Sequelae Following Postnatally Acquired Cytomegalovirus Infection in Very Low-Birth-Weight Neonates: Back to the Future.

I amwriting thisEditorialonOctober 21, 2015. This is thedate when, in thesecond installmentof thehugely successful “Back to the Future” film trilogy, the time-traveling DeLorean arrives forMichael J. FoxandChristopherLloyd tocontinue their onscreenadventures.Likethe years 1984and2001, thisdate reminds me of how what is envisioned as futuristic in some prior era rarely lives up to the billing. Our everyday realities just aren’t as exciting as what brilliant writers (Orwell), directors (Kubrick), or Hollywoodstudios (Universal) imaginedsomanyyears ago.Likeanniversaries 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 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 significant damage to thedeveloping fetuswhenapregnantwoman acquires a strain of the virus towhich they are not previously immune.Congenitally acquiredCMVaccounts for one-fifth of all deafness at birth and, becauseCMV-associatedhearing 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, outcomesofpostnatally acquiredCMVinfectionsare less well characterized. It generally is agreed that postnatal acquisition of CMV in term infants does not lead to symptoms or disease.5 Inpreterm infants, initial case reports suggested that perinatallyandpostnatallyacquiredCMVinfectionscouldproduce severedisease.6-9 Larger series andcase-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 thrombocytopenia.6,14-16 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 lungdisease of prematurity,18,19more recent prospective studies failed to find such a correlation.10,20,21 To this discrepancyKelly et al applied their substantial expertise and resources. Using the vast database from the Pediatrix Medical Group, theywere able to assessmore than 100 000 very lowbirth-weight neonates from 70 neonatal intensive care units over 15 years to identify more than 300 who were diagnosed eithervirologicallyor clinicallywithpostnatallyacquiredCMV. 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 (adjustedodds 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 fromprolonged intubation related 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 its strengths, theKellyetalarticle17hasweaknesses. 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, 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 CMVacross the groups.Given these issues, findingCMVmore 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 work—namely, to use a well-performed retrospective study to develop a hypothesis that can be tested prospectively. At the current time, we do not knowwhether postnatally acquired CMV causes chronic lung disease of prematurity in very low-birth-weightneonates, although theKelly et al study likelywill spur additional investigations that onedaymaydefinitively 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 thebasis of this study. Likewise, anRelated article at jamapediatrics.com Opinion