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Sequelae Following Postnatally Acquired Cytomegalovirus

Infection in Very Low-Birth-Weight Neonates
Back to the Future
David W. Kimberlin, MD

I am writing this Editorial on October 21, 2015. This is the date

when, in the second installment of the hugely successful Back
to the Future film trilogy, the time-traveling DeLorean arrives for Michael J. Fox and Christopher Lloyd to continue their
onscreen adventures. Like the
years 1984 and 2001, this date
Related article at
reminds me of how what is
envisioned as futuristic in
some prior era rarely lives up
to the billing. Our everyday realities just arent as exciting as
what brilliant writers (Orwell), directors (Kubrick), or Hollywood studios (Universal) imagined so many years ago. Like anniversaries or millennial thresholds, though, moments like
these do serve the useful purpose of allowing one to take inventory of how far our knowledge and skills have comeor
more commonly how far we have yet to go. Thus is the story
of cytomegalovirus, or CMV.
Ubiquitous in the environment, CMV can cause significant damage to the developing fetus when a pregnant woman
acquires a strain of the virus to which they are not previously
immune. Congenitally acquired CMV accounts for one-fifth of
all deafness at birth and, because CMV-associated hearing loss
can be delayed in onset, one-quarter of all deafness at 4 years
of age,1,2 along with acute end-organ (eg, hepatitis, cytopenias) and long-term neurologic adverse outcomes.3,4 In contrast, outcomes of postnatally acquired CMV infections are less
well characterized. It generally is agreed that postnatal acquisition of CMV in term infants does not lead to symptoms or
disease.5 In preterm infants, initial case reports suggested that
perinatally and postnatally acquired CMV infections could produce severe disease.6-9 Larger series and case-controlled trials
more recently suggest that symptomatic disease in preterm
babies is less common than asymptomatic infection, and that
long-term sequelae are rare.10-13 That said, acute severe disseminated CMV disease can occur in premature infants,
including life-threatening pneumonitis, hepatitis, and
The report by Kelly et al17 in this issue of JAMA Pediatrics
expands our considerations of possible harm that may be
caused by postnatally acquired CMV in extremely premature
neonates. While initial studies from 30 and 40 years ago suggested that CMV could contribute to the development of
chronic lung disease of prematurity,18,19 more recent prospective studies failed to find such a correlation.10,20,21 To this discrepancy Kelly et al applied their substantial expertise and

sources. Using the vast database from the Pediatrix Medical

Group, they were able to assess more than 100 000 very lowbirth-weight neonates from 70 neonatal intensive care units
over 15 years to identify more than 300 who were diagnosed
either virologically or clinically with postnatally acquired CMV.
Using a sophisticated and well-designed propensitymatched cohort design, they found that very low-birthweight neonates postnatally infected with CMV were more
likely to develop chronic lung disease of prematurity (adjusted odds ratio, 1.33; 95% CI, 1.19-1.50). This certainly is biologically plausible, through direct viral damage to the lungs,
a direct immune-mediated response to the lung infection, or
an indirect effect of barotrauma from prolonged intubation related to the acute viral lung infectionor some combination
of these events. Back to the future indeed.
This is not to say that the final story has been written in
this matter. For all its strengths, the Kelly et al article17 has weaknesses. In the CMV cohort, fully one-third did not have virologic confirmation of CMV infection, relying instead on physician diagnosis to classify the illness as caused by the virus.
The neonatologists who compose the Pediatrix organization
are excellent clinicians, but not definitively ruling in the infection for which the outcome is being attributed is problematic for this study. Conversely, in the control group, CMV was
not ruled out virologically in all selected subjects. It is quite
possible that some proportion of the controls had postnatally
acquired CMV as well, equalizing the potential influence of
CMV across the groups. Given these issues, finding CMV more
frequently in the case cohort may simply have been because
that is the group in which it was sought, rather than it being
causative for the outcome observed (chronic lung disease of
prematurity). Such are the intrinsic limitations of the retrospective observational design, though, and they do not significantly diminish the value of this worknamely, to use a
well-performed retrospective study to develop a hypothesis
that can be tested prospectively.
At the current time, we do not know whether postnatally
acquired CMV causes chronic lung disease of prematurity in
very low-birth-weight neonates, although the Kelly et al study
likely will spur additional investigations that one day may definitively answer this question. In contrast, we do know that
breast milk has tremendous nutritional value for infants, including those who are born prematurely. As such, properly
treated breast milk22 should not be withheld from very lowbirth-weight neonates on the basis of this study. Likewise, an(Reprinted) JAMA Pediatrics Published online December 7, 2015

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Opinion Editorial

tiviral medications should not be used in premature infants

with postnatally acquired CMV for the purpose of decreasing
the likelihood that chronic lung disease of prematurity will develop. Both ganciclovir and valganciclovir have significant toxicities in babies,23,24 and cause cancer in some animal modARTICLE INFORMATION
Author Affiliation: Division of Pediatric Infectious
Diseases, The University of Alabama at
Birmingham, Birmingham.
Corresponding Author: David W. Kimberlin, MD,
Division of Pediatric Infectious Diseases, The
University of Alabama at Birmingham, 1600
Seventh Ave S, CHB 303, Birmingham, AL 35233
Published Online: December 7, 2015.
Conflict of Interest Disclosures: None reported.
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screening: a silent revolution. N Engl J Med. 2006;
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and long-term outcome in children with
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els. Pending more data from studies yet to be performed, the

appropriate clinical response to this article is to dont just do
something, stand there while awaiting more data from the
studies that are sure to be done as a result of this significant
contribution from Kelly et al.

8. Takahashi R, Tagawa M, Sanjo M, et al. Severe

postnatal cytomegalovirus infection in a very
premature infant. Neonatology. 2007;92(4):236-239.

bronchopulmonary dysplasia [published online

December 7, 2015]. JAMA Pediatr. doi:10.1001

9. Hsu ML, Cheng SN, Huang CF, et al. Perinatal

cytomegalovirus infection complicated with
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Tiller RE, Alford CA. Protracted pneumonitis in
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Case-control study of symptoms and neonatal
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cytomegalovirus infection in premature infants.
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low birth weight infants born to cytomegalovirusseropositive mothers fed with their mothers milk:
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17. Kelly MS, Benjamin DK, Puopolo KM, et al.

Postnatal cytomegalovirus infection and the risk for

JAMA Pediatrics Published online December 7, 2015 (Reprinted)

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