Ganciclovir treatment of symptomatic congenital cytomegalovirus infection

Brendan Crowley*

Liverpool Public Health Laboratory, University Hospital Aintree, Liverpool L9 7AL, UK

Sir,

Griffiths’ excellent article1 on the treatment of cytomegalovirus (CMV) infection referred to a controlled clinical trial2 that found significantly less hearing loss in neonates with central nervous system (CNS) symptoms due to congenital CMV who were treated with ganciclovir than untreated controls. Since clinical benefit can now be expected with ganciclovir, is it now time to consider its use in this patient population?

CMV is the commonest congenital viral infection in humans, occurring in 0.4–2.3% of all live births, and is probably the commonest cause of mental retardation and non-hereditary sensorineural deafness in children.3 Approximately 10% of infants with congenital CMV are symptomatic at birth with intra-uterine growth retardation, thrombocytopenia, petechiae, jaundice, hepatosplenomegaly or CNS disease including microcephaly, intra-cranial calcification, chorioretinitis and sensorineural deafness.3 Although 90% of infected neonates are asymptomatic, 5–17% may develop late sequelae including poor neurodevelopmental outcome and deafness. Many of these children require custodial care for life, with significant public health implications.

In January 2001 the diagnosis of congenital CMV infection in two neonates was confirmed at Liverpool Public Health Laboratory by isolation of the virus from urine collected soon after birth. A 23-year-old woman gave birth at 37 weeks gestation to a small-for-dates baby girl. An ultrasound scan during pregnancy showed evidence of intra-uterine growth retardation. Serum collected at birth from the baby did not show evidence of rubella infection or toxoplasmosis. However, CMV IgM was detected and the virus isolated from urine collected 2 days after birth, confirming congenital CMV infection. Although a CT scan of the brain showed a single punctate calcified lesion, CMV was not detected in CSF by PCR or viral culture. Quantitative CMV viral load in blood, measured using real time TaqMan PCR,4 revealed significant viraemia (2 950 760 genome copies/mL). Treatment with ganciclovir (6 mg/kg twice daily for 6 weeks) was discussed with her parents but they declined. After 7 days, the girl left hospital in good condition. At 3 months of age audiological examination was normal, and there were no signs of chorioretinitis on examination. However, at 6 months of age motor delay became apparent. At 13 months the baby had signs of global retardation, but no evidence of deafness on brain-stem audiometry.

A 28-year-old woman delivered a boy with no obvious abnormalities after an uncomplicated pregnancy. At 1 day old the baby developed petechiae and jaundice, and hepatosplenomegaly was found on examination. The baby was transferred to ICU and treated for septicaemia with co-amoxiclav plus gentamicin. Investigations confirmed thrombocytopenia (50 x 103 platelets/mm3), hyperbilirubinaemia (50 µM) and raised liver function tests. Bacterial culture of CSF and blood were negative, but CMV was cultured from urine collected 3 days after birth. Quantitative CMV viral load in blood showed a significant viraemia (280 000 genome copies/mL). CMV was not detected by viral culture or PCR in CSF collected on day 2. However, a CT scan of the brain revealed multiple discrete periventricular calcifications. No chorioretinitis was found on examination, but brain-stem audiometry indicated bilateral sensorineural deafness. Treatment with ganciclovir was not given because the baby was otherwise well. Jaundice and petechiae resolved within 16 days, and hepatosplenomegaly within 8 weeks. Follow-up at 3 months further confirmed profound deafness. At 13 months of age, the boy was normally developed except for deafness.

Poor cognitive and motor outcome, like audiological impairment, are important sequelae of congenital CMV infection, as shown in these two cases. While treatment with ganciclovir can decrease hearing loss,2 it is also important to know whether it beneficially influences growth and development, and improves intellectual outcome in congenitally infected infants. Because myelosuppression and gonadal toxicity are known side-effects of ganciclovir,3 treatment should only be considered in children with CNS disease, with or without intra-cranial calcification, since benefit from an audiological perspective has been shown in this group. Absence of CMV DNA in CSF samples collected soon after birth in these two cases appears to support the notion that infection of the CNS can occur before birth as a result of intra-uterine dissemination of CMV.5 However, continuing low-level CMV replication in the inner ear and brain cannot be excluded. Further data on the efficacy of ganciclovir in improving neurodevelopmental outcome are welcome.

Footnotes

* Tel: +44-151-5294900; Fax: +44-151-5294918; E-mail: BCrowley{at}nw.phls.org.uk Back

References

1 . Griffiths, P. D. (2002). The treatment of cytomegalovirus infection. Journal of Antimicrobial Chemotherapy 49, 243–53.[Abstract/Free Full Text]

2 . Kimberlin, D. W., Lin, C. Y., Sandez, P., Demmler, G., Dankner, W., Shelton, M. et al. (2000). Ganciclovir (GCV) treatment of symptomatic congenital cytomegalovirus (CMV) infections; results of a phase III randomized trial. In Program and Abstracts of the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 2000. Abstract 1942, p. 274. American Society for Microbiology, Washington, DC, USA.

3 . Whitley, R. J., Cloud, G., Gruber, W., Storch, G. A., Demmler, G. J., Jacobs, R. F. et al. (1997). Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Journal of Infectious Diseases 175, 1080–6.[ISI][Medline]

4 . Guiver, M., Fox, A., Mutton, K., Mogulkoc, N. & Egan, J. (2001). Evaluation of CMV viral load using TaqMan CMV quantitative PCR and comparison with CMV antigenemia in heart and lung transplant recipients. Transplantation 71, 1609–15.[ISI][Medline]

5 . Boppana, S. B., Fowler, K. B., Hedlund, G., Stagno, S. & Britt, W. J. (1997). Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics 99, 409–15.[Abstract/Free Full Text]