital CMV involving the CNS receiving intravenous ganciclovir therapy have fewer developmental delays at 6 and 12 months compared with untreated infants. Based on these data as well as the previously published data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy can be considered in the management of babies with symptomatic congenital CMV disease involving the CNS.
    If treatment is initiated, it should be started within the first month of life and patients should be monitored closely for toxicity, especially neutropenia.
    Since existing data only address the treatment of symptomatic congenital CMV disease involving the CNS, these data cannot be extrapolated to neonates with other manifestations of CMV disease, including asymptomatic babies and symptomatic babies who do not have CNS involvement.
  • Figure. Summary of clinical manifestations and treatment are depicted: visual and hearing impairment, antiviral treatments, and
    longitudinal changes in cytomegalovirus viral loads in the urine, blood cells, and plasma specimens measured with the real-time
    polymerase chain reaction assay.

    We report an infant with congenital CMV infection, who required a 6-month course of antiviral therapy to control his chorioretinitis.
    Long-term treatment may be necessary for managing congenital CMV-associated chorioretinitis.

  • Table. Reports on treatment and outcome of chorioretinitis caused by congenital cytomegalovirus infection
    *One patient required 3 additional series of GCV therapy intravenously.
  • This study was performed to assess oral valganciclovir V-GCV (GCV pro-drug), 15 mg/kg bid for 6 weeks to 13 neonates with symptomatic congenital cytomegalovirus (CMV).

    We monitored plasma levels of GCV within 30 days of therapy: C(trough), and C(2h) (before and the 2 hours after administration), we performed viral assessment in plasma and urine and tolerability at baseline, and every fortnight.

    Pharmacokinetics showed GCV stable and effective plasma concentrations: mean C(trough) = 0.51 +/- 0.3 and C(2h) : 3.81 +/- 1.37 microg/ml.
    No significant variability was seen neither intra-patient nor inter-patients.
    One newborn discontinued therapy because of thrombocytopenia, another finished with a neutrophils count of 1,000/microl.
    At the end of therapy 6 out of 12 and 8 out of 12 newborns were negative for CMV in urine and plasma.
    The 4 newborns positive for CMV DNA showed a 90% reduction of pre-therapy values.
    Clinically, the 4 patients reporting hepatic disease and the 3 with thrombocytopenia recovered after 6 weeks of therapy.
    Eight newborns suffered from SNHL; at the 6-month follow-up no patients had worsened, 2 had improved, and no deterioration was reported in 3 newborns with chorioretinitis scarring.
    The paucity of adverse events, and the effectiveness and stability of drug plasma concentrations are the important findings of our study.
  • Although 90% of the congenitally infected infants are asymptomatic at birth, evidence is accumulating that these infants are at risk for audiologic, neurologic and developmental sequelae.

    In symptomatically infected infants, ganciclovir therapy administered in the neonatal period prevents hearing deterioration.

    However, preventative therapy of asymptomatic congenital CMV disease is controversial.

    Here in, we reported a male newborn with asymptomatic congenital CMV with bilateral SNHL.
    Oral treatment with valganciclovir in patient resulted in progressive improvement of SNHL, which effectively reduced the CMV viral load and was well tolerated without apparent adverse effects.
  • Fig. 1 Study outcomes according to BSER status before treatment, total ears analysis
  • BACKGROUND: This study was designed to determine whether elevated viral load in infants and young children is associated with congenital cytomegalovirus (CMV)-related hearing loss.
    METHODS: Blood samples were obtained from 135 children with congenital CMV infection.
    CMV DNA in the peripheral blood was quantitated with a real-time polymerase chain reaction assay.
    Viral load measurements were analyzed in 3 different age groups (<2 months, 2-12 months, 12-36 months).

    RESULTS: In children with symptomatic and asymptomatic infection, CMV DNA levels were not different between children with hearing deficit and those with normal hearing in all 3 age groups.
    In children with asymptomatic infection, the positive predictive value of a peripheral blood viral load >3500 genomic equivalents per milliliter (ge/mL) at <2 months and 2 to 12 months of age is 8%, and at 12 to 36 months of age is 11.8%.
    However, the negative predictive value of a viral load <3500 ge/mL is 94.4% at <2 months of age, and 100% at 2 to 36 months of age.

    CONCLUSIONS: Peripheral blood viral load is not associated with hearing loss in children with congenital CMV infection.
    However, a viral load of <3500 ge/mL is associated with a lower risk of hearing loss in children born with asymptomatic congenital infection.
  • To evaluate the relationship between persistent CMV shedding and delayed sensorineural hearing loss in children born with congenital CMV.
    METHODS: Serial audiologic assessments and CMV cultures of urine and saliva were performed on 580 children who had been diagnosed with congenital CMV infection.

    RESULTS: Prevalence of CMV culture-positivity in any specimen decreased to approximately 50% by the third birthday and approximately 5% after the seventh birthday.
    Intermittent shedding occurred in 28% of children.
    Seventy-seven children had hearing loss at birth and 38 children developed delayed hearing loss by the end of follow-up.

    In multivariate analyses, delayed hearing loss was strongly associated with symptomatic infection at birth (OR = 5.9, 95% CI: 1.8-18.9) and modestly associated with older age at last culture-positive visit (OR = 1.6, 95% CI: 1.1-2.0, comparing 1-year age differences)

    Observed rates of delayed hearing loss were 0.79 per 100 person-years for children asymptomatic at birth and 4.29 per 100 person-years for children symptomatic at birth.

    Between the ages of 6 months and 8 years, we would expect delayed hearing loss to occur in 6.9% of asymptomatic children and in 33.7% of symptomatic children.

    CONCLUSIONS: The strongest risk factor for delayed hearing loss was CMV-related symptoms at birth, but many asymptomatic children also developed delayed hearing loss.
    Longer duration of CMV shedding may also be a predictor of delayed hearing loss.

    TABLE 4
    Logistic regression modeling of the association between persistent positive CMV cultures and delayed hearing loss*
    * The 21 children with delayed hearing loss were matched 3-to-1 by age at last hearing evaluation with 63 randomly selected children who did not develop hearing loss.
    Model A used age at last culture-positive visit as the exposure variable.
    Model B used number of culture-positive visits as the exposure variable. The other covariates were the same for the two models.

    † Comparing 1-month age differences.
    ‡ Comparing 1-visit differences.

    CMV, cytomegalovirus; OR, odds ratio; CI, confidence interval.
    Pediatr Infect Dis J. Author manuscript; available in PMC 2010 June 1.
  • The aim of the present study was to assess the diagnostic and prognostic value of detection and quantification of virus in neonatal blood samples of symptomatic and asymptomatic newborns with CMV congenital infection.

    METHODS: Between January 1997 and December 2003, we studied 99 newborns who were born to women with primary, recurrent, and undefined CMV infection during pregnancy.
    CMV congenital infection was identified by isolation of the virus in urine within the second week of life.
    Fifty-eight of 99 infants were infected and were assessed clinically for disease in the newborn period and classified as having symptomatic or asymptomatic infection on the basis of physical, instrumental, and laboratory findings.
    The infants were followed up from birth according to a protocol of the tertiary NICU at the University of Bologna in a prospective study of long-term sequelae of congenital infection.
    Forty-seven blood samples were obtained from 47 infants in the neonatal period: 34 were examined for pp65 antigenemia test and 44 for qualitative and quantitative polymerase chain reaction (PCR and qPCR).
    Sequelae at 12 months were evaluated in a group of 50 infants.

    RESULTS: Antigenemia was positive in only 10 of 34 samples of infected newborns (29.4% sensitivity).
    PCR was performed in 44 samples of infected newborns and was positive in all (100% sensitivity).
    qPCR showed a finding of > or =100 copies per 10(5) of polymorphonuclear leukocytes (PMNLs) in 39 of 44 samples; in the other 5 cases, the number of copies per 10(5) PMNLs was <100. Between symptomatic and asymptomatic newborns, the mean values of viral blood load determined by qPCR turned out to be significantly higher in symptomatic newborns.

    Mean values of neonatal blood viral load were statistically higher in newborns who developed sequelae than in those who did not.
    Of 20 children with a neonatal viral blood load of <1000 copies per 10(5) PMNLs, 19 did not develop sequelae (negative predictive value: 95%), whereas 2 of 3 with a viral blood load of >10,000 copies did develop sequelae.

    CONCLUSIONS: Different viremia value ranges are correlated to a different risk of sequelae: approximately 70% sequelae were found in newborns with a qPCR higher than 10,000 copies per 10(5) PMNLs.
    Low neonatal viral blood load detected by pp65 antigenemia test and qPCR was highly predictive of absence of sequelae: DNAemia <1000 copies per 10(5) PMNLs has a negative predictive value of 95%.

    As an independent predictive factor of outcome, neonatal viremia is another useful element for neonatal counseling and therapeutic choices in symptomatic and asymptomatic newborns.
  • TABLE 4 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.
  • Fig. 1 Distribution of CMV genotypes.
    Each panel shows the genotyping results of the following subjects: a all analyzed cases (n = 63); b postnatally infected children (n = 31); c congenitally infected cases (n = 32); d congenital cases with SNHL (n = 19). Na sequence data not available. Asterisks indicate a significant difference in the distribution of the genotypes from that of the postnatally infected children
  • Table 2 Relationship between gB genotype and clinical outcome
    a Comparison with the postnatally infected children
    b Twins are counted as one sample
  • Detection of specific IgG and IgM and IgG avidity seem to be the most reliable tests to identify a primary infection but interpretation in a
    clinical context may be difficult.
    If a seroconversion is documented or a fetal infection is suspected by ultrasound markers, an amniocentesis should be performed
    to confirm a vertical transmission.
    In the absence of a confirmed fetal infection with fetal structural anomalies, a pregnancy termination should be discouraged.
    Despite promising results with the use of antiviral drugs and CMV hyperimmune globulin (HIG), results have to be interpreted with caution.

    World Association of Perinatal Medicine, WAPM
  • Viral load and strain polymorphism in amniotic fluid: not indicated.
    Cordocentesis for fetal infection diagnosis: not indicated.
  • If a symptomatic infection diagnosed later in the neonatal period:
    CMV-PCR can be performed on blood adsorbed on Guthrie cards, collected at birth can be used to reassess fetal status at
    birth.
  • If a symptomatic infection diagnosed later in the neonatal period:
    CMV-PCR can be performed on blood adsorbed on Guthrie cards, collected at birth can be used to reassess fetal status at birth.

    The reference method for diagnosing congenital CMV infection involves isolating the virus in cell culture from urine collected within three weeks of birth (urine culture or CMV-DNA testing by PCR) (Table 5).
    After three weeks, a positive CMV result in urine might well be the consequence of exposure to infected vaginal secretions at delivery, or through breast feeding, or untested transfusions. – [22] Demmler GJ. Congenital cytomegalovirus infection. Semin Pediatr Neurol. 1994;1:36–42.

  • Treatment

    1. 1. Treatment & Prognostic factor of Congenital CMV infection SNUH PID Clinical & Research Fellow Ki-Wook, YUN 2010. 07. 07
    2. 2. 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
    3. 3. 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
    4. 4. • 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
    5. 5. Journal of Clinical Virology 46S (2009) S6–S10 (by CDC) Frequency of sequelae among children with congenital CMV infection Permanent disabilities 무엇?
    6. 6. 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 shedding 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 properties
    7. 7. Diagnosis
    8. 8. 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
    9. 9. Radiology: Volume 255: Number 2—May 2010 Number of Pathologic Findings Detected between Examinations P = .0002 P = .05 P = .08 2000–2008, 38 consecutive fetuses with proved CMV infection
    10. 10. 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
    11. 11. Total 38 Women 1st Trimester: 10 3 16 5 Singleton pregnancies with proven vertical transmission of CMV (Primary CMV infection) 2nd Trimester: 19 3rd Trimester: 9 both US scans & MRI normal 5: TOP abnormal US normal MRI 2/3: damage to the auditory system normal US subtle MRI favorable with normal hearing and developmental outcome hyper-intense signal in the white matter, specifically in the Temporal lobe Ultrasound Obstet Gynecol. 2010 Apr 15. Prenatal Imaging (MRI vs. US)
    12. 12. 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 Journal of Medical Virology 81:1773– 1776 (2009) TABLE II. Results of Developmental Testing in Infants With CMV DNA-Positive Cord Blood Samples
    13. 13. Table 2 Clinical and virologic characteristics of CMV-positive patients with bilateral sensorineural hearing loss Eur Arch Otorhinolaryngol (2009) 266:351–355 (by Japan) • 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 Umbilical cord blood samples
    14. 14. Neuroimaging in newborns • In newborns with symptomatic congenital CMV infection, - the best available predictor of neurodevelopmental outcome Eur J Pediatr (2006) 165: 636–645 Table 2 Neuroimaging findings of 14 newborns with symptomatic congenital CMV infection
    15. 15. Neonatology 2008;94:183–186 Eur J Pediatr (2006) 165: 636–645 Concentrations of β2-m in CSF 14 newborns with symptomatic congenital CMV infection Concentrations of β2-m in serum Beta-2 microglobulin Correlation between CSF and neuroimaging findings in 14 newborns with symptomatic congenital CMV infection
    16. 16. Treatment
    17. 17. 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 preventive HIG. Prevention
    18. 18. 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
    19. 19. 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 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.
    20. 20. J Pediatr 2010;-:---) Summary of clinical manifestations and treatment are depicted GCV Tx. for Chorioretinitis
    21. 21. J Pediatr 2010;-:---) Reports on treatment and outcome of chorioretinitis caused by congenital cytomegalovirus infection Long-term treatment necessary for managing congenital CMV-associated chorioretinitis ?!!
    22. 22. 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
    23. 23. 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 follow-up
    24. 24. 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' treatment with ganciclovir ganciclovir for 6 weeks followed by oral valganciclovir to age 12 months
    25. 25. Prognostic Factors
    26. 26. 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. 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 (▲).
    27. 27. 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 between persistent positive CMV cultures and delayed hearing loss
    28. 28. Neonatal cytomegalovirus blood load and risk of sequelae • 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.
    29. 29. 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.
    30. 30. Arch Virol (2008) 153:667–674 Distribution of CMV genotypes of human cytomegalovirus strains collected from congenitally and postnatally infected Japanese children
    31. 31. Arch Virol (2008) 153:667–674 Relationship between gB genotype and clinical outcome
    32. 32. Guidelines (1) J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK)
    33. 33. J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK) Guidelines (2)
    34. 34. J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK) Guidelines (3)
    35. 35. J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK) Guidelines (4)
    36. 36. J. Perinat. Med. 37 (2009) 433–445 (by the WAPM Perinatal Infections Working Group: Spain, France, USA, Italy and UK) Guidelines (5)

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