Simultaneous infection of CMV and EBV in a late preterm neonate

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ESPR441
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History:

A newborn infant is born at 36 weeks to a 27-year-old Gravida 4, Para 3 woman with negative prenatal labs. Pregnancy was complicated by diet-controlled gestational diabetes. The mother reports a travel history to Europe 12 weeks prior to delivery. She worked as a daycare teacher and had clinical symptoms of an acute upper respiratory illness three weeks prior to delivery. The baby was born by spontaneous vaginal delivery at a community hospital. Physical parameters included the weight of 2.085 kg (13th %), length of 43 cm (38th %), and head circumference of 31 cm (16th %).

The patient was transitioned to room air and then at 24- 48 hours of life, the patient presented with hypoglycemia, oliguria with jaundice, and transferred to our tertiary care center.

Physical Examination:

Vitals: Temp 36.9, HR 130, RR 44, Saturation: 98% on room air, BP 58/34 (MAP: 41). Physical exam was notable for icterus, hepatomegaly, splenomegaly, and few petechiae on the abdomen and back.

Investigation:

Initial blood count revealed thrombocytopenia with no leukocytosis. The comprehensive metabolic panel showed abnormal liver enzymes (Figure 1) with initial hyperbilirubinemia (total BR: 18mg/dl; direct 10mg/dl) and abnormal coagulation test with elevated INR of 1.6. Direct hyperbilirubinemia continued to trend up despite interventions with a maximum value of 14.9 mg/dl. The abdominal US showed hepatomegaly. Infectious diseases TORCH evaluation included studies for herpesviruses (herpes simplex, cytomegalovirus, and Epstein Barr virus) and Toxoplasma gondii. Urine sample sent for CMV PCR came back positive and blood sample tested positive for EBV (~1500 copies of DNA/ml). MRI brain showed medial temporal horn cysts, banding of the interventricular regions, immature white matter, and cerebellar vermis hypoplasia (Figure 2).

Final Diagnosis:

Co-infection of CMV and EBV 

Management:

The patient was started on IV ganciclovir and eventually switched to valganciclovir on post-natal day six. The liver enzymes and direct BR were down-trending then. She was discharged home on valganciclovir for 6 months. On the outpatient follow up, she showed progressive developmental delay and sensorineural hearing loss (SNHL).

Discussion:

All neonatal liver dysfunction is "acute" by definition. The common differential diagnosis includes viral infections (20-30%), hemophagocytic lymphohistiocytosis (HLH), mitochondrial cytopathy, and gestational alloimmune liver disease (GALD) which is the most common cause. CMV is very rarely associated with neonatal liver dysfunction, but more often with chronic hepatitis and prominent cholestasis. While congenital CMV is well recognized between 0.5 and 1% of all live infants, in utero infection with EBV is rare as is the occurrence of dual infection.

EBV infection:

Epstein-Barr virus (EBV) is a herpes virus. Vertical transmission of EBV during pregnancy through the placenta has been described. Kim et al. were the first to authenticate latent EBV infection of endometrial glandular epithelial cells without a neoplastic or immunocompromised disorder. 

Icart et al reported outcomes in six pregnant women with primary EBV infection. One woman had a spontaneous abortion, 2 babies were born premature, one died, and one was stillborn with multiple malformations. A case report by Brown and Stenchever reported severe congenital anomalies in an infant exposed to EBV infection from conception to delivery.  Another case report described congenital anomalies such as cryptorchidism, micrognathia, cataract, hypotonia in a male infant exposed to EBV during pregnancy. Two other reports described liver and bile duct anomalies in infants exposed to EBV during pregnancy.

Despite several case reports of fetal outcomes of EBV infection during pregnancy have been published, there is no specific syndrome that can be described. No treatment has been identified for congenital EBV infection.

CMV infection:

In the developed world, congenital CMV is the leading non-genetic cause of SNHL in children. Furthermore, CMV is the leading viral cause of neurodevelopmental delay, with cognitive and psychomotor disabilities reported in symptomatic infants.

The presentation can be with intrauterine growth retardation (IUGR), preterm labor, petechiae, jaundice, hepatomegaly, splenomegaly, and microcephaly. Laboratory and imaging findings include thrombocytopenia, transaminitis, direct hyperbilirubinemia, chorioretinitis, SNHL, and periventricular calcifications. Radiographic findings in the brain are abnormal in 50-70% of children with symptomatic infections at birth and include intracranial calcifications, ventricular dilation, cysts, lenticulostriate vasculopathy, choroid plexus cyst, and echogenic bowel. 

Maternal primary infection can be confirmed reliably by the demonstration of seroconversion. Universal screening of pregnant women has not been recommended because of the lack of proven specific interventions for maternal primary infection. Neonates receiving 6 months of valganciclovir had a 2·6-times increased likelihood of improved total hearing at 12 and 24 months than those who received only 6 weeks of valganciclovir.

Co-infection of CMV and EBV:

Two previous case reports were published by Joncas et al. Diagnosis was made by positive IgM titers for CMV and EBV. Clinical presentation included petechial rash, hepatosplenomegaly, thrombocytopenia, peri-ventricular calcification. Patients did have a gross motor delay with speech delay on follow up.

Message to the clinician:

Our case is unique since our neonate was found to have a simultaneous infection with CMV and EBV. Whether coinfection with EBV is a coincidental finding or have contributed to the baby's severity of symptoms remains uncertain. To our knowledge, this is the third case in the literature to report coinfection with CMV and EBV in neonates.

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University of Pittsburgh Medical Center
University of Pittsburgh Medical Center

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