- Email: [email protected]
Preventing Postnatal Cytomegalovirus Infection in the Preterm Infant: Should It Be Done, Can It Be Done, and at What Cost?
EDITORIALS
April 2015 8. Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Margaret A, Corey L. Plasma and cerebrospinal fluid herpes simplex virus at diagnosis and outcome of neonatal infection. J Pediatr 2015;166:829-33. 9. Kimura H, Futamura M, Kito H, Ando T, Goto M, Kuzushima K, et al. Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis 1991;164:289-93. 10. Barbi M, Binda S, Primache V, Tettamanti A, Negri C, Brambilla C. Use of Guthrie cards for the early diagnosis of neonatal herpes simplex virus disease. Pediatr Infect Dis J 1998;17:251-2. 11. Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J 1999;18: 487-9.
12. Malm G, Forsgren M. Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed 1999;81:F24-9. 13. Kimura H, Ito Y, Futamura M, Ando Y, Yabuta Y, Hoshino Y, et al. Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. J Med Virol 2002;67:349-53. 14. Lewensohn-Fuchs I, Osterwall P, Forsgren M, Malm G. Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. J Clin Virol 2003;26:39-48. 15. American Academy of Pediatrics. Herpes simplex. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 398-408.
Preventing Postnatal Cytomegalovirus Infection in the Preterm Infant: Should It Be Done, Can It Be Done, and at What Cost?
I
n 2012, 56 252 very low birth weight (VLBW, <1500 g) inmaternal CMV seroprevalence and an increasing CMV expofants were born in the US, accounting for 1.4% of all live sure risk through encouragement of maternal milk feeding births.1 These infants encounter numerous morbidities, has resulted in an inadequately informed practice that potenand 25%-30% experience long-term neurodevelopmental tially puts thousands of infants at risk for NDI secondary to a impairment (NDI).2 Consequently, there has been an intense potentially modifiable risk factor. and elusive search for modifiable risk facIn this issue of The Journal, Brecht et al10 See related articles, p 834 tors encountered in the neonatal intensive report the results of neuropsychiatric testing and p 870 care unit (NICU) that impact long-term in 3 groups of adolescents (11-16 years): neurodevelopment. Whether preventing or minimizing former preterm (VLBW or <32 weeks of gestation) infants exposure to these risk factors will prevent NDI, however, rewho acquired early postnatal CMV infection (n = 19), former mains unclear. For example, large, randomized controlled non–CMV-infected VLBW infants (n = 23), and former term trials demonstrate that efforts to minimize exposure to hyinfants (n = 24). The authors demonstrate a significant negaperbilirubinemia, hyperoxia, and hyperglycemia largely are tive effect of early postnatal CMV infection on overall cogniineffective in improving neurodevelopmental (ND) outtive abilities. These findings are especially worrisome, given comes.3-5 Thus, the search continues for preventive measures the lack of demonstrable impact of postnatal CMV infection on NDI when assessed earlier in childhood.11-14 Without that will improve the outcomes of VLBW infants. Cytomegalovirus (CMV) is the most common congenital these important data, we are at risk of making assumptions viral infection in high-resource countries, and infants with regarding the relative innocuous effect of postnatal CMV symptomatic infection are at high risk for NDI.6 Whether infection on preterm infants. The authors must be congratulated for providing us with this thoughtful and thorough postnatal CMV infection in the VLBW infant increases the long-term assessment after early CMV exposure. This study risk of NDI, however, is unclear.7 Although the use of is critically important and potentially identifies postnatal CMV-seronegative, leukoreduced blood products essentially CMV infection as a modifiable risk factor for NDI in preterm eliminates transfusion-associated infection, transmission to infants. Given that preterm infants may be at unique risk for VLBW infants occurs via maternal breast milk and can result NDI because of postnatal CMV infection, and that postnatal in an acute sepsis-like illness.8 In addition, 2 epidemiologic CMV exposure is increasing in the NICU setting after recogfacts indicate that we need to better understand the longnition of the considerable health benefits of breast milk term ND effect of postnatal CMV infection in the VLBW: feeding, we must ask the question: should more be done to (1) In the US, CMV seroprevalence in women of childbearing minimize the risk of postnatal CMV acquisition for hospitalage ranges from 30% to 90%, influenced by socioeconomic ized preterm infants? status and age6; and (2) the clinical use of maternal milk Before this question can be answered, the limitations of the for VLBW is increasing because of its established health bencurrent study must be acknowledged. The authors have efits for this infant population.9 The intersection of high appropriately identified that this is a small study. In addition, CMV ND NDI NICU VLBW
Cytomegalovirus Neurodevelopmental Neurodevelopmental impairment Neonatal intensive care unit Very low birth weight
S.P. serves on the scientific advisory board of Redbiotec. C.W. is a recipient of an Entelligence Young Investigator Award from Actelion Pharmaceuticals US. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.12.062
795
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www.jpeds.com
although known independent risk factors for NDI, such as bronchopulmonary dysplasia, retinopathy of prematurity, and intracerebral hemorrhage were reported, they were not controlled for in the analysis in which the authors compared neuropsychologic test results.15 Furthermore, other known independent risk factors for NDI, including receipt of caffeine or postnatal corticosteroids, duration of mechanical ventilation, sepsis, other congenital infections, necrotizing enterocolitis, and surgery, are not controlled for or reported here. Furthermore, an additional article in this issue of The Journal by Manley et al16 makes it clear that social variables have a unique and demonstrable impact on the cognitive development experienced by VLBW infants between the ages of 2 and 5 years. Because CMV serologic status correlates with lower socioeconomic status, it may be that social risk factors that predict poor cognitive gain after discharge from the NICU have a disproportionately high prevalence in VLBW infants who acquire postnatal CMV, confounding the results reported here. Additional questions remain unanswered regarding the relationship between postnatal CMV infection in the VLBW infant and long-term NDI. Does the infant’s gestational or chronologic age at time of postnatal infection matter? The infants in the cohort described in the current study were born between 23 and 32 weeks of gestation and were infected at 36-190 days.11 Can symptoms or severity of illness at time of infection predict NDI? Infants in this cohort had both symptomatic and asymptomatic infection.11 A more thorough and controlled assessment of these potential confounding factors in a larger population is needed to answer these questions. If we accept that postnatal acquisition of CMV results in NDI in VLBW infants, we have a unique opportunity to further improve their health and development by implementing safe and effective strategies to reduce the risk of CMV acquisition. Infants of mothers who are CMVseronegative should be at no risk of CMV acquisition, barring acute CMV infection of the mother during lactation. Therefore, serologic testing of lactating mothers of preterm infants represents one option to identify at-risk infants. Yet, the lack of well-defined maternal immunologic or virologic correlates that predict postnatal CMV transmission complicates identification of high-risk women-infant pairs. Although 90% of women who are CMV-seropositive shed virus in breast milk,17 only 20% of exposed infants will acquire postnatal CMV infection.7,8 Therefore, routine maternal serologic testing and testing mother’s milk for the presence of CMV are not efficient means of determining which infants are most at risk of infection. Although some studies have suggested that high virus load in milk predicts risk of transmission, the milk viral load is variable over time,18 decreasing the effectiveness of spot testing. Moreover, the maternal cellular and humoral response measured in breast milk does not correlate well with symptomatic CMV disease in preterm infants.19 Finally, the corrected gestational age at which the infant is still at risk of NDI from CMV acquisition is unknown, pre796
Vol. 166, No. 4 venting the establishment of an end point for testing to identify at-risk, hospitalized preterm infants. Therefore, although serologic and breast milk screening for CMV potentially could identify infants who stand to benefit from measures to reduce postnatal CMV acquisition, it is unclear whether this approach is time-efficient or cost-effective. Processing the milk of mothers who are CMV-seropositive of VLBW infants to reduce or eliminate infectious virions is a potential strategy to reduce CMV acquisition while maintaining the health benefits of breast milk for those infants not at risk. However, we must be careful not to seek gains in ND outcomes via reduction in CMV acquisition at the expense of decreasing the benefits of exposure to maternal breast milk. Strong evidence exists that exposure to fresh mother’s milk reduces the risk of morbidities associated with NDI, including necrotizing enterocolitis, late-onset sepsis, and retinopathy of prematurity.20 There also is evidence that supports a long-lasting benefit of breast milk exposure, including a lower risk of metabolic syndrome, less insulin and leptin resistance, and improved ND outcomes.20,21 Thus, avoiding CMV exposure for preterm infants by substituting maternal milk with formula is inappropriate. Routine freezing of mother’s milk before the administration to the infant reduces—but does not eliminate—the risk of postnatal CMV acquisition.22 In addition, the moderate reduction in CMV transmission may come at the expense of losing beneficial human milk components vulnerable to the freeze-thaw process.23 Pasteurization eliminates infectious CMV virions in milk and prevents CMV transmission but destroys many of the protective factors thought to be responsible for the health benefits provided by mother’s milk.23 Because currently we are without means to safely prevent postnatal CMV acquisition for VLBW infants without interrupting the benefits of breast milk feeding, the effectiveness of our therapies for CMV-infected infants must be considered. Long-term treatment with ganciclovir, or its oral derivative valganciclovir, has been shown to effectively improve both the hearing and developmental outcomes of full-term infants with congenital CMV infection.24 Yet, whether this would have the same effect for VLBW who acquire postnatal CMV infection is unknown. Thus, long-term anti-viral treatment of preterm infants who acquire postnatal infection to ameliorate the potential NDI associated with CMV acquisition deserves study. Ongoing pharmacokinetic and pharmacodynamic studies of ganciclovir in preterm infants by the National Institutes of Health Collaborative Antiviral Study Group will provide much needed information on dosing and side effects of CMV treatment in this infant population.25 In summary, providing maternal milk to the preterm infant may have antagonistic effects, ie, protecting against a number of severe morbidities while increasing the risk of postnatal CMV infection. Importantly, the potential identification of a modifiable risk factor in the ND outcome of preterm infants provides a call to action that should not be ignored. Yet, are we stuck between the proverbial “rock and a hard place” in improving ND outcomes for preterm
EDITORIALS
April 2015 infants through reducing the risk of CMV acquisition while maintaining the numerous health benefits of fresh mother’s milk? The benefits of maternal milk for the premature infants are proven,20,21 although the risks of postnatal CMV infection acquired via maternal breast milk in VLBW infants are becoming more evident. However, until it is established that postnatal CMV infection is an independent, modifiable risk factor for NDI, the proven benefits of maternal milk should not be sacrificed. The clinical challenge of safe breast milk feeding for all VLBW infants calls for the same pioneering spirit that has brought lifesaving interventions such as antenatal corticosteroids and surfactant to neonatology. Innovative strategies that will reduce the risk of CMV acquisition while maintaining the health benefits of fresh human milk exposure, such as passive immunization with CMVneutralizing monoclonal antibodies26 or the enteral administration of exogenous antiviral factors such as lactoferrin,27 are potential ideal strategies to prevent NDI in preterm infants. A better understanding of the effects of postnatal CMV infection on the preterm infant provides a unique opportunity to assess our practice and march towards outcomes for preterm infants that are indistinguishable from that of term infants. n Clyde J. Wright, MD Section of Neonatology Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado Sallie R. Permar, MD, PhD Department of Pediatrics and Human Vaccine Institute Duke University Medical Center Durham, North Carolina Reprint requests: Clyde J. Wright, MD, Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Mail Stop F441, Aurora, CO 80045. E-mail: [email protected]
References 1. National Center for Health Statistics. PeriStats. Final natality data [cited Nov. 23, 2014]. www.marchofdimes.org/peristats/faqsp.aspx. Accessed January 22, 2015. 2. Eichenwald EC, Stark AR. Management and outcomes of very low birth weight. N Engl J Med 2008;358:1700-11. 3. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, et al. Early insulin therapy in verylow-birth-weight infants. N Engl J Med 2008;359:1873-84. 4. Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O’Shea TM, et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 2008;359:1885-96. 5. Vaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA, Gantz MG, Walsh MC, et al. Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012;367:2495-504. 6. Swanson EC, Schleiss MR. Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin North Am 2013;60: 335-49. 7. Kurath S, Halwachs-Baumann G, Muller W, Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review. Clin Microbiol Infect 2010;16:1172-8.
8. Josephson CD, Caliendo AM, Easley KA, Knezevic A, Shenvi N, Hinkes MT, et al. Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study. JAMA Pediatr 2014;168:1054-62. 9. Perrine CG, Scanlon KS. Prevalence of use of human milk in US advanced care neonatal units. Pediatrics 2013;131:1066-71. 10. Brecht KF, Goelz R, Bevot A, Krageloh-Mann I, Wilke M, Lidzba K. Postnatal CMV infection in preterm infants has long term neuropsychological sequelae. J Pediatr 2015;166:834-91. 11. Vollmer B, Seibold-Weiger K, Schmitz-Salue C, Hamprecht K, Goelz R, Krageloh-Mann I, et al. Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants. Pediatr Infect Dis J 2004;23:322-7. 12. Bevot A, Hamprecht K, Krageloh-Mann I, Brosch S, Goelz R, Vollmer B. Long-term outcome in preterm children with human cytomegalovirus infection transmitted via breast milk. Acta Paediatr 2012;101:e167-72. 13. Jim WT, Shu CH, Chiu NC, Kao HA, Hung HY, Chang JH, et al. Transmission of cytomegalovirus from mothers to preterm infants by breast milk. Pediatr Infect Dis J 2004;23:848-51. 14. Miron D, Brosilow S, Felszer K, Reich D, Halle D, Wachtel D, et al. Incidence and clinical manifestations of breast milk-acquired Cytomegalovirus infection in low birth weight infants. J Perinatol 2005; 25:299-303. 15. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9. 16. Manley BJ, Roberts RS, Doyle LW, Schmidt B, Anderson PJ, Barrington KJ, et al., the Caffeine for Apnea of Prematurity (CAP) Trial Investigators. Social variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams. J Pediatr 2015;166:870-6. 17. Vochem M, Hamprecht K, Jahn G, Speer CP. Transmission of cytomegalovirus to preterm infants through breast milk. Pediatr Infect Dis J 1998;17:53-8. 18. Jim WT, Shu CH, Chiu NC, Chang JH, Hung HY, Peng CC, et al. High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants. Pediatr Infect Dis J 2009;28:891-4. 19. Ehlinger EP, Webster EM, Kang HH, Cangialose A, Simmons AC, Barbas KH, et al. Maternal cytomegalovirus-specific immune responses and symptomatic postnatal cytomegalovirus transmission in very lowbirth-weight preterm infants. J Infect Dis 2011;204:1672-82. 20. Menon G, Williams TC. Human milk for preterm infants: why, what, when and how? Arch Dis Child Fetal Neonatal Ed 2013;98:F559-62. 21. Underwood MA. Human milk for the premature infant. Pediatr Clin North Am 2013;60:189-207. 22. Maschmann J, Hamprecht K, Weissbrich B, Dietz K, Jahn G, Speer CP. Freeze-thawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant. Arch Dis Child Fetal Neonatal Ed 2006; 91:F288-90. 23. Lawrence RA. Storage of human milk and the influence of procedures on immunological components of human milk. Acta Paediatr Suppl 1999; 88:14-8. 24. Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003;143:16-25. 25. Evaluation of the PK and PD of Ganciclovir in Premature Infants Receiving Treatment for CMV Infection (Gan Premie) [updated December 4, 2014]. http://clinicaltrials.gov/ct2/show/NCT01602614? term=ganciclovir&rank=44. Accessed January 2, 2014. 26. Boeckh M, Bowden RA, Storer B, Chao NJ, Spielberger R, Tierney DK, et al. Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001;7:343-51. 797
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27. Beljaars L, van der Strate BW, Bakker HI, Reker-Smit C, van LoenenWeemaes AM, Wiegmans FC, et al. Inhibition of cytomegalovirus
Vol. 166, No. 4 infection by lactoferrin in vitro and in vivo. Antiviral Res 2004;63: 197-208.
Understanding Pediatric Chronic Pancreatitis: Inspiration and Hard Work Required
P
atient registries are effective in the investigation of disof itself, underscores the need for this type of multiease specific epidemiology, clinical characteristics, and institutional research. outcomes.1 They are especially powerful tools when The median age of patients in the reported cohort is applied to relatively uncommon conditions as data does 13.0 years (IQR 10.5, 17.0 years) with a male to female ratio not need to be limited to single investigators, institutions, of 1:1.3. The vast majority are Caucasian (80%) and nonor regions. Moreover, multi-institutional Hispanic (80%). The children were diagSee related article, p 890 registries effectively eliminate potential nosed with chronic pancreatitis at a median biases inherent to single center data. Examples of highly sucage of 9.9 years (IQR 6.1, 14.0 years) and the first episode of cessful patient registries involving diseases in children and acute pancreatitis occurred at 6.8 years (IQR 4.5, 12.1 years). adolescents include the Cystic Fibrosis Foundation Patient Thus, this is a disease of mid-to-late childhood. The age of Registry developed more than 40 years ago and the more presentation of the first episode of acute pancreatitis is less recently instituted inflammatory bowel disease registry of than what we reported in our evaluation of US national the ImproveCareNow Network.2,3 These registries are more data. We found the median age of hospitalized pediatric patients with acute pancreatitis was 17 years, and over 80% of than data repositories, as each is linked to quality improvepatients were older than 11 years.7 This age difference sugment efforts and serves as a platform for clinical research. The International Study Group of Pediatric Pancreatitis: In gests that those children presenting with acute pancreatitis Search for a Cure (INSPPIRE) consortium was created with at an early age require evaluation and close observation for an overall goal of developing therapies for recurrent acute the possible development of chronic disease. and chronic pancreatitis in children and adolescents, uncomAs discussed by the authors, previous single center studies mon conditions in pediatrics.4 Following a model similar to identified genetic abnormalities as the most common risk factor for chronic pancreatitis in children and adolescents. the Cystic Fibrosis Foundation and the ImproveCareNow In comparison, alcohol and tobacco use are the common Network, one of their first steps was to develop a patient risk factors in adults. Their current study confirms this earlier registry. observation in children and strengthens its relationship. Of In this issue of The Journal, Schwarzenberg et al describe the 76 patients with chronic pancreatitis, genetic testing the clinical characteristics of children with chronic pancreawas performed in 63. Two-thirds of patients have an identititis within the INSPPIRE consortium patient registry.5 fied mutation in genes previously demonstrated to be associUsing a cross-sectional cohort design, they report data ated with chronic pancreatitis. Genetic testing was negative in collected at baseline from 14 medical centers in four coun12 patients. The most common chronic pancreatitis predistries. This baseline data set was collected between September posing genetic mutations were in the cationic trypsinogen, 1, 2012 and August 31, 2013. Importantly, the subjects within PRSS1 gene (n = 33). Other identified genetic mutations the database met a uniform consensus definition of chronic were in the pancreatic secretory trypsin inhibitor SPINK1 pancreatitis; this definition was by necessity developed by gene (n = 14), cystic fibrosis transmembrane conductance the consortium as there were no established pediatric criteria regular, CFTR gene (n = 11), and chymotrypsin C, CTRC for the diagnosis of chronic pancreatitis.6 The diagnosis of gene (n = 2). Of note, not all patients were tested for mutachronic pancreatitis required the presence of imaging findtions in each of these genes. Specifically, 61 patients were ings suggestive of chronic pancreatic damage associated evaluated for PRSS1, 53 for SPINK1, 49 for CFTR, and 40 with abdominal pain consistent with a pancreatic origin, for CTRC. It is not reported which genes were evaluated in evidence of exocrine pancreatic insufficiency, or endocrine the 12 patients testing negative for mutations. Mutations in pancreatic insufficiency or pancreas histopathology features more than 1 gene were identified in 9 patients; a second compatible with chronic pancreatitis. The data in this initial chronic pancreatitis associated mutation was observed in 6 report is derived from 76 patients. Though one of the largest of the 11 patients with CFTR mutations. The combination studies to date describing the clinical characteristics of chilof mutations might increase the risk of chronic pancreatitis dren and adolescents with this disorder, it is relatively small in comparison with multicenter studies of other more common disorders (eg, inflammatory bowel disease). This, in and The authors declare no conflicts of interest.
ERCP
Endoscopic retrograde cholangiopancreatography
0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.12.052
798
April 2015 8. Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Margaret A, Corey L. Plasma and cerebrospinal fluid herpes simplex virus at diagnosis and outcome of neonatal infection. J Pediatr 2015;166:829-33. 9. Kimura H, Futamura M, Kito H, Ando T, Goto M, Kuzushima K, et al. Detection of viral DNA in neonatal herpes simplex virus infections: frequent and prolonged presence in serum and cerebrospinal fluid. J Infect Dis 1991;164:289-93. 10. Barbi M, Binda S, Primache V, Tettamanti A, Negri C, Brambilla C. Use of Guthrie cards for the early diagnosis of neonatal herpes simplex virus disease. Pediatr Infect Dis J 1998;17:251-2. 11. Diamond C, Mohan K, Hobson A, Frenkel L, Corey L. Viremia in neonatal herpes simplex virus infections. Pediatr Infect Dis J 1999;18: 487-9.
12. Malm G, Forsgren M. Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum. Arch Dis Child Fetal Neonatal Ed 1999;81:F24-9. 13. Kimura H, Ito Y, Futamura M, Ando Y, Yabuta Y, Hoshino Y, et al. Quantitation of viral load in neonatal herpes simplex virus infection and comparison between type 1 and type 2. J Med Virol 2002;67:349-53. 14. Lewensohn-Fuchs I, Osterwall P, Forsgren M, Malm G. Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible. J Clin Virol 2003;26:39-48. 15. American Academy of Pediatrics. Herpes simplex. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. p. 398-408.
Preventing Postnatal Cytomegalovirus Infection in the Preterm Infant: Should It Be Done, Can It Be Done, and at What Cost?
I
n 2012, 56 252 very low birth weight (VLBW, <1500 g) inmaternal CMV seroprevalence and an increasing CMV expofants were born in the US, accounting for 1.4% of all live sure risk through encouragement of maternal milk feeding births.1 These infants encounter numerous morbidities, has resulted in an inadequately informed practice that potenand 25%-30% experience long-term neurodevelopmental tially puts thousands of infants at risk for NDI secondary to a impairment (NDI).2 Consequently, there has been an intense potentially modifiable risk factor. and elusive search for modifiable risk facIn this issue of The Journal, Brecht et al10 See related articles, p 834 tors encountered in the neonatal intensive report the results of neuropsychiatric testing and p 870 care unit (NICU) that impact long-term in 3 groups of adolescents (11-16 years): neurodevelopment. Whether preventing or minimizing former preterm (VLBW or <32 weeks of gestation) infants exposure to these risk factors will prevent NDI, however, rewho acquired early postnatal CMV infection (n = 19), former mains unclear. For example, large, randomized controlled non–CMV-infected VLBW infants (n = 23), and former term trials demonstrate that efforts to minimize exposure to hyinfants (n = 24). The authors demonstrate a significant negaperbilirubinemia, hyperoxia, and hyperglycemia largely are tive effect of early postnatal CMV infection on overall cogniineffective in improving neurodevelopmental (ND) outtive abilities. These findings are especially worrisome, given comes.3-5 Thus, the search continues for preventive measures the lack of demonstrable impact of postnatal CMV infection on NDI when assessed earlier in childhood.11-14 Without that will improve the outcomes of VLBW infants. Cytomegalovirus (CMV) is the most common congenital these important data, we are at risk of making assumptions viral infection in high-resource countries, and infants with regarding the relative innocuous effect of postnatal CMV symptomatic infection are at high risk for NDI.6 Whether infection on preterm infants. The authors must be congratulated for providing us with this thoughtful and thorough postnatal CMV infection in the VLBW infant increases the long-term assessment after early CMV exposure. This study risk of NDI, however, is unclear.7 Although the use of is critically important and potentially identifies postnatal CMV-seronegative, leukoreduced blood products essentially CMV infection as a modifiable risk factor for NDI in preterm eliminates transfusion-associated infection, transmission to infants. Given that preterm infants may be at unique risk for VLBW infants occurs via maternal breast milk and can result NDI because of postnatal CMV infection, and that postnatal in an acute sepsis-like illness.8 In addition, 2 epidemiologic CMV exposure is increasing in the NICU setting after recogfacts indicate that we need to better understand the longnition of the considerable health benefits of breast milk term ND effect of postnatal CMV infection in the VLBW: feeding, we must ask the question: should more be done to (1) In the US, CMV seroprevalence in women of childbearing minimize the risk of postnatal CMV acquisition for hospitalage ranges from 30% to 90%, influenced by socioeconomic ized preterm infants? status and age6; and (2) the clinical use of maternal milk Before this question can be answered, the limitations of the for VLBW is increasing because of its established health bencurrent study must be acknowledged. The authors have efits for this infant population.9 The intersection of high appropriately identified that this is a small study. In addition, CMV ND NDI NICU VLBW
Cytomegalovirus Neurodevelopmental Neurodevelopmental impairment Neonatal intensive care unit Very low birth weight
S.P. serves on the scientific advisory board of Redbiotec. C.W. is a recipient of an Entelligence Young Investigator Award from Actelion Pharmaceuticals US. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.12.062
795
THE JOURNAL OF PEDIATRICS
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although known independent risk factors for NDI, such as bronchopulmonary dysplasia, retinopathy of prematurity, and intracerebral hemorrhage were reported, they were not controlled for in the analysis in which the authors compared neuropsychologic test results.15 Furthermore, other known independent risk factors for NDI, including receipt of caffeine or postnatal corticosteroids, duration of mechanical ventilation, sepsis, other congenital infections, necrotizing enterocolitis, and surgery, are not controlled for or reported here. Furthermore, an additional article in this issue of The Journal by Manley et al16 makes it clear that social variables have a unique and demonstrable impact on the cognitive development experienced by VLBW infants between the ages of 2 and 5 years. Because CMV serologic status correlates with lower socioeconomic status, it may be that social risk factors that predict poor cognitive gain after discharge from the NICU have a disproportionately high prevalence in VLBW infants who acquire postnatal CMV, confounding the results reported here. Additional questions remain unanswered regarding the relationship between postnatal CMV infection in the VLBW infant and long-term NDI. Does the infant’s gestational or chronologic age at time of postnatal infection matter? The infants in the cohort described in the current study were born between 23 and 32 weeks of gestation and were infected at 36-190 days.11 Can symptoms or severity of illness at time of infection predict NDI? Infants in this cohort had both symptomatic and asymptomatic infection.11 A more thorough and controlled assessment of these potential confounding factors in a larger population is needed to answer these questions. If we accept that postnatal acquisition of CMV results in NDI in VLBW infants, we have a unique opportunity to further improve their health and development by implementing safe and effective strategies to reduce the risk of CMV acquisition. Infants of mothers who are CMVseronegative should be at no risk of CMV acquisition, barring acute CMV infection of the mother during lactation. Therefore, serologic testing of lactating mothers of preterm infants represents one option to identify at-risk infants. Yet, the lack of well-defined maternal immunologic or virologic correlates that predict postnatal CMV transmission complicates identification of high-risk women-infant pairs. Although 90% of women who are CMV-seropositive shed virus in breast milk,17 only 20% of exposed infants will acquire postnatal CMV infection.7,8 Therefore, routine maternal serologic testing and testing mother’s milk for the presence of CMV are not efficient means of determining which infants are most at risk of infection. Although some studies have suggested that high virus load in milk predicts risk of transmission, the milk viral load is variable over time,18 decreasing the effectiveness of spot testing. Moreover, the maternal cellular and humoral response measured in breast milk does not correlate well with symptomatic CMV disease in preterm infants.19 Finally, the corrected gestational age at which the infant is still at risk of NDI from CMV acquisition is unknown, pre796
Vol. 166, No. 4 venting the establishment of an end point for testing to identify at-risk, hospitalized preterm infants. Therefore, although serologic and breast milk screening for CMV potentially could identify infants who stand to benefit from measures to reduce postnatal CMV acquisition, it is unclear whether this approach is time-efficient or cost-effective. Processing the milk of mothers who are CMV-seropositive of VLBW infants to reduce or eliminate infectious virions is a potential strategy to reduce CMV acquisition while maintaining the health benefits of breast milk for those infants not at risk. However, we must be careful not to seek gains in ND outcomes via reduction in CMV acquisition at the expense of decreasing the benefits of exposure to maternal breast milk. Strong evidence exists that exposure to fresh mother’s milk reduces the risk of morbidities associated with NDI, including necrotizing enterocolitis, late-onset sepsis, and retinopathy of prematurity.20 There also is evidence that supports a long-lasting benefit of breast milk exposure, including a lower risk of metabolic syndrome, less insulin and leptin resistance, and improved ND outcomes.20,21 Thus, avoiding CMV exposure for preterm infants by substituting maternal milk with formula is inappropriate. Routine freezing of mother’s milk before the administration to the infant reduces—but does not eliminate—the risk of postnatal CMV acquisition.22 In addition, the moderate reduction in CMV transmission may come at the expense of losing beneficial human milk components vulnerable to the freeze-thaw process.23 Pasteurization eliminates infectious CMV virions in milk and prevents CMV transmission but destroys many of the protective factors thought to be responsible for the health benefits provided by mother’s milk.23 Because currently we are without means to safely prevent postnatal CMV acquisition for VLBW infants without interrupting the benefits of breast milk feeding, the effectiveness of our therapies for CMV-infected infants must be considered. Long-term treatment with ganciclovir, or its oral derivative valganciclovir, has been shown to effectively improve both the hearing and developmental outcomes of full-term infants with congenital CMV infection.24 Yet, whether this would have the same effect for VLBW who acquire postnatal CMV infection is unknown. Thus, long-term anti-viral treatment of preterm infants who acquire postnatal infection to ameliorate the potential NDI associated with CMV acquisition deserves study. Ongoing pharmacokinetic and pharmacodynamic studies of ganciclovir in preterm infants by the National Institutes of Health Collaborative Antiviral Study Group will provide much needed information on dosing and side effects of CMV treatment in this infant population.25 In summary, providing maternal milk to the preterm infant may have antagonistic effects, ie, protecting against a number of severe morbidities while increasing the risk of postnatal CMV infection. Importantly, the potential identification of a modifiable risk factor in the ND outcome of preterm infants provides a call to action that should not be ignored. Yet, are we stuck between the proverbial “rock and a hard place” in improving ND outcomes for preterm
EDITORIALS
April 2015 infants through reducing the risk of CMV acquisition while maintaining the numerous health benefits of fresh mother’s milk? The benefits of maternal milk for the premature infants are proven,20,21 although the risks of postnatal CMV infection acquired via maternal breast milk in VLBW infants are becoming more evident. However, until it is established that postnatal CMV infection is an independent, modifiable risk factor for NDI, the proven benefits of maternal milk should not be sacrificed. The clinical challenge of safe breast milk feeding for all VLBW infants calls for the same pioneering spirit that has brought lifesaving interventions such as antenatal corticosteroids and surfactant to neonatology. Innovative strategies that will reduce the risk of CMV acquisition while maintaining the health benefits of fresh human milk exposure, such as passive immunization with CMVneutralizing monoclonal antibodies26 or the enteral administration of exogenous antiviral factors such as lactoferrin,27 are potential ideal strategies to prevent NDI in preterm infants. A better understanding of the effects of postnatal CMV infection on the preterm infant provides a unique opportunity to assess our practice and march towards outcomes for preterm infants that are indistinguishable from that of term infants. n Clyde J. Wright, MD Section of Neonatology Department of Pediatrics University of Colorado School of Medicine Aurora, Colorado Sallie R. Permar, MD, PhD Department of Pediatrics and Human Vaccine Institute Duke University Medical Center Durham, North Carolina Reprint requests: Clyde J. Wright, MD, Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Mail Stop F441, Aurora, CO 80045. E-mail: [email protected]
References 1. National Center for Health Statistics. PeriStats. Final natality data [cited Nov. 23, 2014]. www.marchofdimes.org/peristats/faqsp.aspx. Accessed January 22, 2015. 2. Eichenwald EC, Stark AR. Management and outcomes of very low birth weight. N Engl J Med 2008;358:1700-11. 3. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, et al. Early insulin therapy in verylow-birth-weight infants. N Engl J Med 2008;359:1873-84. 4. Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O’Shea TM, et al. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 2008;359:1885-96. 5. Vaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA, Gantz MG, Walsh MC, et al. Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012;367:2495-504. 6. Swanson EC, Schleiss MR. Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin North Am 2013;60: 335-49. 7. Kurath S, Halwachs-Baumann G, Muller W, Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review. Clin Microbiol Infect 2010;16:1172-8.
8. Josephson CD, Caliendo AM, Easley KA, Knezevic A, Shenvi N, Hinkes MT, et al. Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study. JAMA Pediatr 2014;168:1054-62. 9. Perrine CG, Scanlon KS. Prevalence of use of human milk in US advanced care neonatal units. Pediatrics 2013;131:1066-71. 10. Brecht KF, Goelz R, Bevot A, Krageloh-Mann I, Wilke M, Lidzba K. Postnatal CMV infection in preterm infants has long term neuropsychological sequelae. J Pediatr 2015;166:834-91. 11. Vollmer B, Seibold-Weiger K, Schmitz-Salue C, Hamprecht K, Goelz R, Krageloh-Mann I, et al. Postnatally acquired cytomegalovirus infection via breast milk: effects on hearing and development in preterm infants. Pediatr Infect Dis J 2004;23:322-7. 12. Bevot A, Hamprecht K, Krageloh-Mann I, Brosch S, Goelz R, Vollmer B. Long-term outcome in preterm children with human cytomegalovirus infection transmitted via breast milk. Acta Paediatr 2012;101:e167-72. 13. Jim WT, Shu CH, Chiu NC, Kao HA, Hung HY, Chang JH, et al. Transmission of cytomegalovirus from mothers to preterm infants by breast milk. Pediatr Infect Dis J 2004;23:848-51. 14. Miron D, Brosilow S, Felszer K, Reich D, Halle D, Wachtel D, et al. Incidence and clinical manifestations of breast milk-acquired Cytomegalovirus infection in low birth weight infants. J Perinatol 2005; 25:299-303. 15. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9. 16. Manley BJ, Roberts RS, Doyle LW, Schmidt B, Anderson PJ, Barrington KJ, et al., the Caffeine for Apnea of Prematurity (CAP) Trial Investigators. Social variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams. J Pediatr 2015;166:870-6. 17. Vochem M, Hamprecht K, Jahn G, Speer CP. Transmission of cytomegalovirus to preterm infants through breast milk. Pediatr Infect Dis J 1998;17:53-8. 18. Jim WT, Shu CH, Chiu NC, Chang JH, Hung HY, Peng CC, et al. High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants. Pediatr Infect Dis J 2009;28:891-4. 19. Ehlinger EP, Webster EM, Kang HH, Cangialose A, Simmons AC, Barbas KH, et al. Maternal cytomegalovirus-specific immune responses and symptomatic postnatal cytomegalovirus transmission in very lowbirth-weight preterm infants. J Infect Dis 2011;204:1672-82. 20. Menon G, Williams TC. Human milk for preterm infants: why, what, when and how? Arch Dis Child Fetal Neonatal Ed 2013;98:F559-62. 21. Underwood MA. Human milk for the premature infant. Pediatr Clin North Am 2013;60:189-207. 22. Maschmann J, Hamprecht K, Weissbrich B, Dietz K, Jahn G, Speer CP. Freeze-thawing of breast milk does not prevent cytomegalovirus transmission to a preterm infant. Arch Dis Child Fetal Neonatal Ed 2006; 91:F288-90. 23. Lawrence RA. Storage of human milk and the influence of procedures on immunological components of human milk. Acta Paediatr Suppl 1999; 88:14-8. 24. Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003;143:16-25. 25. Evaluation of the PK and PD of Ganciclovir in Premature Infants Receiving Treatment for CMV Infection (Gan Premie) [updated December 4, 2014]. http://clinicaltrials.gov/ct2/show/NCT01602614? term=ganciclovir&rank=44. Accessed January 2, 2014. 26. Boeckh M, Bowden RA, Storer B, Chao NJ, Spielberger R, Tierney DK, et al. Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001;7:343-51. 797
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27. Beljaars L, van der Strate BW, Bakker HI, Reker-Smit C, van LoenenWeemaes AM, Wiegmans FC, et al. Inhibition of cytomegalovirus
Vol. 166, No. 4 infection by lactoferrin in vitro and in vivo. Antiviral Res 2004;63: 197-208.
Understanding Pediatric Chronic Pancreatitis: Inspiration and Hard Work Required
P
atient registries are effective in the investigation of disof itself, underscores the need for this type of multiease specific epidemiology, clinical characteristics, and institutional research. outcomes.1 They are especially powerful tools when The median age of patients in the reported cohort is applied to relatively uncommon conditions as data does 13.0 years (IQR 10.5, 17.0 years) with a male to female ratio not need to be limited to single investigators, institutions, of 1:1.3. The vast majority are Caucasian (80%) and nonor regions. Moreover, multi-institutional Hispanic (80%). The children were diagSee related article, p 890 registries effectively eliminate potential nosed with chronic pancreatitis at a median biases inherent to single center data. Examples of highly sucage of 9.9 years (IQR 6.1, 14.0 years) and the first episode of cessful patient registries involving diseases in children and acute pancreatitis occurred at 6.8 years (IQR 4.5, 12.1 years). adolescents include the Cystic Fibrosis Foundation Patient Thus, this is a disease of mid-to-late childhood. The age of Registry developed more than 40 years ago and the more presentation of the first episode of acute pancreatitis is less recently instituted inflammatory bowel disease registry of than what we reported in our evaluation of US national the ImproveCareNow Network.2,3 These registries are more data. We found the median age of hospitalized pediatric patients with acute pancreatitis was 17 years, and over 80% of than data repositories, as each is linked to quality improvepatients were older than 11 years.7 This age difference sugment efforts and serves as a platform for clinical research. The International Study Group of Pediatric Pancreatitis: In gests that those children presenting with acute pancreatitis Search for a Cure (INSPPIRE) consortium was created with at an early age require evaluation and close observation for an overall goal of developing therapies for recurrent acute the possible development of chronic disease. and chronic pancreatitis in children and adolescents, uncomAs discussed by the authors, previous single center studies mon conditions in pediatrics.4 Following a model similar to identified genetic abnormalities as the most common risk factor for chronic pancreatitis in children and adolescents. the Cystic Fibrosis Foundation and the ImproveCareNow In comparison, alcohol and tobacco use are the common Network, one of their first steps was to develop a patient risk factors in adults. Their current study confirms this earlier registry. observation in children and strengthens its relationship. Of In this issue of The Journal, Schwarzenberg et al describe the 76 patients with chronic pancreatitis, genetic testing the clinical characteristics of children with chronic pancreawas performed in 63. Two-thirds of patients have an identititis within the INSPPIRE consortium patient registry.5 fied mutation in genes previously demonstrated to be associUsing a cross-sectional cohort design, they report data ated with chronic pancreatitis. Genetic testing was negative in collected at baseline from 14 medical centers in four coun12 patients. The most common chronic pancreatitis predistries. This baseline data set was collected between September posing genetic mutations were in the cationic trypsinogen, 1, 2012 and August 31, 2013. Importantly, the subjects within PRSS1 gene (n = 33). Other identified genetic mutations the database met a uniform consensus definition of chronic were in the pancreatic secretory trypsin inhibitor SPINK1 pancreatitis; this definition was by necessity developed by gene (n = 14), cystic fibrosis transmembrane conductance the consortium as there were no established pediatric criteria regular, CFTR gene (n = 11), and chymotrypsin C, CTRC for the diagnosis of chronic pancreatitis.6 The diagnosis of gene (n = 2). Of note, not all patients were tested for mutachronic pancreatitis required the presence of imaging findtions in each of these genes. Specifically, 61 patients were ings suggestive of chronic pancreatic damage associated evaluated for PRSS1, 53 for SPINK1, 49 for CFTR, and 40 with abdominal pain consistent with a pancreatic origin, for CTRC. It is not reported which genes were evaluated in evidence of exocrine pancreatic insufficiency, or endocrine the 12 patients testing negative for mutations. Mutations in pancreatic insufficiency or pancreas histopathology features more than 1 gene were identified in 9 patients; a second compatible with chronic pancreatitis. The data in this initial chronic pancreatitis associated mutation was observed in 6 report is derived from 76 patients. Though one of the largest of the 11 patients with CFTR mutations. The combination studies to date describing the clinical characteristics of chilof mutations might increase the risk of chronic pancreatitis dren and adolescents with this disorder, it is relatively small in comparison with multicenter studies of other more common disorders (eg, inflammatory bowel disease). This, in and The authors declare no conflicts of interest.
ERCP
Endoscopic retrograde cholangiopancreatography
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