Immunological defects in neonatal sepsis and potential therapeutic approaches

Frontiers in Pediatrics

Volumn 5, Issue , 2017, Pages

  Raymond, Steven L ^a   Stortz, Julie A ^a   Mira, Juan C ^a   Larson, Shawn D ^a   Wynn, James L ^a   Moldawer, Lyle L ^a  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Genomics; Host response; Infection; Inflammation; Innate immunity; Shock; Transcriptomics

Indexed keywords

EID: 85021232859     PISSN: None     EISSN: 22962360     Source Type: Journal    
DOI: 10.3389/fped.2017.00014     Document Type: Short Survey

References (73)

1. Shane AL, Stoll BJ. Neonatal sepsis: progress towards improved outcomes. J Infect (2014) 68(Suppl 1):S24-32. doi: 10.1016/j.jinf.2013.09.011
2. Wynn JL. Defining neonatal sepsis. Curr Opin Pediatr (2016) 28:135-40. doi:10.1097/MOP.0000000000000315
3. Camacho-Gonzalez A, Spearman PW, Stoll BJ. Neonatal infectious diseases: evaluation of neonatal sepsis. Pediatr Clin North Am (2013) 60:367-89. doi:10.1016/j.pcl.2012.12.003
4. Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am (2004) 51:939-59, viii-ix. doi:10.1016/j.pcl.2004.03.009
5. Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin Perinatol (2010) 37:421-38. doi:10.1016/j.clp.2009.12.001
6. Cantey JB, Wozniak PS, Sanchez PJ. Prospective surveillance of antibiotic use in the neonatal intensive care unit: results from the SCOUT study. Pediatr Infect Dis J (2015) 34:267-72. doi:10.1097/INF.0000000000000542
7. Hornik CP, Fort P, Clark RH, Watt K, Benjamin DK Jr, Smith PB, et al. Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units. Early Hum Dev (2012) 88(Suppl 2):S69-74. doi:10.1016/S0378-3782(12)70019-1
8. Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal intensive care unit antibiotic use. Pediatrics (2015) 135:826-33. doi:10.1542/peds.2014-3409
9. Shane AL, Stoll BJ. Recent developments and current issues in the epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis. Am J Perinatol (2013) 30:131-41. doi:10.1055/s-0032-1333413
10. Zaghouani H, Hoeman CM, Adkins B. Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol (2009) 30:585-91. doi:10.1016/j.it.2009.09.002
11. Gibbons D, Fleming P, Virasami A, Michel ML, Sebire NJ, Costeloe K, et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat Med (2014) 20:1206-10. doi:10.1038/nm.3670
12. Mold JE, Venkatasubrahmanyam S, Burt TD, Michaelsson J, Rivera JM, Galkina SA, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science (2010) 330:1695-9. doi:10.1126/science.1196509
13. Elahi S, Ertelt JM, Kinder JM, Jiang TT, Zhang X, Xin L, et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature (2013) 504:158-62. doi:10.1038/nature12675
14. Wynn JL, Scumpia PO, Stocks BT, Romano-Keeler J, Alrifai MW, Liu JH, et al. Neonatal CD71+ erythroid cells do not modify murine sepsis mortality. J Immunol (2015) 195:1064-70. doi:10.4049/jimmunol.1500771
15. Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, et al. Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood (2008) 112:1750-8. doi:10.1182/blood-2008-01-130500
16. Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol (2012) 2012:985646. doi:10.1155/2012/985646
17. Kollmann TR, Crabtree J, Rein-Weston A, Blimkie D, Thommai F, Wang XY, et al. Neonatal innate TLR-mediated responses are distinct from those of adults. J Immunol (2009) 183:7150-60. doi:10.4049/jimmunol.0901481
18. Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol (2007) 7:379-90. doi:10.1038/nri2075
19. Mira JC, Moldawer LL. Sepsis diagnostics: from discovery to application. Crit Care Med (2017) 45:129-30. doi:10.1097/CCM.0000000000002117
20. Dopazo J. Genomics and transcriptomics in drug discovery. Drug Discov Today (2014) 19:126-32. doi:10.1016/j.drudis.2013.06.003
21. Martini M, Vecchione L, Siena S, Tejpar S, Bardelli A. Targeted therapies: how personal should we go? Nat Rev Clin Oncol (2011) 9:87-97. doi:10.1038/nrclinonc.2011.164
22. Sweeney TE, Khatri P. Benchmarking sepsis gene expression diagnostics using public data. Crit Care Med (2017) 45:1-10. doi:10.1097/CCM.0000000000002021
23. Sweeney TE, Shidham A, Wong HR, Khatri P. A comprehensive time-course-based multicohort analysis of sepsis and sterile inflammation reveals a robust diagnostic gene set. Sci Transl Med (2015) 7:287ra71. doi:10.1126/scitranslmed.aaa5993
24. Cernada M, Serna E, Bauerl C, Collado MC, Perez-Martinez G, Vento M. Genome-wide expression profiles in very low birth weight infants with neonatal sepsis. Pediatrics (2014) 133:e1203-11. doi:10.1542/peds.2013-2552
25. Wynn JL, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ, Anas N, et al. The influence of developmental age on the early transcriptomic response of children with septic shock. Mol Med (2011) 17:1146-56. doi:10.2119/molmed.2011.00169
26. Srinivasan L, Kirpalani H, Cotten CM. Elucidating the role of genomics in neonatal sepsis. Semin Perinatol (2015) 39:611-6. doi:10.1053/j.semperi.2015.09.008
27. Wynn JL, Guthrie SO, Wong HR, Lahni P, Ungaro R, Lopez MC, et al. Postnatal age is a critical determinant of the neonatal host response to sepsis. Mol Med (2015) 21:496-504. doi:10.2119/molmed.2015.00064
28. Smith CL, Dickinson P, Forster T, Craigon M, Ross A, Khondoker MR, et al. Identification of a human neonatal immune-metabolic network associated with bacterial infection. Nat Commun (2014) 5:4649. doi:10.1038/ncomms5649
29. Feezor RJ, Oberholzer C, Baker HV, Novick D, Rubinstein M, Moldawer LL, et al. Molecular characterization of the acute inflammatory response to infections with Gram-negative versus Gram-positive bacteria. Infect Immun (2003) 71:5803-13. doi:10.1128/IAI.71.10.5803-5813.2003
30. Gentile LF, Nacionales DC, Lopez MC, Vanzant E, Cuenca A, Cuenca AG, et al. Protective immunity and defects in the neonatal and elderly immune response to sepsis. J Immunol (2014) 192:3156-65. doi:10.4049/jimmunol.1301726
31. Mathias B, Mira JC, Rehfuss JP, Rincon JC, Ungaro R, Nacionales DC, et al. LPS stimulation of cord blood reveals a newborn-specific neutrophil transcriptomic response and cytokine production. Shock (2016). doi:10.1097/SHK.0000000000000800
32. Wynn JL, Scumpia PO, Delano MJ, O'Malley KA, Ungaro R, Abouhamze A, et al. Increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis. Shock (2007) 28:675-83. doi:10.1097/SHK.0b013e3180556d09
33. Doeing DC, Borowicz JL, Crockett ET. Gender dimorphism in differential peripheral blood leukocyte counts in mice using cardiac, tail, foot, and saphenous vein puncture methods. BMC Clin Pathol (2003) 3:3. doi:10.1186/1472-6890-3-3
34. Eisenhauer PB, Lehrer RI. Mouse neutrophils lack defensins. Infect Immun (1992) 60:3446-7
35. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol (2004) 172:2731-8. doi:10.4049/jimmunol.172.5.2731
36. Anderson DC, Hughes BJ, Smith CW. Abnormal mobility of neonatal polymorphonuclear leukocytes. Relationship to impaired redistribution of surface adhesion sites by chemotactic factor or colchicine. J Clin Invest (1981) 68:863-74. doi:10.1172/JCI110341
37. Drossou V, Kanakoudi F, Tzimouli V, Sarafidis K, Taparkou A, Bougiouklis D, et al. Impact of prematurity, stress and sepsis on the neutrophil respiratory burst activity of neonates. Biol Neonate (1997) 72:201-9. doi:10.1159/000244485
38. Filias A, Theodorou GL, Mouzopoulou S, Varvarigou AA, Mantagos S, Karakantza M. Phagocytic ability of neutrophils and monocytes in neonates. BMC Pediatr (2011) 11:29. doi:10.1186/1471-2431-11-29
39. Merry C, Puri P, Reen DJ. Defective neutrophil actin polymerisation and chemotaxis in stressed newborns. J Pediatr Surg (1996) 31:481-5. doi:10.1016/S0022-3468(96)90479-0
40. Yost CC, Cody MJ, Harris ES, Thornton NL, McInturffAM, Martinez ML, et al. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood (2009) 113:6419-27. doi:10.1182/blood-2008-07-171629
41. Prosser A, Hibbert J, Strunk T, Kok CH, Simmer K, Richmond P, et al. Phagocytosis of neonatal pathogens by peripheral blood neutrophils and monocytes from newborn preterm and term infants. Pediatr Res (2013) 74:503-10. doi:10.1038/pr.2013.145
42. Marcos V, Nussbaum C, Vitkov L, Hector A, Wiedenbauer EM, Roos D, et al. Delayed but functional neutrophil extracellular trap formation in neonates. Blood (2009) 114:4908-11; author reply 11-2. doi:10.1182/blood-2009-09-242388
43. Wynn JL, Neu J, Moldawer LL, Levy O. Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis. J Perinatol (2009) 29:79-88. doi:10.1038/jp.2009.48
44. Pammi M, Brocklehurst P. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropaenia. Cochrane Database Syst Rev (2011) (10):CD003956. doi:10.1002/14651858.CD003956.pub2
45. Carr R, Brocklehurst P, Dore CJ, Modi N. Granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the PROGRAMS trial): a single-blind, multicentre, randomised controlled trial. Lancet (2009) 373:226-33. doi:10.1016/S0140-6736(09)60071-4
46. Mathias B, Szpila BE, Moore FA, Efron PA, Moldawer LL. A review of GM-CSF therapy in sepsis. Medicine (2015) 94(50):e2044. doi:10.1097/MD.0000000000002044
47. INIS Collaborative Group, Brocklehurst P, Farrell B, King A, Juszczak E, Darlow B, et al. Treatment of neonatal sepsis with intravenous immune globulin. N Engl J Med (2011) 365:1201-11. doi:10.1056/NEJMoa1100441
48. Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev (2015) (3):CD001239. doi:10.1002/14651858.CD001239.pub5
49. Shah PS, Kaufman DA. Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants. Cochrane Database Syst Rev (2009) (2):CD006449. doi:10.1002/14651858.CD006449.pub2
50. Patel M, Kaufman DA. Anti-lipoteichoic acid monoclonal antibody (pagibaximab) studies for the prevention of staphylococcal bloodstream infections in preterm infants. Expert Opin Biol Ther (2015) 15:595-600. doi:10.1517/14712598.2015.1019857
51. Goldstein B, Nadel S, Peters M, Barton R, Machado F, Levy H, et al. ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis. Pediatr Crit Care Med (2006) 7:200-11. doi:10.1097/01.PCC.0000217470.68764.36
52. Kylat RI, Ohlsson A. Recombinant human activated protein C for severe sepsis in neonates. Cochrane Database Syst Rev (2012) (4):CD005385. doi:10.1002/14651858.CD005385.pub3
53. Poindexter BB, Ehrenkranz RA, Stoll BJ, Wright LL, Poole WK, Oh W, et al. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics (2004) 113:1209-15. doi:10.1542/peds.113.5.1209
54. Moe-Byrne T, Brown JV, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database Syst Rev (2016) (4):CD001457. doi:10.1002/14651858.CD001457.pub6
55. Akdag A, Dilmen U, Haque K, Dilli D, Erdeve O, Goekmen T. Role of pentoxifylline and/or IgM-enriched intravenous immunoglobulin in the management of neonatal sepsis. Am J Perinatol (2014) 31:905-12. doi:10.1055/s-0033-1363771
56. Adhikari M, Coovadia HM, Gaffin SL, Brock-Utne JG, Marivate M, Pudifin DJ. Septicaemic low birthweight neonates treated with human antibodies to endotoxin. Arch Dis Child (1985) 60:382-4. doi:10.1136/adc.60.4.382
57. Hartel C, Pagel J, Rupp J, Bendiks M, Guthmann F, Rieger-Fackeldey E, et al. Prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics and outcome in very low birth weight infants. J Pediatr (2014) 165:285-9.e1. doi:10.1016/j.jpeds.2014.04.029
58. Patel AL, Johnson TJ, Engstrom JL, Fogg LF, Jegier BJ, Bigger HR, et al. Impact of early human milk on sepsis and health-care costs in very low birth weight infants. J Perinatol (2013) 33:514-9. doi:10.1038/jp.2013.2
59. Wynn JL, Wilson CS, Hawiger J, Scumpia PO, Marshall AF, Liu JH, et al. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18. Proc Natl Acad Sci U S A (2016) 113:E2627-35. doi:10.1073/pnas.1515793113
60. Cleminson J, McGuire W. Topical emollient for preventing infection in preterm infants. Cochrane Database Syst Rev (2016) (1):CD001150. doi:10.1002/14651858.CD001150.pub3
61. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA (2009) 302:1421-8. doi:10.1001/jama.2009.1403
62. Acunas BA, Peakman M, Liossis G, Davies ET, Bakoleas B, Costalos C, et al. Effect of fresh frozen plasma and gammaglobulin on humoral immunity in neonatal sepsis. Arch Dis Child Fetal Neonatal Ed (1994) 70:F182-7. doi:10.1136/fn.70.3.F182
63. Sood BG, Shankaran S, Schelonka RL, Saha S, Benjamin DK Jr, Sanchez PJ, et al. Cytokine profiles of preterm neonates with fungal and bacterial sepsis. Pediatr Res (2012) 72:212-20. doi:10.1038/pr.2012.56
64. Kleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G. Cytokine levels in the serum of healthy subjects. Mediators Inflamm (2013) 2013:434010. doi:10.1155/2013/434010
65. Grobmyer SR, Lin E, Lowry SF, Rivadeneira DE, Potter S, Barie PS, et al. Elevation of IL-18 in human sepsis. J Clin Immunol (2000) 20:212-5. doi:10.1023/A:1006641630904
66. Savva A, Roger T. Targeting toll-like receptors: promising therapeutic strategies for the management of sepsis-associated pathology and infectious diseases. Front Immunol (2013) 4:387. doi:10.3389/fimmu.2013.00387
67. Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature (2007) 449:819-26. doi:10.1038/nature06246
68. Cuenca AG, Wynn JL, Moldawer LL, Levy O. Role of innate immunity in neonatal infection. Am J Perinatol (2013) 30:105-12. doi:10.1055/s-0032-1333412
69. Raymond SL, Holden DC, Mira JC, Stortz JA, Loftus TJ, et al. Microbial recognition and danger signals in sepsis and trauma. Biochimica et Biophysica Acta (2017) (17):30026-1. doi:10.1016/j.bbadis.2017.01.013
70. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell (2006) 124:783-801. doi:10.1016/j.cell.2006.02.015
71. Burl S, Townend J, Njie-Jobe J, Cox M, Adetifa UJ, Touray E, et al. Age-dependent maturation of toll-like receptor-mediated cytokine responses in Gambian infants. PLoS One (2011) 6:e18185. doi:10.1371/journal.pone.0018185
72. Duthie MS, Windish HP, Fox CB, Reed SG. Use of defined TLR ligands as adjuvants within human vaccines. Immunol Rev (2011) 239:178-96. doi:10.1111/j.1600-065X.2010.00978.x
73. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis (2011) 204:245-52. doi:10.1093/infdis/jir240