Congenital Cytomegalovirus Infection : Evaluation and Management

1. Resident (Phase-B), Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 2. Professor, Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 3. Associate Professor, Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka 4. Professor, Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka Correspondence Md. Benzamin, Email: drmd.benzamin@yahoo.com Introduction


Introduction
Cytomegalovirus (CMV) is an important viral pathogen for humans and most individuals are eventually exposed to this agent. 1,2CMV is a doublestranded DNA virus, member of the human herpes virus family, ~235 kb in size.Humans are its only known host and that replicates within the nucleus of an infected cell and may remain latent in host cells after the primary infection. 3CMV infection is endemic and does not show seasonal variations. 4he heavy disease burden, CMV infection is underdiagnosed because the majority (approximately 80%) of affected mothers are asymptomatic.12,13

Transmission
CMV is transmitted horizontally to mother as a result of contact with infected saliva and urine, sexual contact and also from organ donation and blood transfusion.CMV infection in newborns may be acquired congenitally through transplacental transmission (antepartum) and may also be perinatally (intrapartum and postpartum).Perinatal CMV infection is acquired by contact with contaminated blood and genital secretions during delivery and via breast milk after delivery.The incubation period ranges from 7 to 12 weeks, with an average of 8 weeks. 1417 1

.3 Maternal CMV infection
Maternal CMV infection may be primary infection and non-primary infection (reactivation of latent infection or re-infection with new strain in seropositive women).Primary infection means mothers without preexisting immunity who first acquire CMV infection in pregnancy.Non-primary infection means women with preexisting antibodies (seropositive) to CMV either by reactivation of a previous maternal latent infection or by acquisition of a different viral strain. 18

Congenital CMV infection
Congenital infection is highest following primary maternal infection.About 1-4% of CMV seronegative mothers become infected during pregnancy and women with primary CMV in pregnancy have a risk of congenital infection of 30-50%, rate is as high as 70% with third-trimester exposure. 18,19Among women with a primary infection, 18% of their infants will be symptomatic at the time of birth. 20ong the symptomatic group, 30% may die.Up to 25% are not symptomatic at birth and experience long-term neuro-developmental sequelae during the first 2 years of life.Among infants followed up to 5 years of age, development of sequela occurs as late as 72 months.Severe illness appears to be more likely among fetuses whose mothers experience primary infection during the first half of pregnancy. 21,22About 50-70% women of reproductive age are susceptible to recurrent CMV infection and 0.5-2% fetus will develop CMV infections, <1% of offsprings are symptomatic at birth. 22,23However, 8% of offsprings will develop neurodevelopmental sequelae by age 2 years and 14% by age 5 years. 22Maternal and neonatal risks of CMV infection 24 are shown in Fig 1.

Clinical manifestations
The clinical manifestations of congenital CMV infection varies widely, from the asymptomatic infection to potentially life-threatening disseminated disease. 8,10Clinical features include petechiae, microcephaly, lethargy/hopotonia, poor suck, seizures, jaundice, hepatosplenomegaly, small for gestational age, prematurity etc. Laboratory manifestations include elevated serum transaminases, conjugated hyperbilirubinemia, thrombocytopenia, elevated cerebrospinal fluid protein etc. 25 According to severity of infection different types of CMV infection are summarized in Table I.Definitions of symptoms and signs are shown in Table II.
Long-term sequelae occur following both symptomatic and asymptomatic congenital infections, with the more frequent and severe sequelae occurring in symptomatic infants.It has been estimated that 40-58% of infants who are symptomatic at birth develop sequelae, and these may include sensorineural hearing loss, vision loss, mental retardation, seizure disorder, cerebral palsy, visual deficits, hypotonia, poor feeding, ventriculomegaly, polymicrogyria, periventricular pseudocysts and developmental delay. 8,25,28,29Hearing loss is most common when CMV infection occurs in the first or second trimester. 22Sensorineural hearing loss following symptomatic or asymptomatic congenital infection is often progressive, can be unilateral or bilateral, and may be absent at birth, only to become clinically manifest later in childhood.Among infants with symptomatic congenital CMV infection, SNHL will affect 30% at birth.Among the 90% of asymptomatic infants at birth, 7-15% will develop progressive SNHL later in childhood. 8,20,30,31phthalmologic manifestations of congenital CMV include chorioretinitis, strabismus, microphthalmia, optic nerve atrophy, and cortical visual impairment.

Diagnosis of the cytomegalovirus-infected neonate
A newborn should be evaluated if there are features suggestive of congenital CMV infection or mother having previous history of CMV infection, have to screen for CMV infection.Diagnosis of congenital cytomegalovirus infection in neonates should include real-time PCR of saliva, urine, or both as soon as possible after birth but within the first 3 weeks of life, with saliva as the preferred sample.Both urine and saliva are reliable specimens for neonatal cytomegalovirus screening using PCR.Real-time PCR of saliva showed high sensitivity (>97%) and specificity (99%). 26,32,33V IgG and IgM antibody levels are not recommended for the specific diagnosis of congenital CMV infection because only 20-70% of infected babies will have a positive CMV IgM antibody titer and many newborns will have a positive CMV IgG antibody titer from blood passed to them from their mother 34 (Table III).Other methods for diagnosing CMV have also been described, e.g., CMV-specific IgM, CMV DNAemia in peripheral blood leucocytes, and CMV pp65antigenemia test, urine DEAFF test.35,36 Once the diagnosis is confirmed, further laboratory tests, imaging and eye and hearing assessments are indicated.CBC and LFTs may reveal pancytopenia/ thrombocytopenia and raised ALT, prolonged prothrombin time and coagulation studies may be abnormal in the setting of hepatitis.Renal function is checked prior to beginning of treatment with ganciclovir.Neuroimaging assessment such as cranial ultrasound is a good screening tool with subsequent MRI/CT is recommended for definitive evaluation (Fig 2 ,3).37,38 USG findings also help in prenatal diagnosis of congenital CMV infection.A cranial ultrasound should be performed as soon as possible after birth.Cranial CT and/or MRI should also be considered in the neonatal period if there is a high index of suspicion of neurological involvement with CCMV infection despite normal cranial ultrasound scan.23 Ultrasound abnormalities from cases of confirmed congenital cytomegalovirus infection 39,40 are cerebral calcifications, microcephaly, echogenic bowel, fetal growth restriction, subependymal  Ophthalmologic assessment should be performed on all infants with congenital CMV infection.Audiological assessment should be performed in all infants with congenital CMV infection: as noted, SNHL may be absent at birth, and progressive in nature, and frequent evaluations are required throughout childhood to find out the possibility of hearing deterioration.30

Prenatal diagnosis of fetal cytomegalovirus infection
Prenatal diagnosis of fetal CMV infection can be made by testing amniotic fluid for cytomegalovirus by amniocentesis.It is done in two situations: when there is maternal primary CMV infection during pregnancy, or when there are abnormalities on ultrasound that    41 The presence of cytomegalovirus can be detected using real-time PCR (most sensitive) or virus culture.
3][44] Diagnosis of CMV infection in pregnancy is shown in Table IV.

Treatment
Treatment of congenital CMV infection should be given cautiously and toxicities of antivirals must balance with potential benefits.Neonates with asymptomatic congenital cytomegalovirus infection should not be given antiviral therapy.Neonates with mildly symptomatic congenital cytomegalovirus infection should not routinely be given antiviral therapy.Antiviral therapy is not routinely recommended for congenital cytomegalovirus infection with isolated sensorineural hearing loss and otherwise asymptomatic.Neonates with lifethreatening infection and moderately to severely symptomatic congenital cytomegalovirus disease are considered for immediate treatment which should be initiated within first month of life.Neonates with CNS involvement should be treated.Chorioretinitis can cause sight-threatening infection and hence warrants prompt treatment. 26,27[47] Valganciclovir treatment for 6 months is only recommended for congenitally infected neonates with moderately to severely symptomatic disease. 26imberlin DW et al 48 showed that neonates receiving 6 months of valganciclovir had a 2•6 times increased likelihood of improved total hearing at 24 months than those who received only 6 weeks of valganciclovir treatment.Algorithm of congenital CMV infection management 49 is shown in Fig 4.
Acute side-effects are neutropenia (in up to 63% with ganciclovir and up to 38% with valganciclovir) and neutropenia-related sepsis (rare).Other rare sideeffects are bone marrow suppression, raised liver enzymes, hypokalemia and renal impairment.All these side-effects are reversible after stopping the drug for at least 3-7 days.Other possible risks are gonadal dysgenesis, carcinogenicity etc. 2 Current therapies for petdiatric CMV infection is shown in Table V and monitoring of ganciclovir and valganciclovir is shown Table VI.

Prevention of congenital CMV infection
Strategies to reduce the burden of congenital CMV disease include prevention of maternal infection, prevention of mother to child transmission (MTCT), early detection and intervention by neonatal screening, and neonatal antiviral therapy.

Active immunization
Development of a CMV vaccine is the most promising strategy for addressing the problem of congenital CMV.Ongoing and future clinical trials will hopefully lead to the licensure of a CMV vaccine in the not-todistant future.

Passive immunization
In addition to active immunization strategies, passive immunization based on administration of anti-CMV immune globulin to women at risk of transmitting CMV to the fetus is currently an intensely active area of clinical research.La Torre et al 50 and Nigro et al 51 showed that administration of HIG to women in the primary infection has significant reductions in placental pathology, and regression of cerebral structural abnormalities in some infants.
Buxmann et al 52 showed that HIG administration reduced intrauterine transmission of CMV.The use of HIG during pregnancy has also been reported to be associated with improved neurodevelopmental outcomes in infants in the first year of life. 53ndomized controlled trials of HIG are warranted in high-risk pregnancies, to validate the protective effect of passive immunization.The HIG regimen was 100 U/kg monthly until delivery. 54Society for Maternal-Fetal Medicine do not recommend antenatal treatment with ganciclovir or valacyclovir and we recommend that any antenatal therapy, either with antivirals or CMV HIG, should only be offered as part of a research protocol. 23

Behavioral interventions for pregnant women
• Avoid sharing of food, drinks or spoon used by young children.
• Do not put anything like child's dummy, soother, pacifier, toothbrush etc. used by young children in your mouth.
• Avoid contact with saliva during kissing a child.
• Immediate hand wash with soap and water after changing any material such as nappies, diapers, toys etc. that comes in contact with child's urine and saliva and also after feeding a young child or wiping a young child's nose or saliva.
• Regular cleaning of toys, countertops, and other surfaces that come into contact with children's urine or saliva.

Conclusion
Congenital CMV infection has significant impact and burden on the individual and the society.High index of suspicion based on high risk populations and clinical features of newborn can prevent mortality and morbidity.Effective preventive strategies for reproductive women are warranted for both developed and developing countries.

Fig 1 .
Fig 1. Maternal and neonatal risks of CMV infection24 Cortical calcifications (arrow) and mild passive ventriculomegaly on USG brain 6-month-old girl with microcephaly and agyria-pachygyria and ventriculomegaly

Table I :
26,27definitions of congenital CMV infection26,27 cortical or cerebellar malformations), abnormal cerebrospinal fluid indices for age, chorioretinitis, sensorineural hearing loss, or the detection of cytomegalovirus DNA in cerebrospinal fluid • Mildly symptomatic congenital cytomegalovirus disease: one or two isolated manifestations that are mild and transient (eg, mild hepatomegaly or a single measurement of low platelet count or raised levels of alanine aminotransferase).These might overlap with more severe manifestations.

Table II :
27finitions of symptoms and signs27

Table III :
Interpretation of neonate's CMV antibody

Table IV :
14agnosis of CMV infection in pregnancy14

Table V :
2urrent therapies for pediatric CMV infection2

Table VI :
27nitoring of ganciclovir and valganciclovir27

Table VII :
27,[55][56][57][58]6. Follow-upAll infants both treated and untreated should have regular auditory, ophthalmological and neurological evaluation for detection of cognitive and neurodevelopmental impairment as well as late-onset or progressive SNHL.Recommendation for followup is shown in TableVII.Recommendation for follow-up27