Breast Milk and Saliva Lactoferrin Levels and Postnatal Cytomegalovirus Infection

Abstract

Objective Very low birth weight preterm infants are at risk for life-threatening infections in the NICU. Breast milk protects against infections but carries the risk of infection by cytomegalovirus (CMV) shed in mother's milk. Lactoferrin is a breast milk and saliva protein with potent neutralizing activity against CMV.

Study Design VLBW, maternal breast milk fed infants in the NICU and their lactating mothers were enrolled and followed for 3 months/discharge. Breast milk and infant saliva samples were collected biweekly. Maternal CMV status was determined on breast milk. CMV was measured using quantitative polymerase chain reaction and lactoferrin by enzyme-linked immunosorbent assay.

Results In an in vitro neutralization assay, the IC₉₀ of purified human lactoferrin against CMV was 2.08 ng/mL. Bovine lactoferrins were more potent, IC₉₀s > 10-fold higher. Lactoferrin was detected in all breast milk (median: 3.3 × 10⁶ ng/mL) and saliva (median: 84.4 ng/swab) samples. Median CMV load in breast milk was 893 copies/mL. There was no correlation between breast milk lactoferrin concentration and CMV load. Five infants acquired postnatal CMV. There was no difference in saliva or breast milk lactoferrin concentration for mother–infant pairs and postnatal CMV acquisition.

Conclusion Lactoferrin neutralizes CMV in vitro, but concentrations in breast milk and saliva are likely too low for effective neutralization in vivo.

Keywords

postnatal cytomegalovirus - very low birth weight - preterm - lactoferrin - neonatal intensive care unit - breast milk

Publikationsverlauf

Eingereicht: 15. August 2019

Angenommen: 06. Januar 2020

Artikel online veröffentlicht:
18. Februar 2020

• References

• 1 Greenberg RG, Kandefer S, Do BT. et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Late-onset sepsis in extremely premature infants: 2000-2011. Pediatr Infect Dis J 2017; 36 (08) 774-779
• 2 Garofalo RP, Goldman AS. Expression of functional immunomodulatory and anti-inflammatory factors in human milk. Clin Perinatol 1999; 26 (02) 361-377
• 3 Herrmann K, Carroll K. An exclusively human milk diet reduces necrotizing enterocolitis. Breastfeed Med 2014; 9 (04) 184-190
• 4 Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336 (8730): 1519-1523
• 5 Porcelli P, Schanler R, Greer F. et al. Growth in human milk-fed very low birth weight infants receiving a new human milk fortifier. Ann Nutr Metab 2000; 44 (01) 2-10
• 6 Miller J, Tonkin E, Damarell RA. et al. A systematic review and meta-analysis of human milk feeding and morbidity in very low birth weight infants. Nutrients 2018; 10 (06) 707
• 7 Okulu E, Akin IM, Atasay B, Ciftçi E, Arsan S, Türmen T. Severe postnatal cytomegalovirus infection with multisystem involvement in an extremely low birth weight infant. J Perinatol 2012; 32 (01) 72-74
• 8 Hamprecht K, Maschmann J, Vochem M, Dietz K, Speer CP, Jahn G. Epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding. Lancet 2001; 357 (9255): 513-518
• 9 Cannon MJ, Davis KF. Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health 2005; 5: 70
• 10 Smith RJH, Bale Jr JF, White KR. Sensorineural hearing loss in children. Lancet 2005; 365 (9462): 879-890
• 11 Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 2013; 26 (01) 86-102
• 12 Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17 (04) 253-276
• 13 Josephson CD, Caliendo AM, Easley KA. et al. Blood transfusion and breast milk transmission of cytomegalovirus in very low-birth-weight infants: a prospective cohort study. JAMA Pediatr 2014; 168 (11) 1054-1062
• 14 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
• 15 Capretti MG, Lanari M, Lazzarotto T. et al. Very low birth weight infants born to cytomegalovirus-seropositive mothers fed with their mother's milk: a prospective study. J Pediatr 2009; 154 (06) 842-848
• 16 Lanzieri TM, Dollard SC, Josephson CD, Schmid DS, Bialek SR. Breast milk-acquired cytomegalovirus infection and disease in VLBW and premature infants. Pediatrics 2013; 131 (06) e1937-e1945
• 17 Lombardi G, Garofoli F, Manzoni P, Stronati M. Breast milk-acquired cytomegalovirus infection in very low birth weight infants. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 03) 57-62
• 18 Weimer KED, Kelly MS, Permar SR. et al. Association of adverse hearing, growth, and discharge age outcomes with postnatal cytomegalovirus infection in infants with very low birth weight. JAMA Pediatr 2020; 174 (02) 133-140
• 19 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 (04) 322-327
• 20 Brecht KF, Goelz R, Bevot A, Krägeloh-Mann I, Wilke M, Lidzba K. Postnatal human cytomegalovirus infection in preterm infants has long-term neuropsychological sequelae. J Pediatr 2015; 166 (04) 834-9.e1
• 21 Kelly MS, Benjamin DK, Puopolo KM. et al. Postnatal cytomegalovirus infection and the risk for bronchopulmonary dysplasia. JAMA Pediatr 2015; 169 (12) e153785
• 22 Sawyer MH, Edwards DK, Spector SA. Cytomegalovirus infection and bronchopulmonary dysplasia in premature infants. Am J Dis Child 1987; 141 (03) 303-305
• 23 Mukhopadhyay S, Meyer SA, Permar SR, Puopolo KM. Symptomatic postnatal cytomegalovirus testing among very low-birth-weight infants: indications and outcomes. Am J Perinatol 2016; 33 (09) 894-902
• 24 Nijman J, de Vries LS, Koopman-Esseboom C, Uiterwaal CSPM, 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 (04) F259-F263
• 25 Yoo HS, Sung SI, Jung YJ. et al. Prevention of cytomegalovirus transmission via breast milk in extremely low birth weight infants. Yonsei Med J 2015; 56 (04) 998-1006
• 26 de Cates CR, Gray J, Roberton NR, Walker J. Acquisition of cytomegalovirus infection by premature neonates. J Infect 1994; 28 (01) 25-30
• 27 Jim W-T, Shu C-H, Chiu N-C. et al. Transmission of cytomegalovirus from mothers to preterm infants by breast milk. Pediatr Infect Dis J 2004; 23 (09) 848-851
• 28 Ehlinger EP, Webster EM, Kang HH. et al. Maternal cytomegalovirus-specific immune responses and symptomatic postnatal cytomegalovirus transmission in very low-birth-weight preterm infants. J Infect Dis 2011; 204 (11) 1672-1682
• 29 Fouda GG, Jaeger FH, Amos JD. et al. Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk. Proc Natl Acad Sci U S A 2013; 110 (45) 18220-18225
• 30 Habte HH, de Beer C, Lotz ZE, Tyler MG, Kahn D, Mall AS. Inhibition of human immunodeficiency virus type 1 activity by purified human breast milk mucin (MUC1) in an inhibition assay. Neonatology 2008; 93 (03) 162-170
• 31 Hocini H, Becquart P, Bouhlal H, Adle-Biassette H, Kazatchkine MD, Bélec L. Secretory leukocyte protease inhibitor inhibits infection of monocytes and lymphocytes with human immunodeficiency virus type 1 but does not interfere with transcytosis of cell-associated virus across tight epithelial barriers. Clin Diagn Lab Immunol 2000; 7 (03) 515-518
• 32 McNeely TB, Dealy M, Dripps DJ, Orenstein JM, Eisenberg SP, Wahl SM. Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J Clin Invest 1995; 96 (01) 456-464
• 33 Wang W, Owen SM, Rudolph DL. et al. Activity of alpha- and theta-defensins against primary isolates of HIV-1. J Immunol 2004; 173 (01) 515-520
• 34 Kuhn L, Trabattoni D, Kankasa C. et al. Alpha-defensins in the prevention of HIV transmission among breastfed infants. J Acquir Immune Defic Syndr 2005; 39 (02) 138-142
• 35 Farquhar C, VanCott TC, Mbori-Ngacha DA. et al. Salivary secretory leukocyte protease inhibitor is associated with reduced transmission of human immunodeficiency virus type 1 through breast milk. J Infect Dis 2002; 186 (08) 1173-1176
• 36 Harmsen MC, Swart PJ, de Béthune MP. et al. Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. J Infect Dis 1995; 172 (02) 380-388
• 37 Swart PJ, Kuipers EM, Smit C, Van Der Strate BW, Harmsen MC, Meijer DK. Lactoferrin. Antiviral activity of lactoferrin. Adv Exp Med Biol 1998; 443: 205-213
• 38 Portelli J, Gordon A, May JT. Effect of compounds with antibacterial activities in human milk on respiratory syncytial virus and cytomegalovirus in vitro. J Med Microbiol 1998; 47 (11) 1015-1018
• 39 Florisa R, Recio I, Berkhout B, Visser S. Antibacterial and antiviral effects of milk proteins and derivatives thereof. Curr Pharm Des 2003; 9 (16) 1257-1275
• 40 Clarke NM, May JT. Effect of antimicrobial factors in human milk on rhinoviruses and milk-borne cytomegalovirus in vitro. J Med Microbiol 2000; 49 (08) 719-723
• 41 Beljaars L, van der Strate BWA, Bakker HI. et al. Inhibition of cytomegalovirus infection by lactoferrin in vitro and in vivo. Antiviral Res 2004; 63 (03) 197-208
• 42 Shimizu K, Matsuzawa H, Okada K. et al. Lactoferrin-mediated protection of the host from murine cytomegalovirus infection by a T-cell-dependent augmentation of natural killer cell activity. Arch Virol 1996; 141 (10) 1875-1889
• 43 Pammi M, Abrams SA. Oral lactoferrin for the treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev 2011; (10) CD007138
• 44 Manzoni P, Rinaldi M, Cattani S. et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009; 302 (13) 1421-1428
• 45 Boppana SB, Ross SA, Shimamura M. et al; National Institute on Deafness and Other Communication Disorders CHIMES Study. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med 2011; 364 (22) 2111-2118
• 46 Yamamoto AY, Mussi-Pinhata MM, Marin LJ, Brito RM, Oliveira PFC, Coelho TB. Is saliva as reliable as urine for detection of cytomegalovirus DNA for neonatal screening of congenital CMV infection?. J Clin Virol 2006; 36 (03) 228-230
• 47 Rawlinson WD, Boppana SB, Fowler KB. et al. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis 2017; 17 (06) e177-e188
• 48 Wang D, Li F, Freed DC. et al. Quantitative analysis of neutralizing antibody response to human cytomegalovirus in natural infection. Vaccine 2011; 29 (48) 9075-9080
• 49 Mayer BT, Krantz EM, Swan D. et al. Transient oral human cytomegalovirus infections indicate inefficient viral spread from very few initially infected cells. J Virol 2017;91(12): Doi: 10.1128/JVI.00380-17
• 50 Andersen JH, Osbakk SA, Vorland LH, Traavik T, Gutteberg TJ. Lactoferrin and cyclic lactoferricin inhibit the entry of human cytomegalovirus into human fibroblasts. Antiviral Res 2001; 51 (02) 141-149
• 51 Buccigrossi V, de Marco G, Bruzzese E. et al. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res 2007; 61 (04) 410-414
• 52 Vorland LH, Ulvatne H, Andersen J. et al. Lactoferricin of bovine origin is more active than lactoferricins of human, murine and caprine origin. Scand J Infect Dis 1998; 30 (05) 513-517
• 53 Yang Z, Jiang R, Chen Q. et al. Concentration of lactoferrin in human milk and its variation during lactation in different chinese populations. Nutrients 2018; 10 (09) 1235
• 54 Albenzio M, Santillo A, Stolfi I. et al. Lactoferrin levels in human milk after preterm and term delivery. Am J Perinatol 2016; 33 (11) 1085-1089
• 55 van der Strate BW, Harmsen MC, Schäfer P. et al. Viral load in breast milk correlates with transmission of human cytomegalovirus to preterm neonates, but lactoferrin concentrations do not. Clin Diagn Lab Immunol 2001; 8 (04) 818-821
• 56 Gunkel J, de Vries LS, Jongmans M. et al. Outcome of preterm infants with postnatal cytomegalovirus infection. Pediatrics 2018; 141 (02) e20170635
• 57 Mehler K, Oberthuer A, Lang-Roth R, Kribs A. High rate of symptomatic cytomegalovirus infection in extremely low gestational age preterm infants of 22-24 weeks' gestation after transmission via breast milk. Neonatology 2014; 105 (01) 27-32
• 58 Gunkel J, Wolfs TFW, Nijman J. et al. Urine is superior to saliva when screening for postnatal CMV infections in preterm infants. J Clin Virol 2014; 61 (01) 61-64
• 59 Tengsupakul S, Birge ND, Bendel CM. et al. Asymptomatic DNAemia heralds CMV-associated NEC: case report, review, and rationale for preemption. Pediatrics 2013; 132 (05) e1428-e1434
• 60 Goelz R, Hamprecht K, Klingel K, Poets CF. Intestinal manifestations of postnatal and congenital cytomegalovirus infection in term and preterm infants. J Clin Virol 2016; 83: 29-36