Congenital Cytomegalovirus Infection: Screening and Treatment
Article Outline
CMV, Cytomegalovirus, DBS, Dried blood spots, PCR, Polymerase chain reaction
Although screening newborns for congenital CMV infection has been limited to research studies, it is time to consider such screening on a larger scale. A cost-effective, specific, and sensitive means of newborn screening would make it possible to obtain a more accurate, population-based estimate of the importance of congenital CMV infection as a cause of disability. This could be accomplished by population-based sentinel screening of a small fraction of newborns. Data from a limited screening could inform public health policy makers by showing trends in rates of congenital CMV infection. If a new preventive strategy such as a vaccine for prevention of maternal CMV infection is implemented, sentinel screening could provide valuable information on effectiveness in the same way that active surveillance for varicella infection demonstrated the impact of routine immunization of children against varicella.5 On a larger scale, screening for congenital CMV infection could be viewed as part of the effort toward early identification of hearing impairment. Hearing loss with congenital CMV infection often is delayed in onset or is progressive and is missed by universal newborn hearing screening. Infants known to have congenital CMV infection need repeated testing, especially during their first year or 2 when progressive hearing loss is most likely to occur.
In the past, screening for congenital CMV infection usually was accomplished by viral culture of urine or an adaptation of culture with monoclonal antibody detection of infected tissue culture cells, methods that are relatively time consuming, expensive, and not readily adapted to automation. Although polymerase chain reaction (PCR) eliminates cumbersome cell culture techniques and is at least as sensitive as virus culture for detection of CMV in newborn urine, the problem of collecting urine from newborns remains. Detection of CMV DNA in dried blood spots (DBS) has been studied as a means of diagnosing congenital CMV infection on a readily available newborn sample, (see review).6 The article by Kharazzi et al1 in this issue demonstrates that it is technologically feasible to perform population-based screening of newborns for congenital CMV infection with PCR used to detect viral DNA in DBS. DBS are collected routinely on all newborns in the United States and used to test for metabolic diseases. Procedures for the collection and processing of these samples on a large scale are already in place. In addition, PCR is amenable to automation and could thus be adapted to screening of all newborns. With PCR used to test DBS, the rate of congenital CMV infection in a population-based sample of newborns in California was 0.7%, about what one would expect it to be on the basis of published studies that have screened newborns for congenital CMV infection with urine or saliva.1, 7 A logical next step in evaluation of this approach to screening for congenital CMV infection would be a study that included parallel testing of DBS and culture or PCR testing of urine for CMV along with clinical evaluation of infected infants. Not all newborns with congenital CMV infection are viremic even by sensitive PCR methods, but the proportion of congenitally infected newborns that will be missed by DBS screening is not clear from published studies. In addition, it is not possible to determine whether DBS screening produces false-positive results compared with testing newborns for viruria. Further study clearly is needed.
Treatment of newborns with symptomatic congenital CMV infection with intravenous ganciclovir for 6 weeks has been shown to improve hearing and developmental outcomes.3, 4 Valganciclovir, the mono-valyl ester prodrug of ganciclovir has good oral bioavailability and is converted to ganciclovir after absorption. Pharmacokinetic studies have shown that a 16 mg/kg dose of valganciclovir oral solution twice daily achieves plasma concentrations of ganciclovir in newborns equivalent to those obtained with intravenous administration of 6 mg/kg on the same schedule.8 It seems very likely that that oral valganciclovir will replace intravenous ganciclovir as the preferred treatment for infants with symptomatic congenital CMV infection.
Congenital CMV infection results in shedding of virus in urine for years. Viruria is suppressed by ganciclovir treatment, but it returns promptly after a 6-week treatment. It is reasonable to expect that longer treatment for congenital CMV infection might sustain suppression of viral replication and improve outcome compared with 6 weeks of treatment, the only treatment that has been evaluated in a randomized trial. The report by Shoji et al2 in this issue describes a case that appears to confirm this expectation. An infant with retinitis caused by congenital CMV infection whose disease recurred shortly after completion of 6 weeks of intravenous ganciclovir achieved sustained remission after three additional weeks of intravenous ganciclovir and 7 weeks of oral valganciclovir. A very important observation reported in this article is the recurrence of active retinitis after 6 weeks of ganciclovir, an event that could occur in any infant with chorioretinitis who receives antiviral treatment. Follow-up eye examinations after cessation of antiviral treatment should be used to look for recurrence of eye disease, which can appear rapidly and lead to impaired vision. Chorioretinitis eventually becomes inactive in infants with congenital CMV infection with or without antiviral treatment. However, considering the success of antiviral treatment for CMV retinitis in immunocompromised patients and the potential for loss of sight because of uncontrolled retinitis, it would be very difficult to choose not to treat infants with retinitis caused by congenital CMV infection. The availability of valganciclovir oral solution makes treatment easier, especially longer treatment. However, it is important to recognize that added benefit of longer treatment has not been demonstrated by controlled studies. In addition questions remain regarding the potential short- and long-term toxicities of ganciclovir. A multicenter, randomized, placebo-controlled clinical trial comparing 6 weeks versus 6 months of oral valganciclovir will help define the benefits and risks of longer treatment of symptomatic congenital CMV infection (NCT00466817, www.clinicaltrials.gov). Whether children with congenital CMV infection who are symptom free at birth but have hearing loss would benefit from antiviral treatment is not known. Antiviral treatment of newborns with congenital CMV infection without evidence of newborn disease with the goal of preventing hearing impairment seems ill advised at this time. Approximately 85% of these infants will remain free of hearing impairment. Furthermore, antiviral efficacy has not been demonstrated in this group, and drug toxicity is a concern.
References
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- Is a six-week course of ganciclovir therapy enough for chorioretinitis in an infant with congenital cytomegalovirus infection?. J Pediatr. 2010;157:331–333
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Supported by Virology Branch, Division of Microbiology and Infectious Diseases, NIAID, U01-AI063565. R.P. has received research support from Sanofi Pasteur and is a consultant to Merck
PII: S0022-3476(10)00345-8
doi:10.1016/j.jpeds.2010.04.045
© 2010 Mosby, Inc. All rights reserved.
Refers to article:
- Use of Screening Dried Blood Spots for Estimation of Prevalence, Risk Factors, and Birth Outcomes of Congenital Cytomegalovirus Infection , 19 April 2010
- Is a 6-Week Course of Ganciclovir Therapy Effective for Chorioretinitis in Infants with Congenital Cytomegalovirus Infection? , 19 April 2010
