Controversies in Neonatal Sepsis: Immunomodulation in the Treatment and Prevention of Neonatal Sepsis

  • Samantha J. Moss
  • Andrew R. Gennery
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 582)

6. Conclusion

Whilst the concept of replacing the neonatal immunological deficit to prevent or treat systemic sepsis is theoretically attractive, the results from clinical trials performed to date are perhaps less dramatic than expected. The reasons for this are likely to be multifactorial, but include the recruitment of low risk infants who are not septic or neutropenic, and use of inappropriate immunoglobulin preparations that contains little or no antibody effective against pathogens causing neonatal sepsis. There may well be cheaper, more effective, but less glamorous, methods of preventing infection in the preterm infant. There is accumulating evidence regarding the role of prophylactic broad spectrum antibiotics on neonatal gut flora and the influence of early enteral feeding with a correct milk formula can have on encouraging “friendly” gut bacteria. The role of growth factors and immunoglobulin preparations in the treatment and prophylaxis of neonatal sepsis has not yet been established and these products should only be used in the context of large randomised controlled clinical trials until there is clear evidence of benefit (or absence of benefit) in their use.


Neonatal Intensive Care Unit Intravenous Immunoglobulin Coagulase Negative Staphylococcus Neonatal Sepsis Granulocyte Transfusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ahmad, A., Laborada, G., Bussel, J., and Nesin, M. (2002). Comparison of recombinant granulocyte colony-stimulating factor, recombinant human granulocyte-macrophage colony-stimulating factor and placebo for treatment of septic preterm infants. Pediatr Infect Dis J. 21:1061–1065.PubMedCrossRefGoogle Scholar
  2. Baley, J.E., Stork, E.K., Warkentin, P.I., and Shurin, S.B. (1987). Buffy coat transfusions in neutropenic neonates with presumed sepsis: a prospective, randomized trial. Pediatrics. 80:712–720.PubMedGoogle Scholar
  3. Bedford Russell, A.R., Emmerson, A.J., Wilkinson, N., Chant, T., Sweet, D.G., Halliday, H.L., Holland, B., and Davies, E.G. (2001). A trial of recombinant human granulocyte colony stimulating factor for the treatment of very low birthweight infants with presumed sepsis and neutropenia. Arch Dis Child Fetal Neonatal Ed. 84:F172–F176.PubMedCrossRefGoogle Scholar
  4. Bernstein, H.M., Pollock, B.H., Calhoun, D.A., and Christensen, R.D. (2001). Administration of recombinant granulocyte colony-stimulating factor to neonates with septicemia: A meta-analysis. J Pediatr. 138:917–920.PubMedCrossRefGoogle Scholar
  5. Bilgin, K., Yaramis, A., Haspolat, K., Tas, M.A., Gunbey, S., and Derman, O. (2001). A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics. 107:36–41.PubMedCrossRefGoogle Scholar
  6. Cairo, M.S., Worcester, C.C., Rucker, R.W., Hanten, S., Amlie, R.N., Sender, L., and Hicks, D.A. (1992). Randomized trial of granulocyte transfusions versus intravenous immune globulin therapy for neonatal neutropenia and sepsis. J Pediatr. 120:281–285.PubMedCrossRefGoogle Scholar
  7. Cairo, M.S., Christensen, R., Sender, L.S., Ellis, R., Rosenthal, J., van de Ven, C., Worcester, C., and Agosti, J.M. (1995). Results of a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in very low birthweight neonates: significant induction of circulatory neutrophils, monocytes, platelets, and bone marrow neutrophils. Blood. 86:2509–2515.PubMedGoogle Scholar
  8. Cairo, M.S., Agosti, J., Ellis, R., Laver, J.J., Puppala, B., deLemos, R., Givner, L., Nesin, M., Wheeler, J.G., Seth, T., van de Ven, C., and Fanaroff, A. (1999). A randomized, double-blind, placebocontrolled trial of prophylactic recombinant human granulocyte-macrophage colony-stimulating factor to reduce nosocomial infections in very low birth weight neonates. J Pediatr. 134:64–70.PubMedCrossRefGoogle Scholar
  9. Carr, R., and Davies, J.M. (1990). Abnormal FcRIII expression by neutrophils from very preterm neonates. Blood. 76:607–611.PubMedGoogle Scholar
  10. Carr, R., Modi, N., Dore, C.J., El-Rifai, R., and Lindo, D. (1999). A randomized, controlled trial of prophylactic granulocyte-macrophage colony-stimulating factor in human newborns less than 32 weeks gestation. Pediatrics. 103:796–802.PubMedCrossRefGoogle Scholar
  11. Carr, R., Modi, N., and Dore, C. (2003). G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Syst Rev. 3:CD003066.Google Scholar
  12. Chen, J.Y. (1996). Intravenous immunoglobulin in the treatment of full-term and premature newborns with sepsis. J Formos Med Assoc. 95:839–844.PubMedGoogle Scholar
  13. Christensen, R.D., and Rothstein, G. (1980). Exhaustion of mature marrow neutrophils in neonates with sepsis. J Pediatr. 96:316–318.PubMedCrossRefGoogle Scholar
  14. Christensen, R.D., Anstall, H., and Rothstein, G. (1982a). Neutrophil transfusion on septic neutropenic neonates. Transfusion. 22:151–153.PubMedCrossRefGoogle Scholar
  15. Christensen, R.D., Rothstein, G., Anstall, H.B., and Bybee, B. (1982b). Granulocyte transfusions in neonates with bacterial infection, neutropenia, and depletion of mature marrow neutrophils. Pediatrics. 70:1–6.PubMedGoogle Scholar
  16. Christensen, R.D., Brown, M.S., Hall, D.C., Lassiter, H.A., and Hill, H.R. (1991). Effect on neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis. J Pediatr. 118:606–614.PubMedCrossRefGoogle Scholar
  17. Drossou-Agakidou, V., Kanakoudi-Tsakalidou, F., Sarafidis, K., Taparkou, A., Tzimouli, V., Tsandali, H., and Kremenopoulos, G. (1998). Administration of recombinant human granulocyte-colony stimulating factor to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and beta2 integrin expression. Results of a randomized controlled trial. Eur J Pediatr. 157:583–588.PubMedCrossRefGoogle Scholar
  18. Erdem, G., Yurdakok, M., Tekinalp, G., and Ersoy, F. (1993). The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. Turk J Pediatr. 35:277–281.PubMedGoogle Scholar
  19. Fischer, G.W., Cieslak, T.J., Wilson, S.R., Weisman, L.E., and Hemming, V.G. (1994). Opsonic antibodies to Staphylococcus epidermidis: in vitro and in vivo studies using human intravenous immune globulin. J Infect Dis. 169:324–329.PubMedGoogle Scholar
  20. Fujiwara, T., Kobayashi, T., Takaya, J., Taniuchi, S., and Kobayashi, Y. (1997). Plasma effects on phagocytic activity and hydrogen peroxide production by polymorphonuclear leukocytes in neonates. Clin Immunol Immunopathol. 85:67–72.PubMedCrossRefGoogle Scholar
  21. Gillan, E.R., Christensen, R.D., Suen, Y., Ellis, R., van de Ven, C., and Cairo, M.S. (1994). A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia. Blood. 84:1427–1433.PubMedGoogle Scholar
  22. Golan, Y., Doron, S., Sullivan, B., and Snydman, D.R. (2005). Transmission of vancomycin-resistant enterococcus in a neonatal intensive care unit. Pediatr Infect Dis J. 24:566–567.PubMedCrossRefGoogle Scholar
  23. Gorgen, I., Hartung, T., Leist, M., Niehorster, M., Tiegs, G., Uhlig, S., Weitzel, F., and Wendel, A. (1992). Granulocyte colony-stimulating factor treatment protects rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor-alpha. J Immunol. 149:918–924.PubMedGoogle Scholar
  24. Hanrahan, K.S., and Lofgren, M. (2004) Evidence-based practice: examining the risk of toys in the microenvironment of infants in the neonatal intensive care unit. Adv Neonatal Care. 4:184–201.PubMedCrossRefGoogle Scholar
  25. Haque, K.N., Zaidi, M.H., and Bahakim, H. (1988). IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child. 142:1293–1296.PubMedGoogle Scholar
  26. Haque, K.N., Khan, M.A., Kerry, S., Stephenson, J., and Woods, G. (2004). Pattern of culture-proven neonatal sepsis in a district general hospital in the United Kingdom. Infect Control Hosp Epidemiol. 25:759–764.PubMedCrossRefGoogle Scholar
  27. Heath, P.T., Balfour, G., Weisner, A.M., Efstratiou, A., Lamagni, T.L., Tighe, H., O’Connell, L.A., Cafferkey, M., Verlander, N.Q., Nicoll, A., and McCartney, A.C.; PHLS Group B Streptococcus Working Group. (2004). Group B streptococcal disease in UK and Irish infants younger than 90 days. Lancet. 363:292–294.PubMedCrossRefGoogle Scholar
  28. Hunt, D.W., Huppertz, H.I., Jiang, H.J., and Petty, R.E. (1994). Studies of human cord blood dendritic cells: evidence for functional immaturity. Blood. 84:4333–4343.PubMedGoogle Scholar
  29. Linkin, D.R., Fishman, N.O., Patel, J.B., Merrill, J.D., and Lautenbach, E. (2004). Risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 25:781–783.PubMedCrossRefGoogle Scholar
  30. Mancilla-Ramirez, J., Gonzalez-Yunes, R., Castellanos-Cruz, C., Garcia-Roca, P., and Santos-Preciado, J.I. (1992). [Intravenous immunoglobulin in the treatment of neonatal septicemia] Bol Med Hosp Infant Mex. 49:4–11.PubMedGoogle Scholar
  31. Manroe, B.L., Weinberg, A.G., Rosenfeld, C.R., and Browne, R. (1979). The neonatal blood count in health and disease.I. Reference values for neutrophilic cells. J Pediatr. 95:89–98.PubMedCrossRefGoogle Scholar
  32. Miura, E., Procianoy, R.S., Bittar, C., Miura, C.S., Miura, M.S., Mello, C., and Christensen, R.D. (2001). A randomized, double-masked, placebo-controlled trial of recombinant granulocyte colony-stimulating factor administration to preterm infants with the clinical diagnosis of early-onset sepsis. Pediatrics. 107:30–35.PubMedCrossRefGoogle Scholar
  33. Mohan, P., and Brocklehurst, P. (2003). Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropaenia. Cochrane Database Syst Rev. 4:CD003956.Google Scholar
  34. Mortari, F., Wang, J.Y., and Schroeder, H.W. Jr. (1993). Human cord blood antibody repertoire. Mixed population of VH gene segments and CDR3 distribution in the expressed C alpha and C gamma repertoires. J Immunol. 150:1348–1357.PubMedGoogle Scholar
  35. Nonoyama, S., Penix, L.A., Edwards, C.P., Lewis, D.B., Ito, S., Aruffo, A., Wilson, C.B., and Ochs, H.D. (1995). Diminished expression of CD40 ligand by activated neonatal T cells. J Clin Invest. 95:66–75.PubMedCrossRefGoogle Scholar
  36. Ohls, R.K., Li, Y., Abdel-Mageed, A., Buchanan, G., Jr., Mandell, L., and Christensen, R.D. (1995). Neutrophil pool sizes and granulocyte colony-stimulating factor production in human midtrimester fetuses. Pediatr Res. 37:806–811.PubMedGoogle Scholar
  37. Ohlsson, A., and Lacy, J.B. (2004a). Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev. 1:CD001239.Google Scholar
  38. Ohlsson, A., and Lacy, J.B. (2004b). Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database Syst Rev. 1:CD000361.Google Scholar
  39. Punnonen, J., Aversa, G.G., Vandekerckhove, B., Roncarolo, M.G., and de Vries, J.E. (1992). Induction of isotype switching and Ig production by CD5+ and CD10+ human fetal B cells. J Immunol. 148:3398–1404.PubMedGoogle Scholar
  40. Regev-Yochay, G., Rubinstein, E., Barzilai, A., Carmeli, Y., Kuint, J., Etienne, J., Blech, M., Smollen, G., Maayan-Metzger, A., Leavitt, A., Rahav, G., and Keller, N. (2005). Methicillin-resistant Staphylococcus aureus in neonatal intensive care unit. Emerg Infect Dis. 11:453–456.PubMedGoogle Scholar
  41. Ronnestad, A., Abrahamsen, T.G., Medbo, S., Reigstad, H., Lossius, K., Kaaresen, P.I., Engelund, I.E., Irgens, L.M., and Markestad, T. (2005). Septicemia in the first week of life in a Norwegian national cohort of extremely premature infants. Pediatrics. 115: e262–e268.PubMedCrossRefGoogle Scholar
  42. Samatha, S., Jalalu, M.P., Hegde, R.K., Vishwanath, D., and Maiya, P.P. (1997). Role of IgM-enriched intravenous immunoglobulin as an adjuvant to antibiotics in neonatal sepsis. Karnataka Pediatr J. 11:1–6.Google Scholar
  43. Sanz, I. (1991). Multiple mechanisms participate in the generation of diversity of human H chain CDR3 regions. J Immunol. 147:1720–1729.PubMedGoogle Scholar
  44. Schelonka, R.L., Chai, M.K., Yoder, B.A., Hensley, D., Brockett, R.M., and Ascher, D.P. (1996). Volume of blood required to detect common neonatal pathogens. J Pediatr. 129:275–278.PubMedCrossRefGoogle Scholar
  45. Schibler, K.R., Osborne, K.A., Leung, L.Y., Le, T.V., Baker, S.I., and Thompson, D.D. (1998). A randomized, placebo-controlled trial of granulocyte colony-stimulating factor administration to newborn infants with neutropenia and clinical signs of early-onset sepsis. Pediatrics. 102:6–13.PubMedCrossRefGoogle Scholar
  46. Shenoi, A., Nagesh, N.K., Maiya, P.P., Bhat, S.R., and Subba Rao, S.D. (1999). Multicenter randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis. Indian Pediatr. 36:1113–1118.PubMedGoogle Scholar
  47. Sidiropoulos, D., Boehme, U., Von Muralt, G., Morell, A., and Barandun, S. (1986). Immunoglobulin supplementation in prevention or treatment of neonatal sepsis. Pediatr Infect Dis. 5:S193–194.PubMedCrossRefGoogle Scholar
  48. Smith, J.B., Campbell, D.E., Ludomirsky, A., Polin, R.A., Douglas, S.D., Garty, B.Z., and Harris, M.C. (1990). Expression of the complement receptors CR1 and CR3 and the type III Fc gamma receptor on neutrophils from newborn infants and from fetuses with Rh disease. Pediatr Res. 28:120–126.PubMedCrossRefGoogle Scholar
  49. Stoll, B.J., Gordon, T., Korones, S.B., Shankaran, S., Tyson, J.E., Bauer, C.R., Fanaroff, A.A., Lemons, J.A., Donovan, E.F., Oh. W., Stevenson, D.K., Ehrenkranz, R.A., Papile, L.A., Verter, J., and Wright, L.L. (1996). Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr. 129:63–71.PubMedCrossRefGoogle Scholar
  50. Stoll, B.J., Hansen, N., Fanaroff, A.A., Wright, L.L., Carlo, W.A., Ehrenkranz, R.A., Lemons, J.A., Donovan, E.F., Stark, A.R., Tyson, J.E., Oh, W., Bauer, C.R., Korones, S.B., Shankaran, S., Laptook, A.R., Stevenson, D.K., Papile, L.A., and Poole, W.K. (2002). Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 110:285–291.PubMedCrossRefGoogle Scholar
  51. Stoll, B.J., Hansen, N.I., Adams-Chapman, I., Fanaroff, A.A., Hintz, S.R., Vohr, B., and Higgins, R.D.; National Institute of Child Health and Human Development Neonatal Research Network. (2004). Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 292:2357–2565.PubMedCrossRefGoogle Scholar
  52. Urrea, M., Iriondo, M., Thio, M., Krauel, X., Serra, M., LaTorre, C., and Jimenez, R. (2003). A prospective incidence study of nosocomial infections in a neonatal care unit. Am J Infect Control. 8:505–507.CrossRefGoogle Scholar
  53. Weisman, L.E., Stoll, B.J., Kueser, T.J., Rubio, T.T., Frank, C.G., Heiman, H.S., Subramanian, K.N., Hankins, C.T., Anthony, B.F., and Cruess, D.F. (1992). Intravenous immune globulin therapy for early-onset sepsis in premature neonates. J Pediatr. 121:434–443.PubMedCrossRefGoogle Scholar
  54. Weisman, L.E., Cruess, D.F., and Fischer, G.W. (1994). Opsonic activity of commercially available standard intravenous immunoglobulin preparations. Pediatr Infect Dis J. 13:1122–1125.PubMedCrossRefGoogle Scholar
  55. Wheeler, J.G., Chauvenet, A.R., Johnson, C.A., Block, S.M., Dillard, R., and Abramson, J.S. (1987). Buffy coat transfusions in neonates with sepsis and neutrophil storage pool depletion. Pediatrics. 79:422–425.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Samantha J. Moss
    • 1
  • Andrew R. Gennery
    • 2
  1. 1.Neonatal DepartmentRoyal Victoria InfirmaryNewcastle upon TyneUK
  2. 2.Paediatric Immunology DepartmentNewcastle General HospitalNewcastle upon TyneUK

Personalised recommendations