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European Review for Medical and Pharmacological Sciences 2012; 16: 919-935 Congenital cytomegalovirus infection: current strategies and future perspectives D. BUONSENSO, D. SERRANTI, L. GARGIULLO, M. CECCARELLI, O. RANNO, P. VALENTINI Department of Pediatrics, School of Medicine, Catholic University of the Sacred Heart, Rome (Italy) Abstract. – INTRODUCTION, Cytomegalo-virus photransferase protein), required for the phosphory- is the most comm
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   Abstract. –   INTRODUCTION, Cytomegalo-virusis the most common cause of congenital infec-tions in humans and it produces considerablemorbidity in newborns. AIMS, The present study reviews current con-cepts on epidemiology, clinical manifestations, diag-nosis, treatment, future strategies and prognosis ofchildren with congenital cytomegalovirus infection. RESULTS, Congenital cytomegalovirus infectioncan be symptomatic or not at birth, but about 10-20%of them all will exhibit neurological damage when fol-lowed up. Sensorineural hearing loss is the most fre-quent long-term consequence and is not manifest in-variably at birth or in the neonatal period but in manycases becomes clinically apparent in later childhood.There are growing evidences that newborns withsymptomatic congenital cytomegalovirus infectionwould benefit from treatment with either gancicloviror valganciclovir, the most widely studied drugs inthis setting. It is not yet clear if children with asymp-tomatic or pauci-symptomatic infection at birthwould benefit from treatment. DISCUSSION, Studies evaluating treatment andlong-term follow-up of infants with both sympto-matic and asymptomatic infection are necessary,in order to definitely evaluate the short and long-term effectiveness and safety of both ganciclovirand valganciclovir and to identify risk factors as-sociated to the development of long-term seque-lae. In this way it will be possible to select thosechildren that might benefit for treatment. Key Words:  Cytomegalovirus, Congenital cytomegalovirus in- fection, Diagnosis, Malformations, Complications,Ganciclovir, Valganciclovir. Introduction Cytomegalovirus (CMV) is a double-strandedDNA, β human herpesvirus. The viral genome isdivided into a unique long (UL) region, and aunique short (US) region, which are necessary forthe synthesis of the UL54 protein(DNA poly-merase), the major target of antiviral drugs used totreat CMV infections, and the UL97  protein(phos- Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences Congenital cytomegalovirus infection:current strategies and future perspectives D. BUONSENSO, D. SERRANTI, L. GARGIULLO, M. CECCARELLI,O. RANNO, P. VALENTINI Department of Pediatrics, School of Medicine, Catholic University of the Sacred Heart, Rome (Italy) Corresponding Author:  Piero Valentini, MD; e-mail: pvalentini@rm.unicatt.it  919 photransferase protein), required for the phosphory-lation of ganciclovir (GCV), a necessary step toform its active metabolite in vivo 1 . The outer envelope of the virus, which is de-rived from the host cell nuclear membrane, con-tains multiple virally encoded glycoproteins 2 .Glycoprotein B (gB) and glycoproteinH (gH)seem to be the major determinants of protectivehumoral immunity. Antibodies against these pro-teins are capable of neutralizing the virus, andthese glycoproteins are under study for the devel-opment of CMV subunit vaccines 1 . CMV is the most common cause of congenitalinfections in humans 3 and it produces consider-able morbidity in newborns. Congenital CMV (CCMV) infection is esti-mated to occur in 0.5 to 2% of all deliveries inthe developed world 4 .However, some Authors have recently suggest-ed that the prevalence of CCMV infection in thedeveloped world seems to be slightly lower,ranging between 0.6% and 0.7% 5,6 . These data appear to be more precise than therange of 0.2-2.5% often reported in literature, inagreement with a study held in Lombardia (Italy)reporting a value of 0.47% 7 .The seroprevalence of CMV varies significant-ly according to the analyzed population. In popu-lations of higher socioeconomic status, about40% of adolescents are CMV-seropositive, withoverall annual seroconversion rates reported tobe approximately 1% per year 8 .CMV is transmitted by close contact betweenindividuals, through contamination from urine,saliva, semen, cervical secretions and breastmilk, while droplet contamination is thought tobe less important 9 .Children in daycare facilities represent an im-portant reservoir of CMV. Transmission of virusfrom a day care attendee to a seronegative suscepti-ble woman may, if she is pregnant, result in a pri-mary maternal infection which in turn leads toCCMV infection of the fetus. Therefore, CMV- 2012; 16: 919-935  920 seronegative women working in daycare centersare at increased risk of acquiring CMV infection,while there is no evidence that healthcare providershave an increased risk of acquiring CMVinfection,compared with the general population 1,10,11 .Primary CMV infection is reported in 1-4% of seronegative women during pregnancy and therisk of transmission to the fetus is estimated to beabout 30 to 40% 12 .Reactivation of CMV infection during preg-nancy is reported in 10-30% of seropositivewomen and, in this circumstance, the risk of transmission of the virus is about 1-3% 3,13,14 .CCMV infection most commonly occurs viaintrauterine transmission, but since the virus isshed in body fluids, transmission can also be ac-quired during delivery or through breast milk.Only infants born to mother who had a prima-ry infection during pregnancy have symptomaticdisease at birth when compared with those bornto mother who had a recurrent infection. Also,they are at substantially higher risk for the devel-opment of long-term and severe sequelae 15-17 ,even though a few studies have identified severesymptomatic disease in newborns born to womenwith preconceptional immunity 13,18 .Moreover, women who are seropositive forCMV may become re-infected with a new strainduring pregnancy, and this re-infection can leadto symptomatic disease in the neonate 19 . The risk of severe consequences is muchgreater when CMV infection is acquired in thefirst half of pregnancy 5,20 .In the first months of pregnancy, in fact, CMVhas a teratogenic potential in the fetus, as CMV in-fections may result in migrational disturbances inthe brain 21-23 .Neocortical neurons migrate from their site of production in the periventricular germinativezone towards the cortical plate between the 12 th and 24 th week of gestation 24 .During this period, CMV may disturb the nor-mal development of the brain and produce mal-formations. Later in pregnancy, when the grossmorphology of the brain is completed and myeli-nation is occurring, white matter lesions withoutcerebral cortical malformations can develop 25 .CMV infections acquired during delivery orvia breast milk have no effect on future neurode-velopmental outcome in full term infants, but inpremature infants and low birth-weight newbornshave been demonstrated to cause symptomaticillness, including hepatitis, neutropenia, throm-bocytopenia 9,26,27 , and “sepsis-like” symptoms 28 .About 10-20% of children with CCMV, asympto-matic or symptomatic in the neonatal period, will ex-hibit neurological damage when followed up 13,29,30 . Clinical Manifestations of CCMV Infection  The majority of infants born with CCMV in-fection are asymptomatic at birth (asymptomaticCCMV infection is defined as the presence of CMV in any secretions within the first 3 weeksof life, but with normal clinical, laboratory andimaging evaluations) 13 , and only about 7 to 10%have clinically evident disease at birth 31 .Jaundice (62%), petechiae (58%), and he-patosplenomegaly (50%) are the most frequentlynoted symptoms and constitute the classical triadon CCMV infection 32 .Other clinical manifestations include sen-sorineural hearing loss (SNHL, present in about30% of symptomatic infants at birth) 33 , oligohy-dramnios, polyhydramnios, prematurity, in-trauterine growth retardation, non-immune hy-drops, fetal ascites, hypotonia, poor feeding,lethargy, thermal instability, cerebral ventricu-lomegaly, microcephaly, intracranial calcifica-tions (central nervous system (CNS) involvementis present in approximately two-thirds of infantswith symptomatic CCMV infection) 34 , “blueber-ry muffin” spots, and chorioretinitis 35,36 and, lessfrequently, hepatitis, pneumonia, osteitis, and in-tracranial hemorrhage 37 .Moreover, infants with symptomatic CCMV in-fection may be at increased risk for the presence of congenital malformations such as inguinal hernia inmales, high-arched palate, hydrocephalus, claspthumb deformity, and clubfoot 38,39 . Therefore, children with CCMV infectionneed to be evaluated carefully for the research of such malformations.True mortality rates are difficult to obtain andhave been reported to be as high as 30% for symp-tomatic infants 40 but other Authors have suggesteda more likely average of about 5-10% 41 . Death isusually due to non-CNS manifestations of the in-fection, such as hepatic dysfunction or bleeding 42 . Diagnosis The diagnosis of CCMV infection in a neonateis based on demonstration of the virus by isolationfrom urine, by identification of CMV-DNA bypolymerase chain reaction (PCR) in urine, blood,saliva and cerebrospinal fluid (CSF) sampled be-fore 3 weeks of age or by detection of antigen or D. Buonsenso, D. Serranti, L. Gargiullo, M. Ceccarelli, O. Ranno, P. Valentini  Type of patient Diagnostic method Comments Maternal infectionIgG seroconversion (appearance of Two consecutive maternal blood samples need to be virus-specific IgG in the serum of collected 2-3 weeks apart. IgM can be detected in:a pregnant woman who was reactivations or reinfections; until more than one yearpreviously seronegative)after CMV primary infection; interference due to rheumatoidPresence of anti-CMV IgM andfactor of the IgM class or cellular antigen; false positive IgG antibodiesduring other viral infections (B19 Virus, Epstein Barr Anti-CMV IgG avidity testVirus, etc.).Low avidity means recent maternal infection, but thresholddiffers between virological methods.Fetal infectionAmniocentesis to assess the presencePerform the test after the 21 st week of gestation and afterof CMV by PCR5-6 weeks from the estimated onset of infection. Indications are: woman with compatible clinical signs of primary CMVinfection; compatible ultrasound abnormalities; serologicsuspicion of a recent maternal infection.Neonatal infectionCulture or CMV-DNA testing byIf infection is confirmed, classify as symptomatic or PCR in urine, blood, throat and CSF.asymptomatic and follow-up at 1, 3, 6 and 12 months andannually until school age in order to detect sequelaewith delayed onset. Table I. Diagnostic methods available for the diagnosis of maternal, fetal and neonatal CMV infection. Adapted from Ref. 5. CMV-IgM in blood. A rapid diagnosis may be ob-tained by detection of CMV antigen in blood butthe sensitivity is low. IgG antibodies in neonatesare mostly maternally transferred antibodies,while the demonstration of IgM antibodies in thenewborn is indicative of congenital infection, be-cause maternal IgM antibodies can’t cross the pla-centa. However, only 70% of neonates withCCMV infection have IgM antibodies at birth 43 .Concerning the mother, seroconversion of CMV-IgG between two serum samples obtained in 2-3weeks distance provides the most reliable diagnosisof primary infection. The presence of CMV-IgMsuggests a recent or ongoing infection, but they havea low specificity. However, further confirmation of adiagnosis of primary CMV in pregnancy is alwaysrequired. The CMV-IgG avidity test, a measure of the binding capacity of CMV-IgG antibodies, is auseful tool for confirmation and for dating the timeof a primary CMV infection 44-47 . Low avidity IgG indicates antibody-produc-tion induced by acute or recent primary CMV in-fection, whereas high avidity IgG indicates nocurrent or recent primary infection 45,48-52 .If a high avidity is found in the first 12-16 weeksof gestation, a recent infection can be ruled out 30 .Table I shows diagnostic methods for diagnos-ing maternal, fetal and neonatal CMV infection. Outcome of CCMV Infection  About 10-20% of all children with CCMV in-fection, symptomatic or not in the neonatal peri-od, will exhibit neurological damage when fol-lowed up 13,29,30 .SNHL, mental retardation, seizures, psychomotorand speech delays, learning disabilities, chorioretini-tis, optic nerve atrophy, and defects in dentition arethe most common long-term consequences 53 . SNHL is the most frequent long-term conse-quence and is not manifest invariably at birth orin the neonatal period but in many cases mayfluctuate and be progressive in nature 54-56 , be-coming clinically apparent in later childhood(during the first 6 years of life) 56 .The prevalence of SNHL caused by CCMV in-fection (symptomatic and asymptomatic) at birthis 5.2% and late-onset hearing loss at 6 years is15.4% 40,57-59 .Generally, children with symptomatic neonatalinfection have hearing loss at an earlier age andwith greater severity than infants with asympto-matic infection 30,60 .An estimated 40-58% of infants with sympto-matic CCMV infection suffer from severe neuro-logic sequelae 40,61 , and mortality rates range from5% 41 to 30% of them 40,62 .It is now recognized that also asymptomaticCCMV infection is associated with increased risk of SNHL 41,42 . In particular, different studies reportthat 6 to 25% of asymptomatic children will devel-op late-onset sequelae, overall neurological ones,the most important of them being SNHL, makingCCMV infection as the probable leading non-ge-netic cause of SNHL in childhood 3,54,56-58,63-69 . 921 Congenital cytomegalovirus infection: current strategies and future perspectives  D. Buonsenso, D. Serranti, L. Gargiullo, M. Ceccarelli, O. Ranno, P. Valentini 922 In a longitudinal investigation of CMV-associateddeafness in a cohort of 307 newborns with asymp-tomatic CCMV infection, 22 (7.2%) had SNHL.Among children with hearing loss, further deterio-ration of hearing occurred in 50%. Delayed-onsetSNHL was observed in 18.2% of the children, withthe median age of detection being 27 months 70 .The same Authors demonstrated on 388 con-genitally-infected neonates that a single audio-logical screening in neonatal period identifiedless than 50% of patients suffering from hearingdeficit compared with repetitive screening untilthe age of 6 years (3.9% vs 8.3%) 68 . The implica-tions of these observations are important forhearing-screening programs for newborns be-cause the universal screening of hearing inneonates is estimated to detect less than half of all SNHL caused by CCMV infection 68 .Therefore, infants with documented CCMV in-fection, but normal hearing at the time of the new-born screening, should be monitored throughoutchildhood for evidence of progression to SNHL. Little attention has been focused on the influ-ence of CCMV infection on children’s physicalgrowth and intellectual development. By follow-ing-up asymptomatically infected infants from2003 to 2007, Shan et al 62 investigated changes inaudiology, nervous behavior, intellectual develop-ment, and behavioral development in order to findout the impact of asymptomatic CCMV infection.52 asymptomatic newborns were enrolled in theinfection group. At one year of age, seven ears of 5 cases showed mild abnormal auditory thresholdsin V waves with an abnormal rate of 14%, whileno abnormalities were found in 21 cases in thecontrol group, with a statistically significant dif-ference between the 2 groups. Five ears in 4 casesin the infection group showed prolonged intervalsin I-V waves, whereas 3 ears in 2 cases in the con-trol group showed this abnormality (no statistical-ly significant difference). No significant differ-ences in mental development index (MDI) andpsychomotive development index (PDI) werefound. No abnormalities were found on cranial B-ultrasonographies and cranial computed tomogra-phy scans. This study indicated that asymptomaticCCMV infection had an impact on infant hearing. Fowler et al 54 , through comparison with a con-trol group which consisted of siblings or random-ly selected children, reported that SNHL was on-ly found in the asymptomatic infection group. Numazaki and Fujikawa 66 found that, among17 cases of asymptomatic CCMV infection, 2children developed late-onset SNHL, including 1case of moderately binaural hearing loss and 1case of unilateral hearing loss. Whether infants with asymptomatic infectionare at increased risk of mental retardation is con-troversial.According to some studies, CCMV infectiondid not have a significant influence on total Intel-ligence Quotient of infants 62,71,72 .In contrast, Hanshaw et al 73 compared 44 chil-dren with asymptomatic CCMV infection with con-trols and found school failure and deafness to be as-sociated with asymptomatic CCMV infection 39,73 .Some factors associated with the developmentof long-term sequelae have been found.An analysis of the data of 180 children withCCMV infection showed that the presence of pe-techiae and intrauterine growth retardation wereindependently associated with the developmentof hearing loss 74,75 .Microcephaly, after adjustment for weightdeficit, had a 100% specificity for the predictionof mental retardation and/or major motordeficits 61,74,76 , but not with an increased risk forthe development of SNHL 69,74 .Some investigations 61,69,74,76-78 have shown thatdevelopment of neonates with CNS involvementat birth is impaired, as > 90% of surviving infantsdeveloped significant CNS sequelae, perceptualdefects or both within the first 2 years of life.Normal neuro-imaging at birth in symptomaticCCMV infection predicts a good long-term neu-rologic outcome 61,69,74,76-78 .On the opposite, intracranial lesions on neu-roimaging are associated with severe intellectualimpairment in > 80% of cases 61,77 .Some studies have shown that the amount of CMV copies in blood correlates with neurologicaloutcome irrespective of whether children are consid-ered symptomatic or asymptomatic at birth 59,75,79-81 .Four studies have demonstrated that a high viralload in early infancy expressed by a high amountof virus in the urine (450,000 PFU/mL) is highlypredictive of audiologic impairment 59,74,77,80 . Greater than 70% of symptomatic (with orwithout CNS involvement) infants with viruria of > 5 · 10 4 PFU ⁄mL will have poor neurodevelop-mental outcome when compared with only 4%with viruria of < 3.5 · 10 3 pfu ⁄mL 77,82 . Pathogenesis of Hearing Loss in CCMV infection  The viral and/or host inflammatory mecha-nisms involved in the pathogenesis of CCMV-re-lated auditory dysfunction are still unclear 84 .
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