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Myeloid Colony-Stimulating Factors
Use in the Newborn
Con Sreenan, MB, MRCP;
Horacio Osiovich, MD, FRCPC
Arch Pediatr Adolesc Med. 1999;153:984-988.
ABSTRACT
Bacterial and fungal sepsis are major causes of morbidity and mortality in the newborn. Multiple factors contribute to this increased susceptibility to infection, including quantitative and qualitative neutrophil defects, with a reduction in neutrophil number and function. Neutropenia in the newborn may occur in association with sepsis and has a poor prognosis. In addition to antibiotic therapy and supportive care, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used to reduce morbidity and mortality. Granulocyte CSF is the physiological regulator of neutrophil production and function. Administration of G-CSF results in increased neutrophil production and counts and improved neutrophil function. Several studies of animal and human newborns having neutropenia or suspected sepsis investigated the use of G-CSF and GM-CSF to elevate neutrophil counts and reduce morbidity and mortality in this population. Results of small clinical trials using G-CSF and GM-CSF in very low-birth-weight infants having neutropenia show increased neutrophil counts and a reduced incidence of sepsis during the neonatal period. Despite these promising early results, further studies of the safety and efficacy of G-CSF and GM-CSF administration in neonates are required before their routine use can be recommended as either prophylaxis or treatment for neonatal sepsis.
INTRODUCTION
Bacterial and fungal sepsis are major causes of morbidity and mortality in the newborn. Despite advances in neonatal intensive care in recent decades, sepsis-associated mortality rates in very low-birth-weight infants have remained constant at nearly 15%.1 This plateau in mortality likely reflects an increased susceptibility of the neonate to infection; multiple factors contributing to this include quantitative and qualitative neutrophil defects with reduced numbers of stored and precursor neutrophils per kilogram body weight, delayed upregulation of neutrophil production in response to infection, and reduced neutrophil function.2
Neutropenia in the newborn may occur in association with sepsis or in other situations such as maternal hypertension.3-4 Neutropenia in neonates increases the risk of sepsis and is associated with a poor prognosis.3-8 As a result, in addition to the standard therapy for neonatal sepsis with antibiotic medications and supportive care, several novel forms of immunotherapy such as granulocyte transfusions and intravenous immunoglobulin administration have been used to reduce mortality—without any proven benefit.9-10 Granulocyte colony-stimulating factor (G-CSF) is the physiological regulator of neutrophil production and function. Its actions include increased neutrophil and neutrophil superoxide production and bactericidal activity.11-12 Several studies of animal and human newborns having neutropenia or suspected sepsis investigated the use of G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) to increase neutrophil counts and reduce morbidity and mortality in this population.
NEUTROPHIL PRODUCTION AND FUNCTION
Neutrophils develop from myeloid progenitor cells, passing through a number of stages. Myeloblasts, promyelocytes, and myelocytes all have the capacity for cell division and are referred to as the neutrophil proliferative pool. As neutrophils mature, they lose the capacity for cell division. Metamyelocytes, band neutrophils, and segmented neutrophils are termed the neutrophil storage pool (NSP).13 Results of studies14 in adult humans show that the neutrophil proliferative pool and NSP contain 2x109 and 6x109cells per kilogram body weight, respectively. Although the size of the NSP and the neutrophil proliferative pool have not been quantified as accurately in neonates as in adults, both pools are smaller in newborns than in adults. Several factors enhance the release of cells from the NSP into the blood, including treatment with G-CSF and corticosteroids.14-15 The equilibrium between circulating and marginated neutrophil pools has been shown experimentally in animals and adult humans to be affected by several factors, such as administration of epinephrine or endotoxin, and in neonates by strenuous crying.14, 16 The half-life of neutrophils in the blood is approximately 6 hours because they quickly leave the blood to enter the tissues.17 The length of time that neutrophils spend in the tissues is not completely clear but is affected by the presence of tissue damage or infection.18
Results of studies19 on human abortuses show that virtually no neutrophils are present before 14 weeks' gestation. Subsequently, the neutrophil count rises progressively to term, with a doubling of the absolute neutrophil count from 14 to 18 weeks' gestation and a 4-fold increase by 24 to 32 weeks' gestation.20 At birth, neonates delivered vaginally have higher neutrophil counts than those delivered by cesarean section.21 After birth, neutrophil counts peak between 12 and 24 hours and subsequently decrease, achieving a stable lower value of approximately 1800x109/L by 72 hours of life.22 Neutrophil counts in very low-birth-weight infants have a wider variation and are, on average, lower than in full-term infants, with neutropenia being defined by some authors23 as a concentration less than 1800x109/L at 12 hours and less than 1000x109/L by 48 hours, since this is the lower limit of the 90% reference range.
Results of studies24 in adult animals show that approximately 60 to 90 minutes after inoculation with bacteria, there is neutrophilia with an accompanying increase in band forms. As neutrophils are released from the marrow to the blood, bone marrow NSP decreases. In sepsis, neutrophil production is increased, with an acceleration of cycling of neutrophil precursors. If tissue uptake occurs at a rate greater than neutrophil production and release from the NSP, neutropenia develops. Neutrophil proliferation in neonates is at near-maximum capacity in the normal state, resulting in inadequate reserve production capacity. In human neonates, the latency period for neutrophilia to develop after inoculation is prolonged by an uncertain duration, and a marked increase in neutrophil production is not evident.25
BIOLOGICAL CHARACTERISTICS OF G-CSF
Granulocyte CSF, the primary physiological regulator of neutrophil production, is an 18-kd glycosylated polypeptide consisting of 27 amino acids11 produced primarily by monocytes, macrophages, fibroblasts, and endothelial cells.26 Actions of G-CSF include maturation of committed myeloid progenitors; release of neutrophils from the bone marrow NSP to the blood; and activation of neutrophil functions, including chemotaxis, superoxide generation, phagocytosis, and microbial killing.15 Administration of G-CSF to primates with normal white blood cell counts results in dose-dependent neutrophilia.27
After isolation of murine G-CSF in 1983,28 human G-CSF was isolated in 1985.29 Subsequently, the gene for G-CSF was located on the long arm of chromosome 17.30
Granulocyte CSF has been used in adults having chemotherapy-induced neutropenia since the late 1980s and has been shown to cause a dose-dependent increase in blood neutrophil concentration and to reduce the period of neutropenia.12 Subsequently, G-CSF has been used in children having chemotherapy-induced neutropenia and congenital or acquired neutropenia with similar success.31-34 Use of G-CSF also hastens myeloid recovery after myeloablative therapy for bone marrow transplantation.35
Granulocyte CSF can be measured in cord blood from full-term and preterm neonates.36 In some studies,36-37 the concentration of G-CSF measured in cord blood or in the immediate postnatal period correlated with gestational age and blood neutrophil concentration. However, other studies38-39 did not find any such correlation. Compared with healthy adults, preterm and term infants without neutropenia have higher G-CSF levels.40-41 Levels are higher in preterm than in term infants.41-42 However, despite markedly elevated G-CSF levels in adults having neutropenia, levels in neonates having neutropenia are not elevated, particularly in preterm infants. Elevated G-CSF levels are associated with infection, fetal distress, premature rupture of membranes, birth asphyxia, vaginal delivery compared with cesarean section, and in the second twin delivered compared with the first.42 Neonates with signs of infection have higher G-CSF levels than healthy neonates but not as high as infected adults.37 These effects are explained by the fact that, although neonatal myeloid progenitor cells are equally responsive as adult cells to the actions of G-CSF, monocytes from neonates generate less G-CSF in response to stimulation than adult monocytes because of posttranscriptional instability rather than diminished G-CSF transcription.38, 43-44
USE OF G-CSF IN THE NEONATE
In the first study of the use of G-CSF in a human neonate, Roberts et al45 used G-CSF in a 654-g infant—the result of a pregnancy complicated by severe maternal hypertension—who was persistently neutropenic and had 5 episodes of sepsis. Administration of G-CSF (10 µg/d) resulted in neutrophilia without any further episodes of infection. The drug was administered for 7 months without any adverse effects. Gillan et al46 studied 42 neonates suspected of having sepsis in the first 72 hours of life. The infants were randomized to receive either placebo or G-CSF (1, 5, 10, or 20 µg/kg per day), and a dose-dependent increase in blood and bone marrow neutrophils was demonstrated without any adverse effects.46 Bedford Russell et al47 administered G-CSF (5 µg/kg per day for 5 days, increased to 10 µg/kg per day if no response) to 12 preterm infants having neutropenia and suspected of having sepsis, and showed a significant increase in neutrophil counts after a median of 4 days.
Kocherlakota and La Gamma48 evaluated the administration of G-CSF to neonates suspected of having sepsis complicated by neutropenia. They documented increased circulating neutrophil counts. In a subsequent nonrandomized, nonmasked, preliminary study,49 they demonstrated that administration of G-CSF in neonates having prolonged preeclampsia-associated neutropenia significantly reduced the incidence of sepsis in the first 28 days of life, from 54% to 13%. Several other studies50-51 involving small numbers of neonates having neutropenia due to various causes found increased neutrophil counts associated with use of G-CSF at dosages averaging 5 µg/kg per day.
In a recent study, Schibler et al52 randomized 20 neonates having neutropenia and suspected of having sepsis to receive either G-CSF (10 µg/kg/d) or placebo for the first 3 days of life. Bone marrow aspirates were performed, either at study entry or on day 2. Neutrophil counts increased significantly in both groups over time, with no significant differences in neutrophil count, bone marrow NSP, neutrophil proliferative pool, severity of illness, morbidity, or mortality. The lack of effect for G-CSF use may be explained by the fact that endogenous G-CSF levels were elevated in both groups at study entry, and, during the study, there were no significant differences in their G-CSF concentrations.
Results of initial studies53 suggested that administration of G-CSF to a pregnant woman at risk for imminent preterm delivery might result in transplacental passage of G-CSF and an increased neutrophil count in the neonate. The effect was affected by the time between administration of G-CSF and delivery, and may have been confounded by differences in the degree of prematurity between patients and controls.53 Although results of the above-mentioned studies showed that G-CSF increased neutrophil counts in neonates having neutropenia or suspected of having sepsis, there are no randomized placebo-controlled trials on whether G-CSF improves survival for neonates having early-onset bacterial sepsis, or whether G-CSF improves the outcome for neonates having neutropenia.
GRANULOCYTE-MACROPHAGE CSF
The physiological features of GM-CSF are similiar to those of G-CSF.54 However, GM-CSF is an earlier and more widely acting cytokine than G-CSF, which induces proliferation and differentiation of multilineage hematopoietic progenitors.54 This increases monocyte, macrophage, and eosinophil counts more than G-CSF but has less effect on neutrophil counts.55 In addition, GM-CSF has a greater effect on chemotaxis and the bactericidal function of neutrophils than does G-CSF.55
Studies on the use of GM-CSF in human newborns are limited. Cairo et al56 administered placebo or GM-CSF (5 or 10 µg/kg per day for 7 days) to 20 very low-birth-weight infants starting in the first 72 hours of life. A significant dose-dependent increase in blood and bone marrow neutrophil counts lasted approximately 5 days after administration of the last dose. Subsequently, this group randomized 61 very low-birth-weight infants to receive either placebo or GM-CSF (8 µg/kg per day for 28 days) starting within 3 days of birth.57 A significant (61%) reduction in the incidence of nosocomial infection occurred in the treatment group.
ADVERSE EFFECTS
Although only occasional adverse effects of G-CSF and GM-CSF treatment in neonates have been described, some concerns have been raised.50-51,58-59 Significant reductions in platelet counts have been reported after treatment with G-CSF in several studies in neonates and children. It is not clear whether this thrombocytopenia is an adverse effect of G-CSF administration or whether it may be attributable to associated sepsis and the critically ill state of the population involved.47, 60 However, in a study by Donadieu et al,34 thrombocytopenia occurred after G-CSF administration to children having chronic neutropenia in the absence of sepsis. In contrast, GM-CSF treatment seems to cause an elevation in platelet counts.56 In adults, adverse effects include fever and bone pain and are more common with GM-CSF than with G-CSF.61 In addition, a "first-dose" effect of pulmonary sequestration of neutrophils has been described after high-dose intravenous administration of G-CSF and GM-CSF.61 This effect is avoided by slow intravenous infusion or subcutaneous injection.62 Concerns have been expressed that pulmonary sequestration of neutrophils with activation of cytokine cascades could exacerbate short- and long-term lung injury.58 This effect is a particular concern in extremely premature infants having acute respiratory distress syndrome who are already at considerable risk of bronchopulmonary dysplasia. Indeed, a study52 demonstrated a nonsignificant trend toward a slightly higher incidence of chronic lung disease among G-CSF recipients.
A theoretical concern exists that exposure to G-CSF may predispose neonates to leukemia in later life, although no cases directly attributable to G-CSF treatment have been documented to date, to our knowledge. However, a few children have developed leukemia on treatment with G-CSF in Kostmann syndrome where there is primary congenital neutropenia.63 Several factors other than G-CSF administration may contribute to the increased risk of leukemia in patients having Kostmann syndrome, which in itself may be a preleukemic condition. These factors include structural abnormalities in neutrophils and the G-CSF receptor, and an increase in survival by preventing early neutropenia-related septic deaths using long-term administration of G-CSF.64 Some evidence for the safety of G-CSF treatment comes from a 2-year follow-up65 of 21 neonates who received G-CSF for 3 days and subsequently had normal hematologic, immunologic, and neurologic development.
CONCLUSIONS
Despite evidence of benefit from animal studies and some data in the human newborn that increased neutrophil counts occur with apparent short- and long-term safety, there is insufficient evidence to date to support the use of G-CSF or GM-CSF in routine clinical practice as prophylaxis against or treatment for sepsis in the newborn, with or without neutropenia. Further randomized controlled trials are required to demonstrate the minimum effective dose with an acceptable safety profile. A role may well emerge for a particular CSF (G-CSF or GM-CSF) in certain subgroups such as extremely low-birth-weight infants having neutropenia. The exact role for G-CSF and GM-CSF treatment in the neonatal intensive care unit awaits further clarification.
AUTHOR INFORMATION
Accepted for publication March 11, 1999.
Neither author has any affiliation with or financial interest in any organization or entity that conflicts with or has financial interest in the subject matter discussed in the article.
We thank Paul Byrne, MD, FRCPC, University of Alberta Hospital and University of Alberta, Edmonton, for his critical review of the manuscript.
Reprints: Horacio Osiovich, MD, FRCPC, Neonatal Intensive Care Unit, Royal Alexandra Hospital, 10240 Kingsway Ave, Edmonton, Alberta, Canada T5H 3V9 (e-mail: osiovich{at}gpu.srv.ualberta.ca).
From the Neonatal Intensive Care Unit, Royal Alexandra Hospital; and the Department of Pediatrics, University of Alberta, Edmonton.
REFERENCES
1. Gladstone IM, Ehrenkrantz RA, Edberg SC, Baltimore RS. A ten-year review of neonatal sepsis and comparison with the previous fifty-year experience. Pediatr Infect Dis J. 1990;9:819-825.
WEB OF SCIENCE
| PUBMED
2. Hill H. Host defences in the neonate: prospects for enhancement. Semin Perinatol. 1985;9:2-11.
WEB OF SCIENCE
| PUBMED
3. Keonig J, Christensen RD. Incidence, neutrophil kinetics, and natural history of neonatal neutropenia associated with maternal hypertension. N Engl J Med. 1989;321:557-562.
WEB OF SCIENCE
| PUBMED
4. Doron M, Maklouf R, Katz V, Lawson E, Stiles A. Increased incidence of sepsis at birth in neutropenic infants of mothers with preeclampsia. J Pediatr. 1994;125:452-458.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
5. Rodwell RL, Faims PHD, Taylor KMCD, Tudehope DI, Gray PH. Hematologic scoring system in early diagnosis of sepsis in neutropenic newborns. Pediatr Infect Dis J. 1993;12:372-376.
WEB OF SCIENCE
| PUBMED
6. Wolach B. Neonatal sepsis: pathogenesis and supportive therapy. Semin Perinatol. 1997;21:28-38.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
7. Fanaroff AA, Korones SB, Wright CL, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants: the National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J. 1998;17:593-598.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
8. Mathur NB, Singh A, Sharma VK, Satyanarayana L. Evaluation of risk factors for neonatal sepsis. Indian Pediatr. 1996;33:817-822.
PUBMED
9. Cairo M. Granulocyte transfusions in neonates with presumed sepsis. Pediatrics. 1987;80:738-740.
FREE FULL TEXT
10. Fanaroff AA, Korones SB, Wright L, et al. A controlled trial of intravenous immunoglobulin to reduce nosocomial infections in very low-birth-weight infants. N Engl J Med. 1994;330:1407-1413.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
11. Souza LM, Boone TC, Gabrilove J, et al. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986;232:61-65.
FREE FULL TEXT
12. Morstyn G, Campbell L, Souza LM, et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet. 1988;1:667-672.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
13. Christensen RD. Developmental granulopoiesis. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1998:1753-1761.
14. Athens JW, Raab SO, Haab OP, et al. Leukokinetic studies, III: the distribution of granulocytes in the blood of normal subjects. J Clin Invest. 1961;40:159-164.
WEB OF SCIENCE
| PUBMED
15. Cairo MS. Review of G-CSF and GM-CSF: effect on neonatal neutrophil kinetics. Am J Pediatr Hematol Oncol. 1989;11:238-244.
WEB OF SCIENCE
| PUBMED
16. Christensen RD, Rothstein G. Pitfills in the interpretation of leukocyte counts of newborn infants. Am J Clin Pathol. 1979;72:608-611.
WEB OF SCIENCE
| PUBMED
17. Bishop CR, Rothstein G, Ashenbrucker HE, Athens JW. Leukokinetic studies, XIV: blood neutrophil kinetics in chronic steady state neutropenia. J Clin Invest. 1971;50:1678-1689.
WEB OF SCIENCE
| PUBMED
18. Sola M, Christensen RD. Use of hematopoietic growth factors in the neonatal intensive care unit. J Intensive Care Med. 1997;12:187-205.
FULL TEXT
19. Ohls RK, Li Y, Abdel-Mageed A, et al. Neutrophil pool sizes and granulocyte colony-stimulating factor production in human mid-trimester fetuses. Pediatr Res. 1995;37:806-811.
WEB OF SCIENCE
| PUBMED
20. Thomas DB, Yoffey JM. Human fetal hematopoiesis, I: the cellular composition of fetal blood. Br J Hematol. 1962;8:290-295.
PUBMED
21. Playfair JHL, Wolfendale MR, Kay HEM. The leukocytes of peripheral blood in the human fetus. Br J Hematol. 1963;9:336-344.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
22. Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease, I: reference values for neutrophilic cells. J Pediatr. 1979;95:89-98.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
23. Mouzinho A, Rosenfeld CR, Sanchez PJ, Risser R. Revised reference ranges for circulating neutrophils in very low-birth-weight neonates. Pediatrics. 1994;94:76-82.
FREE FULL TEXT
24. Christensen RD, Macfarlane JL, Taylor NL, et al. Blood and marrow neutrophils during experimental group B streptococcal infection: quantification of the stem cell, proliferation, storage, and circulating pools. Pediatr Res. 1982;16:549-553.
WEB OF SCIENCE
| PUBMED
25. Christensen RD, Harper TE, Rothstein G. Granulocyte-macrophage progenitor cells in term and preterm neonates. J Pediatr. 1986;109:1047-1051.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
26. Weisbart RH, Gasson JC, Golde DW. Colony-stimulating factors and host defence. Ann Intern Med. 1989;110:297-303.
FREE FULL TEXT
27. Welte K, Bonilla MA, Gillio AP, et al. Recombinant human granulocyte colony-stimulating factor: effects on hematopoiesis in normal and cyclophosphamide-treated primates. J Exp Med. 1987;165:941-948.
FREE FULL TEXT
28. Nicola NA, Metcalf D, Matsumoto M, Johnson GR. Purification of a factor inducing differentiation in murine myelomonocytic leukemic cells: identification as granulocyte colony-stimulating factor (G-CSF). J Biol Chem. 1983;258:9017-9023.
FREE FULL TEXT
29. Welte K, Platzer E, Lu L, et al. Purification and biochemical characterization for human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci U S A. 1985;82:1526-1530.
FREE FULL TEXT
30. Simmers RN, Webber LM, Shannon MF, et al. Location of the G-CSF gene on chromosome 17 proximal to the breakpoint in the t(15;17) in acute promyelocytic leukemia. Blood. 1987;70:330-332.
FREE FULL TEXT
31. Bonilla MA, Gillio AP, Ruggeiro M, et al. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med. 1989;320:1574-1580.
WEB OF SCIENCE
| PUBMED
32. Kojima S, Fukuda M, Miyajima Y, Matsuyama T, Horibe K. Treatment of aplastic anemia in children with recombinant human granulocyte colony-stimulating factor. Blood. 1991;77:937-941.
FREE FULL TEXT
33. Pui CH, Boyett JM, Hughes WT, et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med. 1997;336:1781-1787.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
34. Donadieu J, Boutard P, Bernatowska E, et al. A European phase II study of recombinant human granulocyte colony-stimulating factor (Lenograstrim) in the treatment of severe chronic neutropenia in children: Lenograstrim Study Group. Eur J Pediatr. 1997;156:693-700.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
35. Sheridan W, Morstyn G, Wolf M, et al. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet. 1989;2:891-895.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
36. Bailie KEM, Irvine AE, Bridges JM, McGlure BG. Granulocyte and granulocyte-macrophage colony-stimulating factor in cord and maternal serum at delivery. Pediatr Res. 1994;35:164-168.
WEB OF SCIENCE
| PUBMED
37. Gessler P, Kirchmann N, Kientsch-Engel R, Haas N, Lasch P, Kachel W. Serum concentrations of granulocyte colony stimulating factor in healthy term and preterm neonates and in those with various diseases including bacterial infections. Blood. 1993;82:3177-3182.
FREE FULL TEXT
38. Schibler KR, Liechty KW, White WL, Christensen RD. Production of granulocyte colony-stimulating factor in vitro by monocytes from preterm and term neonates. Blood. 1993;82:2478-2484.
FREE FULL TEXT
39. Shimada M, Minato M, Takado M, Takahashi S, Harada K. Plasma concentrations of granulocyte-colony-stimulating factor in neonates. Acta Pediatr. 1996;85:351-355.
WEB OF SCIENCE
| PUBMED
40. Wilimas JA, Wall JE, Fairclough DL, et al. A longitudinal study of granulocyte colony-stimulating factor levels and neutrophil counts in newborn infants. J Pediatr Hematol Oncol. 1995;17:176-179.
WEB OF SCIENCE
| PUBMED
41. Cairo M, Gillan E, Buzby J, van de Ven C, Suen Y. Circulating Steel Factor (SLF) and G-CSF levels in preterm and term newborn and adult peripheral blood. Am J Pediatr Hematol Oncol. 1993;15:311-315.
WEB OF SCIENCE
| PUBMED
42. Ikeno K. Increased granulocyte-colony stimulating factor levels in neonates with perinatal complications. Acta Pediatr Jpn. 1994;36:366-370.
43. Cairo MS, Suen Y, Knoppel E, et al. Decreased G-CSF and IL-3 production and gene expression from mononuclear cells of newborn infants. Pediatr Res. 1992;31:574-578.
WEB OF SCIENCE
| PUBMED
44. Lee SM, Knoppel E, van de Ven C, Cairo MS. Transcriptional rates of granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin 3, and macrophage colony-stimulating factor genes in activated cord versus adult mononuclear cells: alteration in cytokine expression may be secondary to posttranscriptional instability. Pediatr Res. 1993;34:560-564.
WEB OF SCIENCE
| PUBMED
45. Roberts RL, Scelz CM, Scates SM, et al. Neutropenia in an extremely premature infant treated with recombinant human granulocyte colony-stimulating factor. AJDC. 1991;145:808-812.
PUBMED
46. Gillan ER, Christensen RD, Suen Y, Ellis R, van de Ven C, Cairo MS. 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. 1994;84:1427-1433.
FREE FULL TEXT
47. Bedford Russell AR, Graham Davies E, Ball SE, Gordon-Smith E. Granulocyte colony stimulating factor treatment for neonatal neutropenia. Arch Dis Child. 1995;72:F53-F54.
48. Kocherlakota P, La Gamma EF. Human granulocyte colony-stimulating factor may improve outcome attributable to neonatal sepsis complicated by neutropenia. Pediatrics [serial online]. 1997;100:1. Available at: http://www.pediatrics.org/content/full/100/1/e6. Accessed July 1997.
49. Kocherlakota P, La Gamma EF. Preliminary report: rhG-CSF may reduce the incidence of neonatal sepsis in prolonged pre-eclampsia associated neutropenia. Pediatrics. 1998;102:1107-1111.
FREE FULL TEXT
50. Makhlouf RA, Doron MW, Bose CL, Price WA, Stiles AD. Administration of granulocyte colony-stimulating factor to neutropenic low birth weight infants of mothers with preeclampsia. J Pediatr. 1995;126:454-456.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
51. La Gamma EF, Alpan O, Kocherlakota P. Effect of granulocyte colony-stimulating factor on preeclampsia-associated neonatal neutropenia. J Pediatr. 1995;126:457-459.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
52. Schibler KR, Osborne KA, Leung LY, Le TV, Baker SI, Thompson DD. A randomized, placebo-controlled trial of granulocyte colony-stimulating factor administration to newborn infants with neutropenia and clinical signs of early-onset sepsis. Pediatrics. 1998;102:6-13.
FREE FULL TEXT
53. Calhoun DA, Rosa C, Christensen RD. Transplacental passage of recombinant human granulocyte colony-stimulating factor in women with an imminent preterm delivery. Am J Obstet Gynecol. 1996;174:1306-1311.
WEB OF SCIENCE
| PUBMED
54. Nemunaitis J. Granulocyte macrophage–colony-stimulating factor: a review from preclinical development to clinical application. Transfusion. 1993;33:70-83.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
55. Cairo MS, van de Ven C, Toy C, Mauss D, Sender L. Recombinant human granulocyte-macrophage colony-stimulating factor primes neonatal granulocytes for enhanced oxidative metabolism and chemotaxis. Pediatr Res. 1989;26:395-399.
WEB OF SCIENCE
| PUBMED
56. Cairo MS, Christensen RD, Sender LS, et al. Results of a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in very low birth weight neonates: significant induction of circulatory neutrophils, monocytes, platelets, and bone marrow neutrophils. Blood. 1995;86:2509-2515.
FREE FULL TEXT
57. Cairo M, Suen T, Fanaroff A, et al. A double-blinded, randomized, placebo controlled pilot study of rhu GM-CSF in low-birth-weight neonates: preliminary results demonstrate a significant reduction in nosocomial infections with rhu GM-CSF [abstract]. Pediatr Res. 1996;39:294a.
58. Carr R, Modi N. Haematopoietic colony stimulating factors for preterm neonates. Arch Dis Child. 1997;76:F128-F133.
59. Bedford Russell AR. New modalities for treating neonatal infection. Eur J Pediatr. 1996;155(suppl):S21-S24.
60. Barak Y, Leibovitz E, Mogilner B, et al. The in vivo effect of recombinant human granulocyte colony-stimulating factor in neutropenic neonates with sepsis. Eur J Pediatr. 1997;156:643-646.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
61. Leischke GJ, Cebon J, Morstyn G. Characterization of the clinical effects after the first dose of bacterially synthesized recombinant human granulocyte-macrophage colony-stimulating factor. Blood. 1989;74:2634-2643.
FREE FULL TEXT
62. Leischke GJ, Maher D, O'Connor M, et al. Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration. Cancer Res. 1990;50:606-614.
FREE FULL TEXT
63. Bonilla MA, Dale D, Zeidler C, et al. Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor in patients with severe congenital neutropenias. Br J Hematol. 1994;88:723-730.
WEB OF SCIENCE
| PUBMED
64. Naparstek E. Granulocyte colony-stimulating factor, congenital neutropenia, and acute myeloid leukemia. N Engl J Med. 1995;333:516-518.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
65. Rosenthal J, Healey T, Ellis R, Gillan E, Cairo MS. A two-year follow-up of neonates with presumed sepsis treated with recombinant human granulocyte colony-stimulating factor during the first week of life. J Pediatr. 1996;128:135-137.
FULL TEXT
|
WEB OF SCIENCE
| PUBMED
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