cmv-aap-2012

DOI: 10.1542/pir.33-4-1562012;33;156Pediatrics in Review

Erin J. Plosa, Jennifer C. Esbenshade, M. Paige Fuller and Jrn-Hendrik WeitkampCytomegalovirus Infection

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Cytomegalovirus InfectionErin J. Plosa, MD,* Jennifer

C. Esbenshade, MD, MPH,

M. Paige Fuller, PharmD,

Jorn-Hendrik Weitkamp,

MD

Author Disclosure

Drs Plosa, Esbenshade,

Fuller, and Weitkamp

have disclosed no

financial relationships

relevant to this article.

This commentary does

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Educational Gap

There is wide variation among centers regarding prophylactic versus preemptive therapy

for posttransplantation cytomegalovirus infection.

Objectives After completing this article, readers should be able to:

1. Understand the mother-infant cytomegalovirus (CMV) transmission risk based on

maternal antibody status.

2. Recognize the clinical manifestations of congenital and postnatal CMV infection.

3. Explain the appropriate methods for the diagnosis of congenital CMV infection.

4. Describe the specific risk of neurodevelopmental impairment in infants with

congenital CMV infection.

5. State the major antiviral agents for treatment of CMV infection in the

immunocompromised host.

IntroductionCytomegalovirus (CMV) has been identied as an important viral pathogen in humans formore than a century. The histopathology of CMV was rst described in 1904, but the virusitself was not isolated until 1957 by Craig et al. (1) CMV infects multiple human cell types,including salivary gland epithelial cells, hence the original name of the virus: salivary glandvirus. In 1960, Weller designated the virus as CMV based on the appearance of the swollenvirus-infected cells labeled as cytomegalia. (2) Over the next several decades, the prevalenceand importance of CMV as a human pathogen became more apparent. CMV causes themost common perinatal viral infection in developed countries. CMV infects nearly 1% ofall newborns, w40,000 infants per year, in the United States. Infection with CMV isthe most common cause of nonhereditary sensorineural hearing loss (SNHL). (3) In ad-dition to congenital and perinatal infection, CMV causes signicant morbidity in immuno-compromised patients, including chorioretinitis, pneumonia, colitis, and neuropathy. (4)

The VirusCMV is a member of the human herpesvirus family. Its large, linear, double-stranded DNAis w235 kb in size. The genome is divided into a unique long (UL) region and a uniqueshort region. The UL region contains two genes whose protein products are important in

antiviral therapies, including ganciclovir administration. TheUL54 gene product is a DNA polymerase and is the target ofseveral antiviral agents indicated for the treatment of symp-tomatic congenital CMV infection. The UL97 gene productis a phosphotransferase required for phosphorylation of gan-ciclovir to its active metabolite in vivo. The humoral im-mune response against CMV is focused on two envelopeproteins: glycoprotein B and glycoprotein H. Most human

Abbreviations

CMV: cytomegalovirusRL: recipient negative for CMV infectionSNHL: sensorineural hearing lossUL: unique long region

*Instructor in Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Monroe Carell Jr Childrens Hospital at

Vanderbilt, Nashville, TN.Assistant Professor of Pediatrics, Department of Pediatrics , Vanderbilt University School of Medicine, Monroe Carell Jr Childrens

Hospital at Vanderbilt, Nashville, TN.Departments of Pediatrics and Pharmacy, Vanderbilt University School of Medicine, Monroe Carell Jr Childrens Hospital at

Vanderbilt, Nashville, TN.

Article infectious diseases

156 Pediatrics in Review Vol.33 No.4 April 2012


8 cells are infected by CMV, including broblasts, epithe-lial cells, endothelial cells, macrophages, and myocytes.The exact incubation period is unknown, but is thoughtto be 1 to 2 months.

EpidemiologyCMV infection is ubiquitous in human populations world-wide. In the United States, the overall CMV seropreva-lence is w50%, leaving many women of reproductiveage still at risk for primary CMV infection during preg-nancy. Worldwide, CMV seroprevalence among womenin the reproductive age ranges from 45% in developedcountries to 100% in developing countries. With pro-longed, repeated exposure to the virus through salivaor saliva-contaminated surfaces, CMV is spread easilyin the child care setting. Toddlers infected postnatallywith CMV shed the virus in their urine for a mean of18 months (range 640 months). In contrast, healthyadults infected with CMV will shed the virus for onlyup to several weeks. Higher socioeconomic status is asso-ciated with lower rates of CMV prevalence.

Exposure to young children is a risk factor for infec-tion. In women of childbearing age, infection rates for se-ronegative child care employees are between 10% and20% per year. The infection rates for the general seroneg-ative population are 2% per year. In contrast to seroneg-ative child care workers, increased risk of infection forhealth care workers has not been documented.

Although prevalent, CMV infection often is asymp-tomatic in the immunocompetent host. SymptomaticCMV infection occurs primarily when the infection oc-curs congenitally, perinatally in premature infants (butnot term), and in immunocompromised individuals, suchas HIV-positive patients or transplant recipients receivingimmunosuppressive therapy.

TransmissionExposure to CMV can occur from almost all body uids,including urine, saliva, tears, and genital secretions, as wellas from transplanted organs. CMV can bematernally trans-mitted during pregnancy, perinatally, or after postnatal ex-posure. Primary maternal infection during pregnancy hasa 40% transmission rate to the fetus. This transmissionis thought to occur by the transplacental route. In the set-ting of maternal viremia, maternally infected leukocytescross to the placenta. The virus can be isolated fromthe placenta following congenital infection; placentitisis demonstrated on placental pathologic examination.

In women who are seropositive before pregnancy, re-activation of CMV can lead to congenital infection. The

transmission rate to the fetus in a preconceptionally im-munemother shedding CMV virus is 1% vs 40% for primarymaternal CMV infection, and sequelae in the offspringgenerally are less severe.

Alternatively, congenital CMV in a preconceptionallyseropositive mother may result from acquisition of a newstrain of CMV. In addition to in utero transmission, in-fection can occur during the perinatal period from expo-sure to genital secretions during delivery.

Shedding of CMV in toddlers in child care centers canbe as high as 70%. Standard precautions with good handhygiene are sufcient to prevent transmission and shouldbe practiced routinely when taking care of young chil-dren. The Centers for Disease Control and PreventionWeb site gives recommendations for pregnant womenon how to avoid transmission of CMV (www.cdc.gov/cmv/).

Postnatal infection can occur after exposure to humanmilk, blood products, or transplanted organs. Humanmilkassociated CMV infections typically are asymptom-atic in term infants because of passively acquired maternalantibodies. (5) In contrast, extremely premature infantsare at higher risk for symptomatic CMV infection acquiredfrom human milk because of their immature immune sys-tem and paucity of maternal antibodies. Postnatal CMVdisease in this population can present as sepsislike illness,including respiratory symptoms (pneumonitis), hepatomeg-aly, thrombocytopenia, neutropenia, and lymphocytosis.

The risk of CMV transmission in premature infants canbe minimized with the use of pasteurized human milk,leukoreduced blood products, and milk or blood fromCMV-negative donors. (6) Transmission of CMV duringsolid organ transplantation typically occurs when a seroneg-ative recipient receives an organ from a seropositive donor.

Congenital Cytomegalovirus InfectionNinety percent of congenitally infected infants are asymp-tomatic at birth. The remaining 10% of infected infantscan demonstrate a wide range of manifestations affectingmultiple organ systems. The clinical features of congen-ital CMV infection are more severe following primarymaternal CMV infection than from recurrent maternalinfection. Common clinical features of congenital CMVinfection (Table 1) include jaundice, hepatosplenomegaly,prematurity, intrauterine growth restriction, microceph-aly, thrombocytopenia, and skin manifestations (Fig 1),such as petechiae and purpura. Prenatally, congenitalCMV infection can be associated with oligo- or polyhy-dramnios, periventricular calcications (Fig 2), and hy-perechoic bowel on prenatal ultrasonography.

infectious diseases cytomegalovirus

Pediatrics in Review Vol.33 No.4 April 2012 157


The possible neurologic manifestations of congenitalCMV infection are numerous. Hypotonia, poor feeding,ventriculomegaly, cerebellar hypoplasia, polymicrogyria,periventricular pseudocysts, seizures, spasticity, and de-velopmental delay can occur in infants aficted with con-genital CMV infection. Among infants with symptomaticcongenital CMV infection, SNHL will affect 30% at birth.Among the 90% of asymptomatic infants at birth, 7% to15% will develop progressive SNHL later in childhood.Ophthalmologic manifestations of congenital CMV in-clude chorioretinitis, strabismus, microphthalmia, opticnerve atrophy, and cortical visual impairment.

DiagnosisCongenital CMV infection can be diagnosed prenatallyby detecting CMV immunoglobulin M in fetal bloodor by isolating the virus from amniotic uid. Amniocen-tesis is most accurate after 21 weeks, when the fetal kid-ney has matured enough to excrete the virus into theamniotic uid. Postnatally, congenital CMV is conrmedby detection of the virus in urine, blood, or saliva withinthe rst 3 weeks of life by culture or polymerase chain

reaction. The virus can be detected within 24 hours bythe shell-vial assay, in which CMV is identied by immu-nouoresence against nucleic antigens of infected cells.

The differential diagnosis of congenital CMV infectionincludes other congenital infections, such as congenitaltoxoplasmosis. In infants with prominent skin manifesta-tions, bacterial sepsis and erythroblastosis fetalis shouldbe considered.

Routine CMV testing during pregnancy currently isnot recommended in the United States. Although exper-imental treatments for newly infected pregnant womenhave been reported, most infections (w90%) do not re-sult in symptomatic CMV disease. Furthermore, manycases of the most common complication of congenitalCMV infection, SNHL, occur in infants born to motherswith secondary CMV.

Because treatment for CMV has high toxicity and uncer-tain effectiveness, therapy is recommended only in certainsymptomatic cases (eg, central nervous system disease).Although routine CMV testing could facilitate earlier in-terventions for SNHL or earlier identication of delayed-onset hearing loss, it is unclear currently if these benetsoutweigh the risks of parental anxiety, unnecessary treat-ments, or interventions and social stigmatization.

CMV in the Immunocompromised HostThe increased risk for CMV infection and reactivation inimmunocompromised individuals is well recognized. Inthe pediatric population, apart from congenital transmis-sion, CMV infection can occur following bone marrowtransplantation or solid organ transplantation, or in HIV-positive patients. CMV in this setting can present as asymp-tomatic viremia, as CMV syndrome, or as tissue-invasivedisease.

CMV syndrome is dened as CMV viremia associ-ated with one or more clinical signs or symptoms (fever,malaise, leukopenia, thrombocytopenia, atypical lym-phocytosis, or elevated liver enzymes) in the absenceof another cause. Tissue-invasive disease occurs whenthere is tissue-specic disease (pneumonitis, colitis, hep-atitis, retinitis), dened by detection of the virus fromthe tissue itself.

Solid organ transplant recipients who are seronegativebefore transplantation and receive an organ from a sero-positive donor (donor-positive/recipient-negative [R])are most at risk for acquiring CMV infection. The inci-dence of CMV disease in donor-negative/R transplanta-tion is

Because of the varied degree of immunosuppression,the rates of CMV infection vary with the organ trans-planted. Lung and small bowel transplants have the high-est incidence of posttransplant CMV infection. Thedisease burden of CMV is not limited to the infection it-self. CMV disease increases the risk for bacterial, fungal,or viral superinfections. In addition, there is increased riskof posttransplantation lymphoproliferative disease, graftdysfunction, and graft failure. CMV coinfection of HIV-infected infants in the rst 18 months of life can result ingreater HIV-related disease progression and central ner-vous system disease. (7)

There is wide variation among centers regarding pro-phylactic versus preemptive therapy for posttransplanta-tion CMV infection. Universal prophylaxis involvesgiving antiviral medications to either all patients or to a se-lect group of at-risk patients after transplantation. Thisstrategy decreases the risk for other viral infections butdoes so at the increased cost of universal prophylactictherapy, which carries the potential for increased adverseeffects from antiviral medication and increased risk forlate-onset CMV infection after discontinuation of theprophylactic therapy.

With preemptive therapy, patients are tested weeklyfor the presence of viremia. Therapy is initiated whenearly, asymptomatic viremia is detected. With this method,there are decreased drug costs and potentially fewer ad-verse effects from medications. Weekly testing can be bur-densome and costly, however.

There is no strong evidence in pediatric patients tosuggest one strategy over another. In fact, most centershave protocols that incorporate elements of both.

A recent study in the adult literature, the IMPACT(IMproved Protection Against CMV in Transplantation)study, reported decreased incidence of CMV infection at1 year after transplantation, after 200 days of universal pro-phylactic therapy versus 100 days. (8) For pediatric pa-tients, intravenous ganciclovir and enteral valganciclovir arethe most commonly used antiviral agents for posttransplantCMV therapy.

TreatmentThe rst antiviral agent specically licensed for treatingCMV infection was ganciclovir. Treatment for congenitalCMVwith ganciclovir is associated with signicant toxicityand currently is recommended only for those infants withsevere symptomatic disease involving the central nervoussystem who are able to start treatment within the rstmonth after birth. (9) A synthetic acyclic nucleoside an-alog of guanosine, ganciclovir blocks viral DNA synthesisby inhibiting CMVDNA polymerase in infected cells and

Figure 1. Blueberry muffin rash in congenital CMV infection.Reprinted with permission from the Red Book Online VisualLibrary, 2009, American Academy of Pediatrics. Image039_11. Available at: http://aapredbook.aappublications.org/visual.

Figure 2. Periventricular calcifications in congenital CMV infection.Reprinted with permission from the Red Book Online Visual Li-brary, 2009, American Academy of Pediatrics. Image 039_34.Available at: http://aapredbook.aappublications.org/visual




by incorporating itself into CMV DNA, causing chaintermination. Ganciclovir requires in vivo phosphorylationto a triphosphate by the CMV UL97 gene product.

Adverse effects include myelosuppression (anemia,thrombocytopenia, neutropenia), with occasional dose-limiting toxicity from neutropenia. Ganciclovir is dosedat 12 mg/kg per day intravenously for 6 weeks for severecongenital and perinatal CMV infection (Table 2). Thedrug is cleared renally, and adjusted dosing for patientswith renal insufciency is recommended. Resistance toganciclovir has been reported in immunocompromisedpatients after prolonged treatment. New-generation

DNA-sequencing methods may now detect ganciclovir-associated resistance mutations in infants and childrenwith treatment failure against CMV.

Valganciclovir is a valine ester and prodrug of ganci-clovir. This medication is available only in enteral formand is very well absorbed. The drug is indicated currentlyfor treatment of CMV chorioretinitis in HIV-positive pa-tients and as CMV prophylaxis in seronegative transplantrecipients who have a seropositive donor. (10) Random-ized clinical trial data are not yet available for the use ofvalganciclovir in treating congenital CMV. Similar toganciclovir, the major adverse effect is myelosuppression.

Table 2. Current Therapies for Pediatric CMV Infection

DrugRoute ofAdministration Mechanism of Action Adverse Effects

Suggested DosingRegimensa

Ganciclovir Intravenous Inhibits CMV DNApolymerase

Myelosuppression(particularlyneutropenia)

Congenital infection:12 mg/kg/day dividedevery 12 h for 6 wkb (7)

Valganciclovir Enteral Prodrug of ganciclovir;inhibits CMV DNApolymerase

Myelosuppression Congenital infection inneonates >7 d old andinfants 13 mo of age:16 mg/kg/dose every12 hc (8)(9)

Foscarnet Intravenous Inhibits CMV DNApolymerase

Nephrotoxicityd HIV-infected infants andchildren:-disseminated diseaseor retinitis: Induction:180 mg/kg/day dividedevery 8 h for 1421 d,then maintenance: 90-120 mg/kg/dose oncedaily-central nervous systemdisease: 180 mg/kg/daydivided every 8 h untilsymptoms improvefollowed by chronicsuppression (10)

Cidofovir Intravenous Inhibits CMV DNApolymerase, incorporatesinto viral DNA

Nephrotoxicity,e

neutropenia, andmetabolic acidosis

Infection in children:Induction: 5 mg/kg/doseonce weekly 3 2consecutive wk

Maintenance: 35 mg/kg/dose once weekly every2 wk for 24 doses (11)

a Suggested doses are based primarily on consensus because no sufcient clinical data exist to name the appropriate dose for use in infants and children. (12)b Some experts use ganciclovir in immunocompromised hosts and extremely premature infants with severe CMV gastrointestinal tract disease and CMVpneumonitis (with or without CMV immune globulin). Dose adjustment or discontinuation of treatment should be considered for severe neutropenia(absolute neutrophil count < 500 cells/mm3). (7)c A randomized controlled trial comparing 6 weeks versus 6 months of treatment with valganciclovir oral solution to systematically assess the efcacy andsafety outcomes associated with longer-term antiviral treatment of symptomatic congenital CMV disease is ongoing (http://clinicaltrials.gov/ct2/show/NCT00466817?termvalganciclovir&rank7).d Foscarnet sometimes is used in combination with ganciclovir (which increases the risk of adverse effects). (10)e To prevent nephrotoxicity, administration of cidofovir should be given in conjunction with oral probenecid and intravenous hydration.




Foscarnet is second-line antiviral therapy for CMV infec-tion in myelosuppressed patients or in those demonstratingviral resistance to ganciclovir. The mechanism of actionis similar to ganciclovir, inhibiting CMVDNA polymerase;however, foscarnet does not require phosphorylationin vivo. Foscarnet causes less myelosuppression than otherantiviral therapies for CMV, but it is nephrotoxic, andprehydration with saline is often recommended.

An additional second-line therapy for CMV choriore-tinitis in HIV-positive patients is cidofovir. Cidofovir isan acyclic nucleoside phosphonate, a nucleotide analogthat requires phosphorylation. Once in its active form,cidofovir is incorporated into the viral DNA and inhibitsDNA synthesis. Metabolites of cidofovir are cleared bythe kidney and have very long half-lives, allowing weeklydosing schedules.

The adverse effects of cidofovir are nephrotoxicity (re-quiring prehydration with saline), neutropenia, metabolicacidosis, and ocular hypotony. (11) It is recommendedthat clinicians adjust the dosage in patients with renalinsufciency and avoid use with other nephrotoxicagents. Cidofovir administration must be accompaniedby oral probenecid to reduce possible nephrotoxicity.Reportedly, cidofovir is carcinogenic and teratogenicin animals.

CMV immunoglobulin G has been used as prophy-laxis in seronegative solid organ transplant recipientswhose donor was seropositive. CMV immunoglobulinis pooled, high-titer intravenous immunoglobulin is ex-tracted from donors with high CMV titers. The agentis presumed to interact with the CMV viral envelope gly-coproteins. CMV has also been used as adjunctive therapyin immunocompromised patients with severe systemicCMV infection. It is effective in treating CMV pneumo-nia in bone marrow transplant recipients. CMV immuno-globulin has been tested as a treatment for women orfetuses infected with CMV during pregnancy. Data fromrandomized controlled clinical trials have not yet beenpublished, but CMV immunoglobulin is sometimes con-sidered for treating high-risk cases of fetal injury and asa possible alternative to pregnancy termination.

Prevention of Sensorineural Hearing LossOver the past decade, investigations have been ongoingto determine the safety and efcacy of antiviral treatment forprevention of SNHL in patients having congenital CMV in-fections. In 2003, Kimberlin et al (9), for the National In-stitute of Allergy and Infectious Diseases CollaborativeAntiviral Study Group, published a phase III randomizedcontrolled trial of a 6-week course of intravenous

ganciclovir versus no treatment in infants who havesymptomatic congenital CMV infection. Despite differ-ential loss to follow-up rates, the data suggested that gan-ciclovir may prevent hearing deterioration at 6 monthsand may prevent hearing deterioration at 1 year, as mea-sured by brainstem-evoked response.

In 2010, Amir et al published a retrospective case se-ries of 23 infants with symptomatic congenital CMV in-fection with central nervous system involvement treatedwith 6 weeks of intravenous ganciclovir, followed bylong-term oral valganciclovir to 1 year of age. (12) Thismost recent retrospective study suggests that a prolongedtreatment course with the addition of oral valganciclovirto intravenous ganciclovir may lessen hearing impairmentat 1 year of age when compared with intravenous ganci-clovir alone. A phase III, randomized, placebo-controlledblinded investigation for safety and efcacy comparinga 6-week course to a 6-month course of oral valganciclo-vir is in progress (ClinicalTrials.gov: NCT00466817).

VaccinesGiven the ubiquitous nature of CMV and the potentiallydevastating neurodevelopmental consequences of con-genital infection, development of a CMV vaccine is a highpriority. The rst human study of a CMV vaccine was com-pleted in the 1970s using the laboratory strain AD169 tomake a live, attenuated vaccine. Although study partici-pants produced CMV-specic antibody, this CMV strainwas highly weakened in its virulence (attenuated), and asa result was not sufciently immunogenic to be an effec-tive vaccine candidate.

The next live, attenuated strain studied was the CMVTowne strain. Efcacy studies have been completed in re-nal transplant candidates and healthy CMV-seronegativeadult men. Similar to the AD169 vaccine, the immuneresponse was inadequate when challenged with thenaturally occurring CMV Toledo strain. This vaccineprevented infection after a low-dose Toledo strain chal-lenge, but did not prevent infection during a high-dosechallenge.

Work is ongoing on development of subunit vaccinesagainst several viral proteins. The viral protein that has beenmost studied is glycoprotein gB, the gene product of theCMV UL55 gene. This protein is the target of neutraliz-ing antibodies occurring after natural infection. Initialsafety studies in both adults and toddlers are reassuring,and a phase III efcacy study is ongoing in seronegativewomen of childbearing age. Other viral proteins under in-vestigation as potential vaccine targets are pp65, pp150,pp28, pp50/52, and pp71.




References1. Craig JM, Macauley JC, Weller TH, Wirth P. Isolation ofintranuclear inclusion producing agents from infants with illnessesresembling cytomegalic inclusion disease. Proc Soc Exp Biol Med.1957;94(1):4122. Kluge RC, Wicksman RS, Weller TH. Cytomegalic inclusiondisease of the newborn: report of case with persistent viruria.Pediatrics. 1960;25:3539

3. American Academy of Pediatrics, Joint Committee on InfantHearing. Year 2007 position statement: principles and guidelinesfor early hearing detection and intervention programs. Pediatrics.2007;120(4):8989214. Coats DK, Demmler GJ, Paysse EA, Du LT, Libby C.Ophthalmologic ndings in children with congenital cytomegalo-virus infection. J AAPOS. 2000;4(2):1101165. Bryant P, Morley C, Garland S, Curtis N. Cytomegalovirustransmission from breast milk in premature babies: does it matter?Arch Dis Child Fetal Neonatal Ed. 2002;87(2):F75F776. Gartner LM, Morton J, Lawrence RA, et al; American Academyof Pediatrics Section on Breastfeeding. Breastfeeding and the use ofhuman milk. Pediatrics. 2005;115(2):4965067. Mofenson LM, Brady MT, Danner SP, et al; Centers for DiseaseControl and Prevention; National Institutes of Health; HIVMedicine Association of the Infectious Diseases Society of America;Pediatric Infectious Diseases Society; American Academy of Pedi-atrics. Guidelines for the prevention and treatment of opportunisticinfections among HIV-exposed and HIV-infected children: recom-mendations from CDC, the National Institutes of Health, the HIVMedicine Association of the Infectious Diseases Society of America,the Pediatric Infectious Diseases Society, and the American Academyof Pediatrics. MMWR Recomm Rep. 2009;58(RR-11):11668. Humar A, Limaye AP, Blumberg EA, et al. Extended valganci-clovir prophylaxis in D/R- kidney transplant recipients is associ-ated with long-term reduction in cytomegalovirus disease: two-yearresults of the IMPACT study. Transplantation. 2010;90(12):142714319. Kimberlin DW, Lin CY, Snchez PJ, et al; National Institute ofAllergy and Infectious Diseases Collaborative Antiviral StudyGroup. Effect of ganciclovir therapy on hearing in symptomaticcongenital cytomegalovirus disease involving the central nervoussystem: a randomized, controlled trial. J Pediatr. 2003;143(1):162510. Kimberlin DW, Acosta EP, Snchez PJ, et al; NationalInstitute of Allergy and Infectious Diseases Collaborative Antivi-ral Study Group. Pharmacokinetic and pharmacodynamic assess-ment of oral valganciclovir in the treatment of symptomaticcongenital cytomegalovirus disease. J Infect Dis. 2008;197(6):83684511. Cesaro S, Zhou X, Manzardo C, et al. Cidofovir for cytomeg-alovirus reactivation in pediatric patients after hematopoietic stemcell transplantation. J Clin Virol. 2005;34(2):12913212. Amir J, Wolf DG, Levy I. Treatment of symptomatic congen-ital cytomegalovirus infection with intravenous ganciclovir followedby long-term oral valganciclovir. Eur J Pediatr. 2010;169(9):1061106713. American Academy of Pediatrics. Cytomegalovirus infection.In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. RedBook: 2009. Report of the Committee on Infectious Diseases. 28thed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:780782

Summary

Although commonly asymptomatic, congenital CMVinfection is the leading cause of nonhereditary SNHL.Other sequelae that may be evident only after theneonatal period can include chorioretinitis,neurodevelopmental delay with mental or motorimpairment, and microcephaly. (13)

Congenital CMV infection is confirmed by detection ofthe virus in urine, blood, or saliva within the first 3weeks of life by culture or polymerase chain reaction.A positive test does not necessarily confirmsymptomatic CMV disease or need for treatment. (13)

Postnatal CMV infections transmitted through humanmilk have been reported and may be clinically relevantin extremely premature infants; however, the risk-benefit ratio of pasteurizing human milk for theprevention of postnatal CMV infection is unclear.

Ganciclovir, valganciclovir, foscarnet, cidofovir, andCMV hyperimmune globulin are effective in treatingor preventing CMV infections in theimmunocompromised host, but require closemonitoring for associated toxicities. Treatment forcongenital CMV is associated with significant toxicityand uncertain effectiveness.

Based on strong evidence, anticipatory guidance forcongenital CMV infection should include hearing testsand neurodevelopmental assessments until school age.(3) In patients with symptomatic congenital CMVinfection, lifelong ophthalmologic screening shouldbe included. (4)

Based primarily on consensus, owing to lack ofrelevant clinical studies, it is not recommended towithhold human milk produced by CMV-seropositivemothers from healthy term infants. (5)(6)

Based on some research evidence, as well as consensus,treatment for congenital CMV is recommended only insymptomatic infants with central nervous systeminvolvement. (9)




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1. The mother of one of your patients has recently started work at a day care center. She is known to beCMV-seronegative and is thinking about having more children. She asks you about the likelihood of contractingCMV over the next year. Of the following, the most accurate estimate of her risk of CMV infection per year is:

A. 2%.B. 10%.C. 35%.D. 50%.E. 75%.

2. Of the following, which is the best explanation for avoiding recommendation of routine CMV testing duringpregnancy?

A. Complications of intrauterine CMV infection are rare.B. Medical therapy of intrauterine CMV is highly toxic to the mother.C. Most intrauterine CMV infections do not result in symptomatic disease.D. No reliable diagnostic test for CMV in utero exists.E. The virus is not secreted into the amniotic fluid.

3. Of the following, which is the most common complication of congenital CMV infection?

A. Cholestasis.B. Chorioretinitis.C. Hearing loss.D. Hypotonia.E. Thrombocytopenia.

4. A 3-year-old girl receives a cadaveric liver transplant for biliary atresia. She is placed on systemicimmunosuppression with corticosteroids and tacrolimus. Of the following situations, which places her atthe highest risk of CMV infection posttransplantation?

A. The organ donor is CMV antibodynegative, the recipient is CMV antibodynegative.B. The organ donor is CMV antibodynegative, the recipient is CMV antibodypositive.C. The organ donor is CMV antibodypositive, the recipient is CMV antibodynegative.D. The organ donor is CMV antibodypositive, the recipient is CMV antibodypositive.E. The above scenarios all have a similar risk of CMV transmission.

5. Of the following therapies for CMV, which carries the lowest risk of myelosuppression?

A. Cidofovir.B. Foscarnet.C. Gancyclovir.D. Immunoglobulin.E. Valgancyclovir.




DOI: 10.1542/pir.33-4-1562012;33;156Pediatrics in Review

Erin J. Plosa, Jennifer C. Esbenshade, M. Paige Fuller and Jrn-Hendrik WeitkampCytomegalovirus Infection

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