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Cytomegalovirus in Neonates

Jan 13, 2016

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Cytomegalovirus in Neonates. David K. Hong, MD Pediatrics/Infectious Diseases & Immunology/Allergy Stanford University Medical School Santa Clara Valley Medical Center. Objectives. 1.  Describe the clinical features of congenital infection with CMV - PowerPoint PPT Presentation

  • Cytomegalovirus in NeonatesDavid K. Hong, MDPediatrics/Infectious Diseases & Immunology/AllergyStanford University Medical SchoolSanta Clara Valley Medical Center

  • Objectives1. Describe the clinical features of congenital infection with CMV2. Review current treatment options for congenital CMV infections3. Discuss the unique features of CMV infections in premature infants

  • CytomegalovirusBeta herpesvirus - dsDNACo-evolved with humansLargest virus to infect humans 230 proteins

    CMV infection is not cleared. Chronic infection leads to intermittent viral shedding

    1956 Margaret Smith isolated virus from human salivary gland1965 1st recognized CMV disease in a healthy adult (Br Med J. 1965;1099:102)

  • CMV - PathologyCell enlargement with intranuclear inclusionsCytomegalic inclusion disease

    Cytomegalia in viscera and parotid glands.salivary gland virus

    Margaret Smith. Proc Soc Exp Biol Med 1956, 92:424

  • Thomas Weller named virus CytomegalovirusHistorical InterestVirologic and Clinical Observations on Cytomegalic Inclusion Disease. Thomas Weller and JB Hanshaw. NEJM 1962

  • Clinical Manifestations of acute CMV infectionImmunocompetent IndividualsPrimary CMV infection in immunocompetent children and adults is usually asymptomatic

    Clinical features of acute infection overlap with EBV

    Mononucleosis syndrome more common in EBVfever, lymphadenopathy, lymphocytosisMean duration of fever is 2 weeks

    Sore throat with enlarged exudate-covered tonsils more common in EBV

    Low level elevation of liver transaminases common (>90%)

  • CMV infection is very CommonPrevalence of CMV by Age Group and Ethnic GroupBates SL et al, CID 2010 vol. 50 (11) pp. 1439-1447

  • Stagno S et al, Clin Obstet Gynecol. 1982 Sep;25(3):563-76CMV is the most common congenital infectionStanford/El Camino Hospital/SCVMC 0.6%

  • Stagno S et al, N Engl J Med 1982; 306:945-9

  • Multiple studies have shown maternal acquisition of CMV leads to fetal infection from 3375%

    Disease rates may be as high as 50% if infection occurs during first half of pregnancy

  • 10%90%Disease manifestations Congenital CMV

  • Symptomatic at birth10%Newborn infected with CMVCongenital CMV Asymptomatic90%90%10%Progressive hearing lossNo symptomsDeath5-10%Sensorineural hearing lossIQ < 70Microcephaly, seizures, paralysis~3% with bilateral hearing lossSurvival50%~33% with bilateral hearing loss55%52%IQ < 70, Microcephaly, seizures, paralysis3%

  • Clinical abnormalities in symptomatic congenital CMVBoppana SB et al, Pediatr Infect Dis J. 1992 Feb;11(2):93-9

  • Laboratory abnormalities in symptomatic congenital CMVBoppana SB et al, Pediatr Infect Dis J. 1992 Feb;11(2):93-9

  • Symptomatic Congenital CMV10% die

    45% - 90% will have CNS sequelae

    Sequelae Sensorineural hearing lossDevelopmental & cognitive deficits Chorioretinitis

  • Congenital CMV Risk FactorsCaring for preschool children in the year before deliveryOnset of sexual activity 3 peopleMaternal age < 25Seroconversion between children and delivery of subsequent child within 2 yearsHIV infectionPre-term deliveryLower socioeconomic statusBlack race

    Fowler KB, Pass RF Pediatrics (2006) 118:e286; Fowler KB, Stagno S, Pass RF. Clin Infect Dis 2004; 38:10351037; Kenneson A, Cannon MJ. Rev Med Virol 2007; 17:253276.

  • Diagnosis of Congenital CMVVirus should be isolated within the first 2-3 weeks of lifeIsolation of CMV after this time may represent acquisition at birth or post-natallyOptions for isolation of virus include viral culture or PCR from saliva or urineCMV IgM lacks adequate sensitivity or specificity compared with culture or PCR

  • Stagno S et al, N Engl J Med 1982; 306:945-9CMV-infect infants shed virus in their urine for many months

  • CMV viral testingConventional viral culture can take 2-4 weeks to isolate CMVCMV shell vial identification can occur in 24-48 hoursCMV PCR in urine is available at LPCH

    Specimen is centrifuged onto cover slip covered with fibroblasts to accelerate virus entry

    CMV is detected with fluorescent antibodies against early CMV proteins

  • How many CMV urine tests are needed?1st test2nd test3rd testTwo CMV urine tests are adequate to screen for CMV infectionCourtesy N. Srinivas, LPCH

    Viral culturePOSNEGShellPOS13114Sensitivity = 1NEG0753753Specificity = .99913754PPV = 0.923NPV = 1

    Viral culturePOSNEGShellPOS16117Sensitivity = 1NEG012201220Specificity = 0.999161221PPV = 0.941NPV = 1

    Viral culturePOSNEGShellPOS20121Sensitivity = 1NEG015301530Specificity = 0.999201531PPV = 0.952NPV = 1

  • Treatment of Congenital CMVAntiviral against CMV is availableGanciclovir - IVWhich patients do you treat?How long do you treat?How do you know if it worked?

  • J Pediatr 2003; 143:16-25Enrolled 100 patients with symptomatic CMV disease involving the CNSPatients received 6 weeks of IV ganciclovirPatients were followed for 1 year and had hearing evaluations at 6 months and 1 yearFound less hearing loss at 6 months and possibly less hearing loss at 1 year

  • Kimberlin DW. J Pediatr 2003, 143:16;

  • Ganciclovir therapy appears to be beneficialAfter 6 weeks of IV ganciclovir

    At 6 months, 84% (21/25) improved or maintained hearing status59% (10/17) controls

    At 12 months, 21% (5/24) worse hearing68% (13/19) controlsKimberlin DW. J Pediatr 2003, 143:16;

  • Major caveats100 subjects enrolled; 42 with full follow-up for analysis63% (29/46) grade 3 or 4 neutropeniaDosage modifications 14/29 patientsGCSF in 2 patientsGram negative sepsis in 1 patientWhat about mildly symptomatic or asymptomatic patients?How do you know 6 weeks is enough?CMV can be detected in inner ear fluid (perilymph/endolymph) in patients getting cochlear implants

  • 1. Virus in the urine increases after treatment2. Viral load in blood increases after treatment3. CMV genome detected in perilymph3 Reasons for Prolonged Ganciclovir TherapyWhitley RJ, et al. JID 1997, 175:1080; KImberlin DW, et al. JID, 2008, Mar 15; Bauer PW, et al. Laryngoscope 2005, 115:223Sugiura S, et al. J mEd Virol 2003, 69:72

  • Valganciclovir is a form of ganciclovir that can be given orallyDosing information is now available for infants

    J Infect Dis (2008) 197:836-45

  • CASG 112

  • CASG 112

  • CASG 112

  • Symptomatic at birth10%Newborn infected with CMVCongenital CMV Asymptomatic90%90%10%Progressive hearing lossNo symptomsDeath5-10%Sensorineural hearing lossIQ < 70Microcephaly, seizures, paralysis~3% with bilateral hearing lossSurvival50%~33% with bilateral hearing loss55%52%IQ < 70, Microcephaly, seizures, paralysis3%

  • Asymptomatic congenital CMV90% of infants infected with CMV have no symptoms5-10% will progress to sensorineural hearing lossWe do not knowWhich infants will have progressive hearing loss.If ganciclovir treatment would prevent hearing lossIf treatment is helpful, how long would you need to treat?Routine screening of newborns and treatment of newborns is NOT recommended at this time

  • Can anti-CMV immunoglobulin prevent severe congenital infection?Nigro G et al, N Engl J Med 2005 vol. 353 (13) pp. 1350-1362Congenital CMV disease1 (3%) 7 (50%)6 (16%)19 (40%)

  • Prospective, double-blind, placebo-controlled randomized controlled trial evaluating the effectiveness of CMV hyperimmune globulin (Cytogam) at preventing congenital CMV infection in babies born to moms with primary CMV infection during the first half of pregnancy

    Inclusion Criteria:Primary CMV infection in a mother prior to :24wks gestational age Singleton pregnancy

    Intervention:Cytogam 100mg/kg how many doses?

    Primary outcome measures:fetal loss (spontaneous or termination)confirmed fetal CMV infection from amniocentesisneonatal congenital CMV infection diagnosed by urine or saliva collected by 3 weeks of age that is positive for CMV by culture (the intent will be to obtain in the first two days of life)

    A Randomized Trial to Prevent Congenital Cytomegalovirus (CMV) - NCT01376778

  • CMV Vaccine?The ideal vaccine would:induce high levels of CMV neutralizing antibodiesWould be targeted at women of child-bearing ageWould have to induce immunity better than natural immunity

  • recent phase 2 trial showed 50% vaccine efficacy at preventing CMV infection in CMV-seronegative women over 42 months1 infant had congenital CMV in vaccine group (1%), while 3 infants had congenital CMV in placebo group (3%) more women became pregnant in the placebo group

    CMV glycoprotein B vaccine with MF59

    Pass RF et al, N Engl J Med (2009) 360:1191

  • Acquired CMV infection in premature infantsPerinatal infections can be acquired from exposure to virus in maternal genital secretions, breast milk, or transfusion

    Incubation period is 4-12 weeks

    Most infections are asymptomatic with no long-term sequelae

    Premature infants (750-1500g) at greater risk of symptomatic postnatal CMV infectionCMV from maternal source led to hepatosplenomegaly, neutropenia, lymphocytosis, thrombocytopenia. Longer oxygen requirementYeager AS et al, J Pediatr (1983)102:918

    Transfusion associated CMV occurred in 13.5% of 74 infants of seronegative mothers who were exposed to blood donors with CMV

    Severe or fatal CMV disease in infants born to seronegative mothers who received CMV+ blood all were 1200g or less (

  • What about CMV acquisition via breastmilk in ELBW and VLBW babies?CMV is shed intermittently in breast milk

    Rates of symptomatic infection in VLBW and ELBW infants from brea

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