Diagnosis and management of congenital cytomegalovirus infection

Dr. Soren Gantt, MD PhD MPH FRCPC (biography and disclosures)
No disclosures. Valganciclovir has not been approved for the treatment of congenital cytomegalovirus (cCMV) infection by Health Canada and coverage requires application to the Special Authority Program. Only published trial data are presented. Recommendations are consistent with current practice patterns.

What I did before

Approximately 1 out of every 150 live-born infants has congenital CMV infection (cCMV). Of these, most are asymptomatic. However, more than 20% will suffer permanent neurologic sequelae, including hearing loss, intellectual disability, and visual deficits. In fact, cCMV is responsible for 25% of all childhood hearing loss, and is the second most common cause of intellectual disability after Down syndrome. Despite this burden of disease, there is no way to prevent cCMV and, until recently, there was no strong evidence for treatment.

Presentation of disease due to cCMV can be subtle, and most symptomatic newborns are not diagnosed (1, 2). To definitively diagnose cCMV and exclude post-partum infection, virus must be detected within the first 3 weeks of life. This is best done using PCR or culture of urine or saliva, which contain high levels of virus; CMV PCR from a dried blood spot can sometimes be helpful if it is positive but is only ~30% sensitive.

Traditionally, cCMV diagnosis has depended on clinical suspicion, and only the most severe cases were identified (e.g., those with multiple signs like microcephaly, seizures, petechiae, hepatosplenomegaly, etc.). For those infants, I usually recommended treating with IV ganciclovir and/or oral valganciclovir for 6 weeks (depending on severity, whether hospitalized, etc), based on a small randomized trial of IV treatment and pharmacokinetic (pK) studies indicating that oral valganciclovir can achieve levels comparable to IV ganciclovir.  However, the efficacy of IV treatment for 6 weeks was debatable, and there were no cCMV treatment trials (only pK data) on which to base PO therapy. As such, I was reluctant to treat less severely symptomatic infants if they happened to be identified, and I was ambivalent about more aggressive testing, including universal screening.

What changed my practice

Last year, a long-awaited study was published in the New England Journal (3). This was a multicenter trial of 96 newborns with symptomatic cCMV who were randomized to either 6 months or 6 weeks of therapy with oral valganciclovir (a no-treatment group was not considered ethical). There was no difference in hearing between the 2 groups at 6 months, the primary end-point. However, there were modest but statistically significant improvements both in hearing and in neurodevelopmental assessments in the 6-month treatment group at 12 and 24 months of age. The regimen appears quite safe, as adverse events including neutropenia (the most common toxicity) were similar in the two groups between 6 weeks and 6 months.

In addition, a comprehensive paper was recently published by leaders in the field regarding the benefits of screening for cCMV (4). Using conservative assumptions (and without the more recent, stronger valganciclovir treatment data described above), the authors estimated that universal screening would provide clinical benefit to several thousands of children each year in the US. They stated that this is similar to or higher than, the number of children who benefit from diseases included in current universal newborn screening programs. Interestingly, these benefits would come largely from earlier identification of hearing loss (as opposed to antiviral treatment), since over half of children with hearing loss from cCMV will not be identified by newborn hearing screening.

What I do now

I now encourage more active case finding for cCMV. For example, I support sending a saliva swab for CMV PCR testing on newborns that have an isolated finding consistent with cCMV, such as a failed hearing screen or intrauterine growth retardation. Testing should be done as soon as possible after birth by saliva or urine PCR, which are performed at BC Children’s. If the test is positive, prompt evaluation by a pediatrician is needed to confirm the PCR result, and to determine the presence and severity of symptoms. Confirmatory testing should be done using a bagged (non-sterile) urine CMV PCR for breast-fed infants since CMV can be detected in breast milk and might result in false-positive saliva PCR tests. Infected newborns who fail the hearing screen should have an expedited diagnostic auditory brainstem response (ABR), to confirm or rule-out hearing loss; it is important to recognize that most infants who fail the 2-stage newborn hearing screen will have normal hearing by diagnostic ABR testing. Any child with cCMV, with or without symptoms, should have close audiologic follow-up until they reach school-age to monitor for late-onset or progressive hearing loss.

In addition, I now routinely treat severely affected newborns with cCMV orally using 6 months of valganciclovir, which I also offer for newborns with milder disease (e.g., isolated hearing loss). It should be noted that the newborns included in treatment trials so far all had relatively severe cCMV infection, and experts differ with respect to which infants they would treat (5-7). Treatment is NOT currently recommended for completely asymptomatic newborns or for symptoms that present beyond the newborn period, due to the lack of data for these indications. Because of these complexities, I recommend that any treatment of cCMV infection be discussed with a pediatric infectious diseases specialist.

Although the experience of treating newborns with valganciclovir has been promising so far, longer-term follow up is needed to see the durability of benefit. Safety has been reassuring, but laboratory monitoring for bone marrow, liver and kidney toxicity is still required while on therapy. Dose adjustment or GCSF is occasionally required for myelosuppression. There were also theoretical concerns for carcinogenicity and gonadotoxicity with (val)ganciclovir noted in animal studies that have not been seen in humans, but which temper enthusiasm for “prescription creep” or treatment for indications beyond what has been studied.

In the absence of an effective CMV vaccine, I now think that universal newborn cCMV screening would provide enormous benefits to families. However, cost-effectiveness and acceptability of a provincial program still need to be confirmed (8), especially since dried-blood spots do not appear to perform well and infrastructure would be needed to collect a different newborn sample type (likely saliva). Until then, I advocate for testing all newborns that fail the newborn hearing screen or have other symptoms consistent with cCMV infection. A program has been developed at BC Children’s and Women’s Hospital to test for and manage cCMV infection in such newborns (9).

References

1. Vaudry W, Lee BE, Rosychuk RJ. Congenital cytomegalovirus infection in Canada: Active surveillance for cases diagnosed by paediatricians. Paediatrics & child health. 2014;19(1):e1-5. View
2. Sorichetti B, Goshen O, Pauwels J, Kozak FK, Tilley P, Krajden M, et al. Symptomatic Congenital Cytomegalovirus Infection Is Underdiagnosed in British Columbia. J Pediatr. 2016;169:316-7. (View with CPSBC or UBC)  DOI: 10.1016/j.jpeds.2015.10.069
3. Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933-43. View
4. Cannon MJ, Griffiths PD, Aston V, Rawlinson WD. Universal newborn screening for congenital CMV infection: what is the evidence of potential benefit? Rev Med Virol. 2014;24(5):291-307. View
5. Gwee A, Curtis N, Garland SM, Connell TG, Daley AJ. Question 2: which infants with congenital cytomegalovirus infection benefit from antiviral therapy? Archives of disease in childhood. 2014;99(6):597-601. (View with CPSBC or UBC) DOI: 10.1136/archdischild-2014-306082
6. Harrison GJ. Current Controversies in Diagnosis, Management, and Prevention of Congenital Cytomegalovirus: Updates for the Pediatric Practitioner. Pediatr Ann. 2015;44(5):E115-E25.
   (Request with CPSBC or view with UBC)  DOI: 10.3928/00904481-20150512-11
7. Kimberlin DW, Aban I, Acosta EP. Valganciclovir for Congenital Cytomegalovirus. N Engl J Med. 2015;372(25):2463.View
8. Gantt S, Dionne F, Kozak FK, Goshen O, Goldfarb DM, Park AH, Boppana SB, Fowler K. Cost-effectiveness of universal and targeted newborn screening for congenital cytomegalovirus infection. JAMA Pediatrics. (in press)
9. Congenital CMV: Diagnosis and Management Guideline. 2016. View

Resources

BC Children’s Hospital: http://bccwhcms.medworxx.com/Site_Published/bcc/SiteSearchResults.aspx?searchKeyword=cmv
BC Early Hearing Program: http://www.phsa.ca/our-services/programs-services/bc-early-hearing-program/hearing-testing

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