White Blood Cell Changes Following Treatment with a Combination of Recombinant Human Granulocyte Colony Stimulating Factor (rhG-CSF) and Intravenous Immunoglobulin (IVIG) in Necrotizing Enterocolitis (NEC)

Abstract

Objective We sought to determine whether recombinant human granulocyte colony stimulating factor (rhG-CSF) and intravenous immunoglobulin (IVIG) combination can increase white blood cell (WBC) count and improve the survival of extremely low-birth-weight (ELBW) neonates having necrotizing enterocolitis (NEC) with Bell stage II or above.

Methods This retrospective chart review consisted of ELBW neonates with NEC provided with standard of care (standard group) or standard of care and a combination of rhG-CSF along with IVIG (treated group) at the discretion of the treating physician. Serial blood counts (days 0,1,2,3, and 7 to 10), survival, need for surgical intervention, time to reach full feeds, and time to discharge were compared between the two groups.

Results The treated (27 neonates) and the standard (35 neonates) groups had birth weights of 857 ± 52 g and 1,009 ± 50 g; gestational ages of 26 ± 0.5 and 28 ± 0.5 weeks; WBC counts of 7,950 ± 6,452 and 14,105 ± 9,578/mm³; absolute neutrophil count (ANC) of 3,930 ± 5,152 and 7,117 ± 7,545/mm³, respectively (p < 0.05). During the study, WBC count and ANC increased in the treated group till days 7 to 10, but decreased till day 3 in the standard group (p < 0.05). ANC (11-fold) and monocytes (4-fold) increased in the treated patients with neutropenia by days 7 to 10 (p < 0.05). There was no change in the survival, need for surgery, time to reach full feed, or time to discharge between the two groups.

Conclusion The combination of rhG-CSF and IVIG increased WBC, ANC, and monocytes in the treated group but did not affect the survival, need for surgery, time to reach full feed, or time to discharge.

Keywords

absolute neutrophil count - intravenous immunoglobulin - neutropenia - necrotizing enterocolitis - recombinant human granulocyte colony stimulating factor

Contributors' Statement

Prabhakar Kocherlakota contributed to the design, acquired data, performed the initial analysis, drafted the manuscript, and approved the final manuscript as submitted.

Sri K.P. Narayanan acquired the data, performed the initial analysis, reviewed the initial manuscript, and approved the final manuscript as submitted.

Jonathan Blau acquired the data, performed the initial analysis, reviewed initial manuscript, and approved the final manuscript as submitted.

Edmund La Gamma conceptualized and designed the study, designed the data collection instruments, drafted the initial manuscript, and approved the final manuscript as submitted.

• References

• 1 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364 (03) 255-264
• 2 Gordon PV, Swanson JR. Necrotizing enterocolitis is one disease with many origins and potential means of prevention. Pathophysiology 2014; 21 (01) 13-19
• 3 Lee WH, Soraisham AS, Shah VS. , et al. Incidence and timing of presentation of necrotizing enterocolitis in preterm neonates. Pediatrics 2012; 129: e298-e304
• 4 Ahle M, Drott P, Andersson RE. Epidemiology and trends of necrotizing enterocolitis in Sweden: 1987-2009. Pediatrics 2013; 132 (02) e443-e451
• 5 Henry MC, Moss R. Necrotizing enterocolitis. In: Holcom III GW, Murphy J. , eds. Aschcraft's pediatric surgery. 5^th edition. Philadelphia: Saunders; 2010: 439-455
• 6 Patel RM, Kandefer S, Walsh MC. , et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N Engl J Med 2015; 372 (04) 331-340
• 7 Blakely ML, Lally KP, McDonald S. , et al; NEC subcommittee of the NICHD Neonatal Research Network. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005; 241 (06) 984-989 , discussion 989–994
• 8 Sharma R, Hudak ML. A clinical perspective of necrotizing enterocolitis: past, present, and future. Clin Perinatol 2013; 40 (01) 27-51
• 9 Miner CA, Fullmer S, Eggett DL, Christensen RD. Factors affecting the severity of necrotizing enterocolitis. J Matern Fetal Neonatal Med 2013; 26 (17) 1715-1719
• 10 Maheshwari A. Immunologic and hematological abnormalities in necrotizing enterocolitis. Clin Perinatol 2015; 42 (03) 567-585
• 11 Dominguez KM, Moss RL. Necrotizing enterocolitis. Clin Perinatol 2012; 39 (02) 387-401
• 12 La Gamma EF, Alpan O, Kocherlakota P. Effect of granulocyte colony-stimulating factor on preeclampsia-associated neonatal neutropenia. J Pediatr 1995; 126 (03) 457-459
• 13 Kocherlakota P, La Gamma EF, Breen C. , et al. Effects of rhG-CSF on neutrophil Fcy and complement receptors in ventilated very low birth weight human neonates in neonatal hematology and immunology III. In: Bellanti JA, Bracci R, Prindull G, Xanthou M. , eds. Elsevier Science B.V; 1997: 39-48
• 14 Kocherlakota P, Vakkalanka R, Crow MK. , et al. Effect of human granulocyte colony stimulating factor (rhG-CSF) on cytokines in VLBW neonates. Pediatr Res 1998; 44: A1044
• 15 Ahmad M, Fleit HB, Golightly MG, La Gamma EF. In vivo effect of recombinant human granulocyte colony-stimulating factor on phagocytic function and oxidative burst activity in septic neutropenic neonates. Biol Neonate 2004; 86 (01) 48-54
• 16 Bell MJ, Ternberg JL, Feigin RD. , et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187 (01) 1-7
• 17 Mouzinho A, Rosenfeld CR, Sánchez PJ, Risser R. Revised reference ranges for circulating neutrophils in very-low-birth-weight neonates. Pediatrics 1994; 94 (01) 76-82
• 18 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163 (07) 1723-1729
• 19 Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010; 125 (05) 1020-1030
• 20 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92 (04) 529-534
• 21 Fierson WM. ; American Academy of Pediatrics Section on Ophthalmology; American Academy of Ophthalmology; American Association for Pediatric Ophthalmology and Strabismus; American Association of Certified Orthoptists. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2013; 131 (01) 189-195
• 22 Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS. New intrauterine growth curves based on United States data. Pediatrics 2010; 125 (02) e214-e224
• 23 Gibbs RS, Duff P. Progress in pathogenesis and management of clinical intraamniotic infection. Am J Obstet Gynecol 1991; 164 (5 Pt 1): 1317-1326
• 24 Boyer KM, Gadzala CA, Burd LI, Fisher DE, Paton JB, Gotoff SP. Selective intrapartum chemoprophylaxis of neonatal group B streptococcal early-onset disease. I. Epidemiologic rationale. J Infect Dis 1983; 148 (05) 795-801
• 25 Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood 1991; 78 (11) 2791-2808
• 26 Kocherlakota P, La Gamma EF. Preliminary report: rhG-CSF may reduce the incidence of neonatal sepsis in prolonged preeclampsia-associated neutropenia. Pediatrics 1998; 102 (05) 1107-1111
• 27 Kocherlakota P, La Gamma EF. Human granulocyte colony-stimulating factor may improve outcome attributable to neonatal sepsis complicated by neutropenia. Pediatrics 1997; 100 (01) E6
• 28 Carr R, Modi N, Doré C. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database Syst Rev 2003; 3 (03) CD003066
• 29 Bedford Russell AR, Emmerson AJ, Wilkinson N. , et al. 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 2001; 84 (03) F172-F176
• 30 Nayeri F, Soheili H, Kaveh M, Oloomi Yazdi Z, Shariat M, Dalili H. Comparison of two regimens of RhG-CSF in neutropenic neonatal septicemia: a randomized clinical trial. Acta Med Iran 2011; 49 (09) 575-578
• 31 Ohlsson A, Lacy J. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database Syst Rev 2010; 3 (03) CD001239
• 32 Bialek R, Bartmann P. Is there an effect of immunoglobulins and G-CSF on neutrophil phagocytic activity in preterm infants?. Infection 1998; 26 (06) 375-378
• 33 Ragazzi S, Pierro A, Peters M, Fasoli L, Eaton S. Early full blood count and severity of disease in neonates with necrotizing enterocolitis. Pediatr Surg Int 2003; 19 (05) 376-379
• 34 Canpolat FE, Yurdakök M, Korkmaz A, Yiğit S, Tekinalp G. Enteral granulocyte colony-stimulating factor for the treatment of mild (stage I) necrotizing enterocolitis: a placebo-controlled pilot study. J Pediatr Surg 2006; 41 (06) 1134-1138
• 35 Calhoun DA, Maheshwari A, Christensen RD. Recombinant granulocyte colony-stimulating factor administered enterally to neonates is not absorbed. Pediatrics 2003; 112 (02) 421-423
• 36 Simmonds A, LaGamma EF. Toward improving mucosal barrier defenses: rhG-CSF plus IgG antibody. Indian J Pediatr 2006; 73 (11) 1019-1026
• 37 Clark RH, Gordon P, Walker WM, Laughon M, Smith PB, Spitzer AR. Characteristics of patients who die of necrotizing enterocolitis. J Perinatol 2012; 32 (03) 199-204
• 38 Stey A, Barnert ES, Tseng CH. , et al. Outcomes and costs of surgical treatments of necrotizing enterocolitis. Pediatrics 2015; 135 (05) e1190-e1197
• 39 Kelleher J, Mallick H, Soltau TD, Harmon CM, Dimmitt RA. Mortality and intestinal failure in surgical necrotizing enterocolitis. J Pediatr Surg 2013; 48 (03) 568-572
• 40 Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C. Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentrations of plasma immunoglobulins and patterns of infections. Pediatr Res 1986; 20 (09) 899-904