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 jamapediatrics.com 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 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 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 rejamapediatrics.com
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 (dkimberlin@peds.uab.edu). Published Online: December 7, 2015. doi:10.1001/jamapediatrics.2015.3841. Conflict of Interest Disclosures: None reported. REFERENCES 1. Morton CC, Nance WE. Newborn hearing screening: a silent revolution. N Engl J Med. 2006; 354(20):2151-2164. 2. Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF. Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. J Am Acad Audiol. 2000;11(5): 283-290. 3. Boppana SB, Fowler KB, Vaid Y, et al. Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection. Pediatrics. 1997;99(3):409-414. 4. Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA. Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. Pediatr Infect Dis J. 1992;11(2):93-99. 5. Stronati M, Lombardi G, Di Comite A, Fanos V. Breastfeeding and cytomegalovirus infections. J Chemother. 2007;19(suppl 2):49-51. 6. Vochem M, Hamprecht K, Jahn G, Speer CP. Transmission of cytomegalovirus to preterm infants through breast milk. Pediatr Infect Dis J. 1998;17(1): 53-58. 7. Maschmann J, Hamprecht K, Dietz K, Jahn G, Speer CP. Cytomegalovirus infection of extremely low-birth weight infants via breast milk. Clin Infect Dis. 2001;33(12):1998-2003.
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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 /jamapediatrics.2015.3785.
9. Hsu ML, Cheng SN, Huang CF, et al. Perinatal
cytomegalovirus infection complicated with pneumonitis and adrenalitis in a premature infant. J Microbiol Immunol Infect. 2001;34(4):297-300.
Tiller RE, Alford CA. Protracted pneumonitis in young infants associated with perinatally acquired cytomegaloviral infection. J Pediatr. 1976;89(1): 16-22.
10. Neuberger P, Hamprecht K, Vochem M, et al.
Case-control study of symptoms and neonatal outcome of human milk-transmitted cytomegalovirus infection in premature infants. J Pediatr. 2006;148(3):326-331. 11. Mussi-Pinhata MM, Yamamoto AY, do Carmo Rego MA, Pinto PC, da Motta MS, Calixto C. Perinatal or early-postnatal cytomegalovirus infection in preterm infants under 34 weeks gestation born to CMV-seropositive mothers within a high-seroprevalence population. J Pediatr. 2004; 145(5):685-688. 12. Yasuda A, Kimura H, Hayakawa M, et al. Evaluation of cytomegalovirus infections transmitted via breast milk in preterm infants with a real-time polymerase chain reaction assay. Pediatrics. 2003;111(6, pt 1):1333-1336. 13. Vollmer B, Seibold-Weiger K, Schmitz-Salue C, et al. Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants. Pediatr Infect Dis J. 2004;23(4):322-327. 14. Hamprecht K, Maschmann J, Jahn G, Poets CF, Goelz R. Cytomegalovirus transmission to preterm infants during lactation. J Clin Virol. 2008;41(3): 198-205. 15. Capretti MG, Lanari M, Lazzarotto T, et al. Very low birth weight infants born to cytomegalovirusseropositive mothers fed with their mothers milk: a prospective study. J Pediatr. 2009;154(6):842-848. 16. Dworsky M, Yow M, Stagno S, Pass RF, Alford C. Cytomegalovirus infection of breast milk and transmission in infancy. Pediatrics. 1983;72(3): 295-299.
19. Sawyer MH, Edwards DK, Spector SA.
Cytomegalovirus infection and bronchopulmonary dysplasia in premature infants. Am J Dis Child. 1987; 141(3):303-305. 20. Nijman J, de Vries LS, Koopman-Esseboom C, Uiterwaal CS, van Loon AM, Verboon-Maciolek MA. Postnatally acquired cytomegalovirus infection in preterm infants: a prospective study on risk factors and cranial ultrasound findings. Arch Dis Child Fetal Neonatal Ed. 2012;97(4):F259-F263. 21. Prsch S, Lienicke U, Priemer C, et al. Human adenovirus and human cytomegalovirus infections in preterm newborns: no association with bronchopulmonary dysplasia. Pediatr Res. 2002;52 (2):219-224. 22. American Academy of Pediatrics. Cytomegalovirus infection. In: Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:317-322. 23. Kimberlin DW, Lin CY, Snchez PJ, et al; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16-25. 24. Kimberlin DW, Jester PM, Snchez PJ, et al; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933-943.
17. Kelly MS, Benjamin DK, Puopolo KM, et al.
Postnatal cytomegalovirus infection and the risk for
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