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Sequelae FollowingPostnatally Acquired Cytomegalovirus
Infection in Very Low-Birth-Weight NeonatesBack to the
FutureDavidW. Kimberlin,MD
I amwritingthis EditorialonOctober, .This isthe date
when,in thesecond installment of thehugely successful “Back
to the Future” film trilogy, the time-traveling DeLorean ar-
rives forMichael J.Fox andChristopherLloydto continue their
onscreenadventures.Likethe
years and , thisdate
reminds me of how what is
envisioned as futuristic in
some prior erararely lives up
to the billing. Our everyday realities just aren’t as exciting
as
what brilliant writers (Orwell), directors (Kubrick), or
Holly-
woodstudios(Universal)imagined somany years ago. Like an-
niversaries or millennial thresholds, though, moments like
these do serve the useful purpose of allowing one to take
in-
ventory of how far our knowledge and skills have come—or
more commonly how far we have yet to go. Thus is the story
of cytomegalovirus, or CMV.
Ubiquitous in the environment, CMV can cause signifi-
cantdamage to thedeveloping fetus whena pregnant woman
acquires a strainof thevirus to which they arenot previously
immune.Congenitally acquiredCMV accounts forone-fifth
of
all deafness at birth and,because CMV-associatedhearing
losscanbe delayed in onset,one-quarter of alldeafnessat years
of age,, along with acute end-organ (eg, hepatitis, cytope-
nias) and long-term neurologic adverse outcomes., In con-
trast, outcomes of postnatallyacquiredCMVinfectionsare less
well characterized.It generallyis agreed thatpostnatal
acqui-
sition of CMV in term infants does not lead to symptoms or
disease. In preterminfants, initialcase reportssuggestedthat
perinatallyand postnatally acquiredCMVinfectionscould pro-
duce severedisease.-Largerseries and case-controlled trials
more recently suggest that symptomatic disease in preterm
babies is less common than asymptomaticinfection, and
that
long-term sequelae are rare.- That said, acute severe dis-
seminated CMV disease can occur in premature infants,including
life-threatening pneumonitis, hepatitis, and
thrombocytopenia.,-
The reportby Kelly et al inthisissue 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 and years agosug-
gested that CMV could contribute to the development of
chronic lung disease of prematurity,, morerecentprospec-
tivestudiesfailed to find such a correlation.,, Tothisdis-
crepancy Kelly et al applied their substantialexpertise and
re-
sources. Using the vast database from the Pediatrix Medical
Group, they were able to assess more than very low-
birth-weight neonates from neonatal intensive care
units
over years to identify more than who were diagnosed
either virologicallyor clinically withpostnatally
acquiredCMV.
Using a sophisticated and well-designed propensity-
matched cohort design, they found that very low-birth-
weight neonates postnatally infected with CMV were more
likely to develop chronic lung disease of prematurity (ad-
justed odds ratio,.; % CI, .-.). This certainly is
bio-
logically plausible, through direct viral damage to the
lungs,
a direct immune-mediated response to the lung infection, or
an indirecteffectof barotraumafrom prolongedintubationre-
lated to the acute viral lung infection—or some combination
of these events. Back to the future indeed.
This is not to say that the final story has been written in
thismatter.Forall itsstrengths,the Kelly et al
articlehasweak-
nesses. In the CMV cohort, fully one-third did not have
viro-
logic confirmation of CMV infection, relying instead on phy-
sician 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
in-fection forwhichthe outcome is being attributed is problem-
atic for this study. Conversely, in the control group,
CMVwas
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
CMVacrossthe groups.Given these issues,findingCMV 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
retro-
spective observational design, though, and they do not sig-
nificantly diminish the value of this work—namely, to use a
well-performed retrospective study to develop a hypothesisthat
can be tested prospectively.
At thecurrent time, we do notknow whether postnatally
acquired CMV causes chronic lung disease of prematurity in
verylow-birth-weight neonates, althoughthe Kelly et al study
likely will spuradditional investigations that one daymay
de-
finitively answer this question. In contrast, we do know
that
breast milk has tremendous nutritional value for infants,
in-
cluding those who are born prematurely. As such, properly
treated breast milk should not be withheld from very low-
birth-weight neonateson the basis of this study. Likewise,
an-
Related article at
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tiviral medications should not be used in premature infants
with postnatally acquired CMV for the purpose of decreasing
thelikelihoodthatchronic lung diseaseof prematurity willde-
velop. Both ganciclovirand valganciclovir have
significanttox-
icities in babies,, and cause cancer in some animal mod-
els. Pending more data from studies yetto be performed, the
appropriate clinical response to this article is to “don’t 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.
ARTICLEINFORMATION
Author Affiliation: Division of Pediatric InfectiousDiseases,
TheUniversity of Alabamaat
Birmingham, Birmingham.
Corresponding Author: DavidW. Kimberlin, MD,
Division of Pediatric Infectious Diseases, The
Universityof Alabama at Birmingham,1600
Seventh Ave S,CHB 303,Birmingham,AL 35233
([email protected]).
Published Online: December 7, 2015.
doi:10.1001/jamapediatrics.2015.3841.
Conflict of Interest Disclosures: Nonereported.
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Opinion Editorial
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