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

Host defenses in the human neonate are limited by immaturity in phagocytic immunity. Such limitations seem to predispose infected newborns to neutropenia from an exhaustion of the neutrophil reserve. Among the critical defects thus far identified in neonatal phagocytic immunity is a specific reduction in the capacity of mononuclear cells to express granulocyte colony-stimulating factor (G-CSF) after stimulation. However, the safety, pharmacokinetics, and biological efficacy of administration of recombinant human (rh)G-CSF to infected human newborns to compensate for this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of age) with presumed bacterial sepsis within the first 3 days of life were randomized to receive either placebo or varying doses of rhG-CSF (1.0,5.0, or 10.0 pglkg every 24 hours 136 patients] or 5.0 or 10.0 pglkg every 12 hours [6 patients]) on days 1, 2, and 3. Complete blood counts with differential and platelet counts were obtained at hours 0,2,6,24,48,72, and 96. Circulating G-CSF concentrations were determined at hours 0,2,6, 12, 14, 16, 18,24, and 36. Tibial bone marrow aspirates were obtained after 72 hours for quantification of the bone marrow neutrophil ACTEFUAL SEPSIS occurs in 1 to 10 per 1,000 term infants and is three to four times more common in infants delivered prematurely. '. ' The mortality rate for neonates with bacterial sepsis varies between 15% and 75% depending on the virulence of the organism, associated complications, and gestational age. '33 Neutropenia commonly occurs in neonates with sepsis"6 and is associated with increased risk of deah7 The kinetic and molecular explanations for the neutropenia observed in neonates with sepsis have been the subjects of previous investigations. We previously observed quantitative deficiencies in myelopoiesis in the neonatal rat. *-" These deficiencies include a relatively small supply of granulocyte progenitor cells (colony-forming unit granulocyte-macrophage) (Cm-GM), a small neutrophil storage pool (NSP) (polymorphonuclear leukocytes, band neutrophils, and metamyelocytes), and an increased tendency to neutropenia associated with a depleted NSP during experimental sepsis. These observations suggested that new methods of treatment, which induce an increase in the neutrophil supply, might be beneficial for newborn infants with bacterial sepsis. We previously showed that there is far less granulocyte colony-stimulating factor (G-CSF) production by cells of preterm infants than term infant^,""^ and a failure to increase G-CSF mRNA expression after infection in newborn animals.I6 We also observed that administration of a single dose of recombinant human (rh)G-CSF to l-day old newborn rats induced significant neutr~philia,'~**~ whereas administration for 7 days induced neutrophilia and increased the bone marrow neutrophil storage and progenitor pools. '9 Neonatal rats inoculated with lethal doses of group B streptococcus (GBS) and a single pulse of G-CSF had a significantly higher survival rate compared with those treated with antibiotics B storage pool (NSP), neutrophil proliferative pool, granulocyte progenitors, and pluripotent progenitors. Functional activation of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or placebo administration. Intravenous rhG-CSF was not associated with any recognized acute toxicity. RhG-CSF induced a significant increase in the blood neutrophil concentration 24 hours after the 5 and 10 pglkg doses every 12 and 24 hours and it was sustained as long as 96 hours. A dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil C3bi expression was rignificantly increased at 24 hours after 10 pglkg every 24-hour dose of rhG-CSF. The half-life of rhG-CSF was 4.4 & 0.4 hours. The rhG-CSF was well tolerated at all gestational ages treated. The rhG-CSF induced a significant increase in the peripheral blood and bone marrow absolute neutrophil concentration and in C3bi expression. Future clinical trials aimed at improving the outcome of overwhelming bacterial sepsis and neutropenia in newborn infants might include the use of rhG-CSF. 0 1994 by The American Society of Hematology.