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. Randomized trial of granulocyte transfusions versus intravenous immune globulin therapy for neonatal neutropenia and sepsis. A randomized, controlled trial of prophylactic granulocyte-macrophage colony-stimulating factor in human newborns less than 32 weeks gestation. A randomized trial of granulocyte-macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Granulocyte transfusions in neonates with bacterial infection, neutropenia, and depletion of mature marrow neutrophils. A controlled study of the efficacy of granulocyte transfusions in patients with neutropenia. A trial of recombinant human granulocyte colony stimulating factor for the treatment of very low birthweight infants with presumed sepsis and neutropenia. 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. Comparison of recombinant granulocyte colony-stimulating factor, recombinant human granulocyte-macrophage colony-stimulating factor and placebo for treatment of septic preterm infants.
The objective of this study was to investigate the effect of treatment with recombinant human granulocyte-colony stimulating factor (rhG-CSF) on the neutrophil count and function of preterm neonates with documented sepsis. For this purpose 62 preterm neonates with proven sepsis and 19 healthy preterm ones were studied. Of the 62 patients, 27 septic neonates had an absolute neutrophil count (ANC) > 5000/mm3 (group A) and were scheduled not to receive rhG-CSF and 35/62 had an ANC < 5000/mm3 (n=35) and were randomly assigned either to receive rhG-CSF (group B) or not to receive it (group C). rhG-CSF (10 microg/kg) was administered for 3 consecutive days (0, 1, 2). The ANC, plasma levels of G-CSF (ELISA), neutrophil respiratory burst activity (NRBA) and neutrophil expression of CD11a, CD11b and CD11c (flow cytometry) were measured in all septic neonates on days 0 (onset of sepsis), 1, 3 and 5 and in the healthy neonates once within the first 2 days of life. We found that on day 0, G-CSF levels of all groups of septic neonates were significantly higher than those of the healthy ones. The highest levels were observed in group A. NRBA was diminished only in groups B and C and the expression of CD11a and CD11c was reduced in all groups of septic neonates. Administration of rhG-CSF resulted in a rapid and significant increase in ANC, NRBA and CD11a, CD11b and CD11c expression that persisted throughout the follow up. CONCLUSION; The administration of granulocyte colony stimulating factor to septic neonates significantly increases the absolute granulocyte count and enhances the neutrophil respiratory burst and beta2 integrin expression. We prospectively studied newborn infants with sepsis and neutropenia who were randomly selected to receive standard supportive care and either adjuvant granulocyte transfusions or intravenous immune globulin (IVIG) infusions; 21 infants received granulocyte transfusions and 14 received IVIG infusions. Half of the patients were premature (gestational age less than or equal to 32 weeks); the average postnatal age was 5 days (range 3 to 8 days). All infants had neutropenia by the criteria of Manroe et al., and the mean average bone marrow neutrophil storage pool ranged between 35% and 37%. There were no significant differences with respect to serum IgG, IgA, IgM, and total hemolytic complement values between treatment groups or between survivors and nonsurvivors. Clinical severity as defined by hypoxia, acidosis, and hypotension was similar between treatment groups. Group B streptococcus was the most common organism identified and accounted for almost 33% of all bacterial isolates. There was a significantly different survival rate in the group receiving polymorphonuclear leukocyte transfusions (100%, 21/21) compared with the group receiving IVIG infusions (64%, 9/14; p = less than 0.03). There were no significant complications in either treatment group with respect to fluid overload, secondary infection, blood group sensitization, pulmonary complications, or graft-versus-host disease. This pilot study suggests a possible benefit of granulocyte transfusions compared with 'IVIG therapy in the adjuvant treatment of neonatal neutropenia and overwhelming bacterial sepsis. Preterm neonates undergoing intensive care have high morbidity from sepsis. These infants also frequently develop neutropenia, and when this is associated with sepsis, mortality is high. This study investigates the potential for granulocyte-macrophage colony-stimulating factor (GM-CSF) to effect a clinically relevant increase in neutrophil number when used prophylactically in high-risk preterm neonates, and assesses its safety in this population.
                In an open, randomized, controlled study, 75 neonates (25 small for gestational age) <32 weeks gestation were randomized to receive GM-CSF (10 microg/kg/d) by subcutaneous injection for 5 days from <72 hours after birth, or to a control group. The primary outcome measure was the neutrophil count during 14 days from study entry. The infants were monitored for potential toxicity. Clinical outcomes, sepsis, and mortality, were recorded, but this initial study was not designed to address clinical benefit.
                Prophylactic GM-CSF therapy completely abolished neutropenia in treated infants, when both well and septic, throughout the period of study. Neutropenia (</=1.7 x 10(9)/L) developed in 16 of 39 control infants. Five control infants experienced an acute decrease in neutrophil count coincident with the onset of sepsis. There was no evidence of hematologic, respiratory, or gastrointestinal toxicity in treated infants. Treated infants had a trend to fewer symptomatic, blood culture positive septic episodes than controls during 2 weeks from study entry (11/36 vs 18/39).
                Five-day prophylactic GM-CSF completely abolishes postnatal neutropenia and sepsis-induced neutropenia in preterm neonates at high risk of sepsis, and so removes an important risk factor for sepsis and sepsis-related mortality.GM-CSF, preterm neonates, neutropenia, sepsis. To determine whether adjunctive therapy with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) could reverse sepsis-associated neonatal neutropenia and improve neonatal survival and to assess its safety compared with conventional therapy in a control group.
                This prospective, randomized, controlled trial was performed in 60 infants with neutropenia and clinical signs of sepsis. A subcutaneous injection of rhGM-CSF (5 microgram/kg/day) was administered to 30 of the patients for 7 consecutive days. Hematologic parameters (absolute neutrophil, eosinophil, monocyte, lymphocyte counts, and platelet number) and outcome were compared with 30 conventionally treated (control) patients.
                Twenty-five patients from the GM-CSF-treated group and 24 from the conventionally treated group had early-onset sepsis (</=3 days' postnatal age), and the other 11 patients had late-onset sepsis (>3 days' postnatal age). There was no difference between groups in terms of birth weight; gestational age; gender; maturity; maternal age; and incidence of prolonged rupture of membranes, maternal hypertension, or severity of sepsis. All neonates tolerated GM-CSF well with no adverse reactions. The absolute neutrophil count on day 7 was significantly increased in the GM-CSF-treated group compared with the conventionally treated group: 8088 +/- 2822/mm(3) versus 2757 +/- 823/mm(3). The mean platelet count was significantly higher on days 14 in the GM-CSF-treated group compared with conventionally treated group: 266 867 +/- 55 102/mm(3) versus 229 200 +/- 52 317/mm(3). Hematologic parameters were otherwise similar between groups before treatment and on day 28. Twenty-seven neonates in the rh-GMCSF group and 21 in the control group survived to hospital discharge. The mortality rate in the rhGM-CSF group (10%) was significantly lower than in the conventionally treated group (30%).
                Treatment with rhGM-CSF is associated with an increase in absolute neutrophil, eosinophil, monocyte, lymphocyte, and platelet counts and decreased mortality in critically ill septic neutropenic neonates. These results suggest that rhGM-CSF may be effective in the treatment of neonatal sepsis with neutropenia, and further randomized trials are needed to confirm its beneficial effects. During a three-year period, 26 neonates with bacterial infection and neutropenia were studied. In order to assess the marrow neutrophil reserves, bone marrow aspirates were obtained from each of these patients. The neutrophil storage pool (percent polymorphonuclear + band neutrophils + metamyelocytes in 1,000 nucleated marrow cells) was significantly greater in those who survived their infection (mean = 20.1%, range 3.2% to 60.8%) than in those who died (mean = 1.9%, range 0.4% to 5.2%, P less than .002). In an attempt to improve survival in this group, seven neutrophil-depleted patients with sepsis were given granulocyte transfusions and all survived. In contrast only one of nine nontransfused and all survived. In contrast only one of nine nontransfused, neutrophil-depleted infants with sepsis survived (P less than .01). The seven granulocyte recipients were examined for possible adverse effects of the transfusions and none were detected. It is suggested that infected, neutropenic neonates with depletion of mature marrow neutrophils are at high risk for death from sepsis, and that these infants may benefit from granulocyte transfusion therapy. A randomized clinical trial to determine the efficacy of granulocyte transfusions in neutropenic patients with infection was conducted. Criteria for patient selection included a proved infection, a granulocyte count of less than 300/mm3, availability of a suitable donor and failure to respond to at least 72 horus of appropriate antibiotic therapy. Thirty patients were assigned at random to receive either granulocyte transfusions or to serve as a control group. Antibiotic therapy was continued in both groups. Responses were judged by the degree of diminution of infectious episodes and survival. The results showed that 11 of 13 control patients failed to respond during the period of observation, whereas 10 of 17 patients given transfusions responded. The results were statistically significantly different (p less than 0.05). The median survival was 22.5 days in the group given transfusions (group 2) and 7.7 in the control group (group 1) (p less than 0.01). The granulocyte transfusions were most effective in patients with hypocellular marrows who failed to recover during the period of observation. These results indicate that granulocyte transfusions are effective in the short-term control of infections in neutropenic patients. The primary objective was to investigate the safety of recombinant human granulocyte colony stimulating factor (rhG-CSF) for the treatment of very low birthweight infants (VLBW) with sepsis and relative neutropenia, specifically with regard to worsening of respiratory distress and thrombocytopenia and all cause mortality. Secondary objectives were to evaluate duration of ventilation, intensive care, and antibiotic use as markers of efficacy.
                Neonates (< or = 28 days) in intensive care, with birth weights of 500-1500 g, absolute neutrophil count (ANC) of < or = 5 x 10(9)/l, and clinical evidence of sepsis, were randomly assigned to receive either rhG-CSF (10 microg/kg/day) administered intravenously (n = 13), or placebo (n = 15) for a maximum of 14 days, in addition to standard treatment and antibiotics. All adverse events, oxygenation index, incidence of thrombocytopenia, all cause mortality, duration of ventilation, intensive care and antibiotic treatment, and ANC recovery were compared between the two groups.
                Adverse events and oxygenation index were not increased by, and thrombocytopenia was not attributable to, treatment with rhG-CSF. At 6 and 12 months postmenstrual age, there were significantly fewer deaths in the group receiving rhG-CSF (1/13 v 7/15; p < or = 0.038). There was a non-significant trend towards a reduction in duration of ventilation, intensive care, and antibiotic use in the rhG-CSF group. There was a significantly more rapid increase in ANC in the rhG-CSF treated babies (p < 0.001).
                In a small randomised placebo controlled trial in a highly selected group of neonates, adjuvant treatment with rhG-CSF increased ANC rapidly, and no treatment related adverse events were identified. Mortality at 6 and 12 months postmenstrual age was significantly lower in the treatment group. A large trial investigating efficacy in a similar group of neonates is warranted. We performed a randomized, double-masked, parallel-groups, placebo-controlled trial of recombinant granulocyte colony-stimulating factor (rG-CSF) administration to 44 preterm neonates who had blood cultures obtained and antibiotics begun because of the clinical diagnosis of early-onset sepsis. Two primary outcome variables were tested 1) mortality and 2) development of nosocomial infections over the 2-week period after dosing.
                The treatment group (n = 22) received 10 microgram/kg/day of intravenous rG-CSF once daily for 3 days and the placebo group (n = 22) received the same volume of a visually indistinguishable vehicle. Mortality and culture-proven nosocomial infections were recorded. Immediately before the first, second, and third doses, and again 10 days after the first dose, serum concentrations were determined for tumor necrosis factor-alpha, interleukin 6, granulocyte-macrophage colony stimulating factor, and G-CSF, and blood leukocyte counts, absolute neutrophil counts, immature/total neutrophil ratios, platelet counts, and hemoglobin concentrations were measured.
                The treatment and placebo groups were of similar gestational age (29 +/- 3 vs 31 +/- 3 weeks) and birth weight (1376 +/- 491 vs 1404 +/- 508 g), and had similar Apgar scores and 24-hour Score for Neonatal Acute Physiology scores. The mortality rate was not different between treatment and placebo groups. However, the occurrence of a subsequent nosocomial infection was lower in the rG-CSF recipients (relative risk:.19; 95% confidence interval:.05-.78). rG-CSF treatment did not alter the serum concentrations of the cytokines measured (except for G-CSF). Serum G-CSF levels and blood neutrophil counts were higher in the treatment than in the placebo group 24 hours and 48 hours after dosing.
                Administration of 3 daily doses of rG-CSF (10 microgram/kg/day) to premature neonates with the clinical diagnosis of early-onset sepsis did not improve mortality but was associated with acquiring fewer nosocomial infections over the subsequent 2 weeks. To reduce morbidity and mortality adjuvant cytokine therapy was administered to septic neonates with variable results. The objective of this case series was to compare the effectiveness of recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) and recombinant granulocyte colony-stimulating factor (rG-CSF) with that of placebo in correcting neutropenia induced by sepsis.
                Symptomatic, septic premature neonates with or without a positive blood culture were eligible. Twenty-eight patients were randomized: 10 received rG-CSF (5 microg/kg/dose i.v. twice a day); 10 received rhuGM-CSF (4 microg/kg/dose i.v. twice a day) and 8 received placebo for a maximum of 7 days, or until an absolute neutrophil count (ANC) of 10,000 cells/mm was reached.
                A significant increase in the ANC above the baseline was present on Day 2 in the rG-CSF group (P = 0.015) and on Day 5 in the rhuGM-CSF (P = 0.002) and placebo (P = 0.027) groups. The ANC of the rG-CSF group was significantly above that in the rhuGM-CSF and placebo groups on Day 7 (P = 0.03). Mortality and neonatal intensive care unit morbidity was not significantly different between the groups.
                The neutrophil count in the rG-CSF-treated group increased significantly faster than that in the placebo or rhuGM-CSF group.
Currently, there is inconclusive evidence from randomised controlled trials (RCTs) to support or refute the routine use of granulocyte transfusions in neutropenic, septic neonates. Researchers are encouraged to conduct adequately powered multi-centre trials of granulocyte transfusions in neutropenic septic neonates.