Treatment, when indicated, should consist of oral valganciclovir suspension. The suggested dose is 16 mg/kg orally twice daily. In infants unable to tolerate oral therapy, intravenous therapy with ganciclovir can be considered. Treatment should be commenced in the first month of life. The finding of CMV by PCR or culture in urine, saliva, or blood in an infant aged older than 21 days cannot be presumed to be diagnostic of cCMV infection because breastfed babies, as noted above, may acquire infection postnatally.15 This confounds the interpretation of diagnostic studies in infants who have clinical features of congenital infection.
The author’s laboratory (www.cmvscreening.org/) will perform CMV DNA PCR on saved, archived newborn dried blood spots if available (routinely obtained in the course of normal newborn care and retained in most states), with permission of the infant’s family and the respective state health department. Clinicians interested in this service can contact the lab for further discussion. In some cases, the test helps resolve the question of whether an infant was born with cCMV infection.18,19
Active clinical studies are also examining whether delayed initiation of antiviral therapy (ie, beyond age 1 month) is beneficial. These studies, in particular, are being pursued in infants with previously unexplained SNHL that is recognized later in infancy or early childhood to be attributed to cCMV. Again, consultation with a pediatric infectious disease specialist is recommended in this circumstance.
Evidence of benefit conferred by therapy with oral valganciclovir was demonstrated in a randomized, placebo-controlled trial that showed a statistically significant benefit of treatment in symptomatic neonates.20 All symptomatic cytomegalovirus-infected neonates received valganciclovir for 6 weeks and were then randomized to receive either placebo or additional valganciclovir treatment to complete a 6-month course. Neonates receiving 6 months of valganciclovir had an increased likelihood of improved hearing at 24 months versus those who received only 6 weeks of valganciclovir treatment (followed by placebo). Importantly, neurodevelopmental outcomes also were improved with therapy.20 Based on these data, antiviral therapy with valganciclovir should be considered in all infants with symptomatic cCMV infection.
Laboratory monitoring is essential in infants treated with valganciclovir. Treatment is associated with neutropenia, and absolute neutrophil counts should be followed weekly for 6 to 8 weeks, then monthly for the duration of therapy. Transaminases should be followed monthly throughout therapy. For infants with drug-induced neutropenia, although there are no consensus management guidelines on this issue, therapy with G-CSF can be offered as needed. This allows many infants to complete a full 6-month course of treatment.
Many parents and clinicians become invested in their commitment to finish a 6-month course of therapy, and G-CSF can safely enable this. The author also recommends that audiologic testing be done at 3-month intervals for the first 3 years of life in all cases of cCMV, irrespective of whether symptoms are present at birth or whether the infant is treated with valganciclovir, and, at a minimum, annually thereafter through adolescence (ages 10 to 19 years).
Serial developmental assessments, beginning at the first year of life, are helpful in some children with symptomatic cCMV disease, as is additional neuroimaging. Because some infants with cCMV with evolving SNHL are or become candidates for cochlear implantation, brain magnetic resonance imaging (MRI) can be considered at the same time that temporal bone MRI is performed prior to implant placement.
Treatment and monitoring of cCMV involves much more than just antiviral therapy and monitoring for drug toxicity. It requires a coordinated, team-based approach including, in many instances, specialists in ophthalmology, audiology, otolaryngology, neurology, developmental pediatrics, occupational and physical therapy, orthopedic surgeons, physiatrists, and pediatric infectious disease specialists. The pediatrician can play a central role in coordinating and managing the multidisciplinary evaluations required by many of these infants.
Finally, the infant with cCMV can and should receive routine childhood immunizations, including infants on antiviral therapy, given that there is no evidence such infants have overarching immune deficiencies or problems handling live-virus vaccines.
Why newborn CMV screening?
Infants with asymptomatic cCMV are at risk for long-term sequelae, in particular SNHL. Thus, there has been considerable interest in universal newborn CMV screening, and, in particular, the question of whether cCMV should be added to the Recommended Uniform Screening Panel (RUSP; www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html), which is recommended for all newborns.
Two major issues have so far precluded adding cCMV to the RUSP panel. First, it is not yet clear what constitutes the optimal specimen for newborn screening for CMV infection. Performing PCR for CMV DNA on the dried newborn blood spot would, in principle, represent an ideal strategy given that it is obtained routinely in the nursery. Therefore, using the blood spot for this purpose would obviate the need for procuring additional samples for CMV testing. However, a multicenter cCMV screening study of blood spot PCR demonstrated suboptimal sensitivity.21 Alternative approaches could include PCR testing of saliva or urine samples, but the cost associated with obtaining such samples in all newborns may be prohibitive.
Second, in contrast to most newborn screening tests (which are typically performed to identify uniformly serious and even life-threatening conditions), cCMV screening will identify many infants who are destined to have a normal clinical outcome. On the other hand, advocates for universal cCMV screening point out that even asymptomatic congenitally infected infants are at risk for development of SNHL, even if they pass the newborn hearing screen, and that identification of such infants is not only capable of improving their clinical outcomes but is also cost-effective.22,23 Further study is required to resolve this issue.
A compromise that has emerged in some states is “targeted screening,” that is, testing for cCMV in all infants who fail the newborn hearing screen. Such programs will miss the majority of cases of cCMV but will facilitate timely diagnosis and early intervention for many infants who could benefit from intervention.24 An exciting development has been the engagement of state legislative bodies across the United States addressing the issue of targeted screening. Several bills have been passed in recent years that variably mandate targeted screening and/or require state health departments to provide educational resources, aimed in particular at healthcare providers and young women of childbearing age, about the problem of cCMV infection (Figure).
For example, a CMV knowledge and awareness bill, the Vivian Act, is currently under consideration by the state of Minnesota House of Representatives (www.house.leg.state.mn.us/members/pressrelease.asp?pressid=28204&party=2&memid=15434). It is hoped that these measures can address the substantial and disconcerting knowledge deficit that exists, both among the lay public and among physicians, regarding the risks of acquiring CMV infections during pregnancy.9,25 In fact, such legislation could have a significant impact on future cCMV infections given that education about simple hygienic precautions women can take to avoid infection has been shown in other studies to be effective in preventing acquisition of CMV during pregnancy.26
The future: CMV vaccines
Ultimately, prevention of cCMV will most likely require the development and implementation of an effective vaccine. Several CMV vaccine platforms have been developed and assessed in preclinical models, and in phase 1 and phase 2 human studies.27 The best-studied candidate to date, a purified and adjuvanted recombinant vaccine against the immunodominant glycoprotein B present in the CMV viral envelope, has demonstrated efficacy ranging from 43% to 50% in preventing primary CMV infection in young women.28,29
Many questions remain about how a CMV vaccine would be used in clinical practice. Should a CMV vaccine be given universally to young children toward the goal of universal coverage (“herd” immunity), using a paradigm that was successful for vaccine-mediated protection against congenital rubella syndrome? Or, should a vaccine selectively target young women (and young men) of children-bearing age to enhance protection during the childbearing years? Should serologic screening be performed before the administration of vaccine to young women, knowing that the greatest risk for disability in infants occurs in the context of primary maternal infection during pregnancy? Or, should all women be vaccinated prior to pregnancy, irrespective of CMV serology results, given that it is becoming clear that CMV “immune” women can become reinfected with new strains during pregnancy that can result in congenital transmission? Although reinfection probably results in fewer sequelae than does primary maternal infection during pregnancy,30 a strong case can be made for universal immunization of women of childbearing age, since “boosting” natural immunity may prove useful in preventing reinfections.
Regardless of how these questions play out, these are exciting times with encouraging prospects ahead for solving the problem of cCMV. The combination effects of increased awareness, evolution of newborn screening programs, and development and deployment of an effective vaccine should synergize on the near horizon to give clinicians the solutions for this common, underrecognized, and disabling infection in newborns.
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