Granulocyte macrophage-colony stimulating factor (GM-CSF) in neonatal neutropenia

Neutropenia in neonates is often associated with sepsis, prematurity and maternal hypertension with increased risk of mortality. We describe two neonates with neutropenia treated with granulocyte macrophage colony stimulating factor. The total and absolute neutrophil counts showed a marked response and led to a favourable outcome. Human granulocyte macrophage colony stimulating factor may be used as an adjuvant therapy for neonatal neutropenia of different aetiologies.     

A trial of recombinant human granulocyte colony stimulating factor for the treatment of very low birthweight infants with presumed sepsis and neutropenia

OBJECTIVES: 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. DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.     

Administration of recombinant human granulocyte-colony stimulating factor to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and β2 integrin expression Results of a randomized controlled trial

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 μg/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 β₂ integrin expression. Received: 25 March 1997 and in revised form: 5 August 1997 / Accepted: 14 October 1997     

新生儿败血症的免疫及辅助治疗进展

尽管有合理的抗生素治疗,新生儿败血症发病率和病死率仍很高.免疫及辅助疗法已成为能减少新生儿败血症发病率和病死率的一种有效治疗方法.该文对新生儿败血症时应用静脉注射免疫球蛋白、集落刺激因子、微生态制剂、谷氨酰胺、重组人蛋白C、乳铁蛋白和黄嘌呤衍生物等的最新临床试验进行综述.     

Myeloid colony-stimulating factors: use in the newborn.

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.     

Failure of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in a patient with Kostmann syndrome

We present a seven-month-old boy referred to our hospital with a history of recurrent suppurative infections starting in his neonatal period. Anemia, absolute neutropenia absolute neutrophil count (ANC: 500 cells/microl), pneumonia, purulent otitis media and maturational arrest of granulocytes at promyelocyte-myelocyte level in bone marrow were detected on his admission. He was diagnosed as Kostmann syndrome and recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy was started at a dose of 10 microg/kg/d, gradually increasing up to 120 microg/kg/d in sequential seven-day courses. As there was no response, rhG-CSF was stopped and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was started subcutaneously with 2.5 microg/kg/d and was escalated by doubling the dose every seven days to 20 mg/kg/d. By this therapy absolute neutrophil count (ANC) transiently reached above 500 cells/microl, but eosinophilia developed with a total white cell count of 88.200 cells/microl, and a differential count showing 86 percent eosinophils. Since eosinophilia of this magnitude has deleterious effects, and neutrophil production did not significantly increase, we tried combined therapy with rhG-CSF and rhGM-CSF at doses of 10-20 microg/kg/d and 5-10 microg/kg/d, respectively, without any effect on absolute neutrophil count. The patient succumbed from sepsis eight months after the diagnosis.     

白血病患儿重组粒细胞集落刺激因子血药浓度监测及临床意义

目的研究急性白血病患儿反复应用重组粒细胞集落刺激因子(rhG-CsF)的药代动力学及其与临床的关系。方法应用酶联免疫吸附测定(ELIsA)方法检测46例白血病患儿的血清G-CSF浓度。结果获得29例患儿用rgG-CSF后的标本,其血清G-CSF浓度为(5.335±5.597)μg/L。反复应用rhG-CSF的患儿在下次用药前血清G-CSF水平恢复正常;少数未应用rgG-CSF患儿可检测到较高浓度的G-CsF。血清G-CSF浓度与粒细胞绝对计数值呈负相关(r=-0.8746,P＜0.01)。结论rhG-CSF的药代动力学中存在有粒细胞介导的清除机制,反复应用无药物蓄积作用。     

Prophylactic or simultaneous administration of recombinant human granulocyte colony stimulating factor in the treatment of group B streptococcal sepsis in neonatal rats.

Despite the emergence of newer antibiotic treatments, group B streptococcal infection still carries a high mortality rate in the newborn and is characterized by reduced neutrophil proliferative pools, neutrophil storage pools, neutropenia, and polymorphonuclear cell dysfunction. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) has recently been demonstrated to induce neutrophilia and modulate neutrophil proliferative pools and neutrophil storage pools in the newborn rat. We therefore investigated the adjuvant effect of rhG-CSF given to group B streptococcus (GBS) septic Sprague-Dawley newborn (less than 36 h) rats treated with and without antibiotic therapy. After inoculation of GBS, a GBS survival curve established the LD50 at 50 h to be approximately 3 X 10(6) organisms/gm. Newborn rats were divided into four treatment groups after GBS inoculation. rhG-CSF was administered at the same time as GBS inoculation. At 24 h, there was approximately 100% survival in all groups. However, by 72 h after GBS inoculation, there was a significant difference in survival. Group 1, PBS/Alb, had a survival rate of 4%; group 2, rhG-CSF, 9%; group 3, antibiotics, 28%; and group 4, antibiotics plus rhG-CSF, 91% (p less than or equal to 0.001). Additionally, when rhG-CSF was administered prophylactically (6 h before GBS), a similar significant synergistic effect in survival was demonstrated with granulocyte colony stimulating factor plus antibiotics versus antibiotics alone (70 versus 10%) (p less than or equal to 0.01). These preliminary data suggest that either simultaneous or prophylactic pulse administration of rhG-CSF may have a synergistic and protective effect on survival in antibiotic-treated experimental GBS in the neonatal rat.     

Assessing the efficacy of the recombinant human granulocyte colony-stimulating factor "rhG-CSF" in the treatment of early neonatal sepsis in premature neonates

OBJECTIVE: To evaluate the efficacy of the recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the treatment of early-onset neonatal sepsis among premature infants.MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled trial was performed among forty-four preterm neonates who had "clinical diagnosis" of early-onset sepsis. The treatment group (n=22) received 10 micro g/kg/d of rhG-CSF, IV once daily for three consecutive days, and the placebo group (n=22) received the same volume of a visually-indistinguishable vehicle. Prior to the first dose, and prior to the second and third doses, and again 10 days after the first dose, we measured tumor necrosis factor-a, interleukin-6, granulocyte-macrophagocyte colony-stimulating factor, G-CSF, leukocyte count, absolute neutrophil count, immature/total neutrophil ratio, platelet count, and hemoglobin concentration. A bone marrow aspiration was performed seven days after the first dose, and both the neutrophil storage pool (NSP) percent and the NSP/NPP (neutrophil proliferative pool) ratios were tabulated.RESULTS: The treatment and placebo groups were of similar gestational age (29-/+ 3 vs 31-/+ 3 weeks) and birth weight (1376 -/+ 491 vs 1404 -/+ 508 grams). They had similar Apgar scores and 24 hour SNAP scores. No deaths occurred during the first week of life among the treatment group while three deaths occurred in the placebo group. RhG-CSF treatment did not alter the serum concentrations of the cytokines measured (except for G-CSF). Serum G-CSF levels, blood leukocyte counts, absolute neutrophil counts, NSP percentages, and NSP/NPP ratios were higher in the treatment group 24 hours and 72 hours after dosing. The occurrence of a subsequent infection over the two week period following dosing was significantly lower in the treatment group (n=2) than in the placebo group (n=9; p<0.02, RR 0.19 [0.05-0.78]). The overall mortality rate during the entire hospitalization was not different between treatment and placebo groups.CONCLUSIONS: Administration of rhG-CSF to premature neonates with the clinical diagnosis of early-onset sepsis was associated with lower incidence of nosocomial infection over the ensuing three weeks period, but it did not change the overall mortality rate.     

Transient effect of granulocyte colony-stimulating factor in allo-immune neonatal neutropenia

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration at 10 microg/kg/day for 15-30 min over 3 consecutive days in 3 preterm neonates with allo-immune neonatal neutropenia (ANN) is reported. Patients 1 and 2 had antibodies against antigen NA2, while patient 3 had antibodies against NA1. All neonates developed a rapid increase in absolute neutrophil count which reached the normal range within 48 h (from 75-640/mm(3) to 2,520-4,700/mm(3)). However, 23-25 days later, all 3 neonates relapsed into a second phase of severe neutropenia (408-870/mm(3)). Antibodies against neutrophil antigens were still positive during this period. This second-phase neutropenia persisted for 20-30 days and resolved spontaneously. It may be possible that when rhG-CSF is administered within a short time after birth in neonates with ANN, its effect is exhausted before the concentration of circulating antibodies decreases, with the result that a second phase of neutropenia can be expected.     

Modulation of neonatal myelopoiesis in newborn rats after 7 days' administration of either granulocyte-monocyte colony stimulating factor or interleukin-3

Single-pulse administration of either recombinant human granulocyte-monocyte colony stimulating factor or recombinant human granulocyte colony stimulating factor to newborn rats has previously been demonstrated to increase the peripheral neutrophil count and modulate bone marrow (BM) neutrophil pools. In our present study, we investigated the effects of 7 d of either recombinant murine granulocyte-monocyte colony stimulating factor (rmGM-CSF) (75 micrograms/kg/d) or recombinant murine IL-3 (rm IL-3) (10 micrograms/kg/d) on newborn rat myelopoiesis. Sprague Dawley newborn rats (greater than or equal to 24 h) were injected (intraperitoneally) daily for 7 d with either rmGM-CSF, rmIL-3, or PBS/BSA. rmGM-CSF induced a significant increase in the peripheral neutrophil count on d 3 (p less than 0.03) and d 7 (p less than 0.001) (75% increase). Additionally, rmGM-CSF induced a 50% increase in the BM neutrophil storage pool (p less than 0.025). rmIL-3 increased the BM colony forming unit-granulocyte monocyte pool (p less than 0.001); however, it failed to increase the peripheral neutrophil count or BM neutrophil storage pool. Neither CSF increased the BM neutrophil proliferative pool or BM colony forming unit-granulocyte monocyte proliferative rate. Additionally, 7 d of rmGM-CSF with or without antibiotics did not synergistically alter the mortality rate after group B streptococcol inoculation. This study suggests that rmIL-3 appears to stimulate more neonatal myeloid committed progenitor cell activity compared with rmGM-CSF. Optimal modulation of neonatal myelopoiesis may require the use of a sequential combination of hematopoietic CSF, namely an early-acting CSF followed by a more lineage myeloid-specific CSF.     

Recombinant human granulocyte colony-stimulating factor in preterm neonates with sepsis and relative neutropenia: a randomized, single-blind, non-placebo-controlled trial

We performed a prospective, randomized, single-blind, non-placebo-controlled trial on preterm (<37 weeks) neonates (birth weight <2000g) with sepsis and absolute neutrophil counts (ANC) <5000?cells?mm(-3) to study the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on all-cause-neonatal mortality and hematological parameters (total leucocyte (TLC, ANC, absolute monocyte and absolute platelet counts). The rhG-CSF group (n?=?20) received 10?μg/kg/day of intravenous infusion of rhG-CSF once daily for 5 days along with conventional therapy, and the control group (n?=?20) received conventional therapy alone. Hematological parameters on Days 0, 1, 3, 5, 7 and 14 of study entry and all-cause mortality rates at discharge were recorded. Baseline characteristics between the rhG-CSF and control group including mean birth weight (1395?±?289 vs. 1500?±?231g), mean gestational age (31.5?±?2.68 vs. 32.6?±?2.23 weeks), initial neonatal complaints and maternal characteristics were comparable. Mortality rates were significantly less among the rhG-CSF group (3/20 (15%) vs. 7/20 (35%), p?5000?cells?mm(-3) faster in the rhG-CSF group, with 80% babies having ANC >5000?cells?mm(-3) by Day 7 of study entry compared with 35% in the control group (p?相似文献   

Recombinant granulocyte colony-stimulating factor administered enterally to neonates is not absorbed

Granulocyte colony-stimulating factor (G-CSF) is present in liquids swallowed by the fetus and neonate; specifically, amniotic fluid, colostrum, and human milk. The swallowed G-CSF has local effects on enteric cells, which express the G-CSF receptor. However, some portion of the G-CSF ingested by the fetus and neonate might be absorbed into the circulation and have systemic actions, such as stimulating neutrophil production. To assess this possibility we sought to determine if circulating G-CSF concentrations of neonates increase after enteral administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). This was a single-center, prospective, blinded, randomized, 2 x 2 crossover study, with each infant receiving 1 dose of rhG-CSF (100 microg/kg) and 1 dose of placebo. Plasma G-CSF concentrations were measured at 2 and 4 hours after administration of the test solution. No significant change in plasma G-CSF concentration was observed after the enteral administration of rhG-CSF. On this basis, we conclude that orally administered rhG-CSF is not absorbed in significant quantities, and we speculate that the G-CSF swallowed by the fetus and neonate has local but not systemic effects.     

In vivo effect of recombinant human granulocyte colony-stimulating factor on phagocytic function and oxidative burst activity in septic neutropenic neonates

Neutrophil dysfunction may contribute to an increased risk of sepsis in very-low-birth-weight (VLBW) neonates. The current study was designed to determine whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) affects absolute neutrophil count (ANC), phagocytic function, and oxidative burst in neutropenic VLBW neonates. Fourteen ventilated VLBW neonates were treated with rhG-CSF (10 microg/kg/day x 3 days i.v.). Phagocytic activity and oxidative burst were assessed before and after treatment with rhG-CSF using flow cytometry and fluorescence labeled opsonized Staphylococcus aureus. Control (nonseptic, nonneutropenic, n = 4), preeclamptic neutropenic (PET; nonseptic, n = 5), and septic neutropenic (n = 5) neonates with a gestational age ranging from 24 to 30 weeks were studied. In both PET and septic neonates, posttreatment phagocytosis more than doubled, but did not achieve matching control levels, whereas rhG-CSF treatment maintained the level of the phagocytic activity in the control group. The oxidative burst increased in all groups, but, again, PET and septic groups did not achieve matching control values. These effects occurred independent of a 2- to 12-fold increase in ANC. These results suggest that other disease-specific factors delay full functional recovery even after rhG-CSF treatment. We speculate that PET and septic neonates may remain susceptible to infection due to deficient neutrophil-killing capacity, even though their ANC returns to normal ranges. Augmenting immune function beyond the immediate period of ANC recovery suggests that prophylaxis with rhG-CSF may be an important risk reduction strategy for susceptible VLBW neonates.     

Immunomodulation, part II: granulocyte colony-stimulating factors

Although rhG-CSF and rhGM-CSF appear to have no adverse side effects, their usefulness in treating and preventing sepsis in preterm infants remains uncertain. Adequately powered, random, controlled clinical trials of neutropenic infants are needed to further evaluate efficacy of these agents as adjuncts to antibiotic therapy. Carr and associates assert that available data do not support further study of rhG-CSF and rhGM-CSF in septic infants who are not neutropenic. A United Kingdom study of the efficacy of prophylactic GM-CSF in reducing systemic infection or mortality in infants at high risk for postnatal neutropenia is underway. No plans exist for a long-term follow-up study, however. Because infection has the potential to cause both short-term mortality and long-term neurologic disability, it is recommended that all future studies include long-term neurologic and neurodevelopmental follow-up. The next part of this series will explore the use of intravenous immunoglobulins to prevent and treat neonatal sepsis.     

Neonatal neutropenia: what diagnostic evaluation is needed and when is treatment recommended?

Neutropenia is a relatively frequent finding in the neonatal intensive care unit, particularly in very low birth weight neonates during the first week of life. Healthy term and preterm neonates have blood neutrophil counts within the same basic range as adults, but their neutrophil function, and their neutrophil kinetics during infection, differ considerably from those of adults. Neutrophil function of neonates, particularly preterm neonates, is less robust than that of adults and might also contribute to the increase in propensity to infection. In premature infants, early-onset neutropenia is correlated with sepsis, maternal hypertension, intrauterine growth restriction, severe asphyxia, and periventricular haemorrhage, and might be associated with an increase in the incidence of early-onset sepsis, nosocomial infection, and Candida colonisation. Some varieties of neutropenia in the NICU are very common and others are extremely rare. The most common causes of neutropenia in the NICU have an underlying cause that is often evident, and require little diagnostic evaluation. Unlike, persistent neutropenia should prompt evaluation even if it is of moderate severity. The laboratory tests to consider are those that provide a specific diagnosis. The first tests that should be ordered are a blood film, a complete blood count on the mother, and, if her blood neutrophil concentration is normal, maternal neutrophil antigen typing and an anti-neutrophil antibody screen. A bone marrow biopsy can be useful in cases with prolonged, unusual, or refractory neutropenia. Various treatments have been proposed as means of enhancing neutrophil production and function in preterm infants. Both recombinant granulocyte stimulating factor and recombinant granulocyte macrophage-colony-stimulating factor have been tried with variable success. Intravenous immunoglobulin, corticosteroids, granulocyte transfusions, and gamma interferon did not show a clear adequate beneficial role for the therapy of neonatal neutropenia.     

Stimulation of fetal granulopoiesis by intrauterine injection of recombinant human granulocyte colony- stimulating factor into rat fetuses.

The small neutrophil reserve and exaggerated release of stored neutrophils are factors which predispose neonates to neutrophil reserve exhaustion during bacterial sepsis. Our objective is to try to improve in utero the myelopoietic function of the fetus before delivery. In the first series, recombinant human (rh) granulocyte colony-stimulating factor (G-CSF) (rhG-CSF; 100 microg/kg) was injected subcutaneously into rat fetuses at the indicated times to assess drug absorption and fetal response. In the second series, rhG-CSF (100 microg/kg) or saline (control) was injected into the fetuses once every other day to investigate the effect of repeated injections of rhG-CSF on enhancing fetal myelopoiesis preceding birth. Delivery was performed by cesarean section on embryonic day 21. The plasma concentration of G-CSF was determined by ELISA. The effect of rhG-CSF injection on granulopoiesis was assessed by measurement of the neutrophil count in the fetal peripheral blood and by histological examination of the fetal bone marrow, spleen, and liver. Fetally administered rhG-CSF enhanced fetal myelopoiesis preceding birth.     

Comparison of recombinant granulocyte colony-stimulating factor,recombinant human granulocyte-macrophage colony-stimulating factor and placebo for treatment of septic preterm infants

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The neutrophil count in the rG-CSF-treated group increased significantly faster than that in the placebo or rhuGM-CSF group.     

Concentrations of granulocyte colony-stimulating factor in human milk after in vitro simulations of digestion

Human milk contains proteins that survive digestion in the neonatal gastrointestinal tract. Our group and others have reported that granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine that influences neutrophil proliferation and differentiation, is present in human milk. We also reported that specific receptors for G-CSF are expressed on the villous enterocytes of neonates. However, the physiologic role of milk-borne G-CSF is not known. Thus, we sought to evaluate the capacity of human milk to protect G-CSF against proteolytic degradation after exposure to gastric secretions obtained from preterm (PT) and term (T) neonates at pH concentrations of 3.2, 5.8, and 7.4. Specifically, we examined degradation of 1) endogenous G-CSF in PT (n = 15) and T (n = 15) human milk; 2) recombinant human G-CSF (rhG-CSF) added to a protein-free buffer (n = 10, 5 PT and 5 T); and 3) rhG-CSF added to human milk (n = 12, 6 PT and 6 T), various commercially prepared infant formulas (n = 15), and cow's milk (n = 5). Endogenous G-CSF and rhG-CSF added to human milk resisted degradation at 1 and 2 h. However, when rhG-CSF was added to commercial formulas, >95% was degraded at 1 and 2 h at each pH level. Similarly, approximately 60% of rhG-CSF added to cow's milk was degraded at I and 2 h. We conclude that 1) endogenous G-CSF and rhG-CSF added to human milk are protected from degradation after exposure to gastric secretions at physiologic pH levels, 2) rhG-CSF added to infant formulas is not protected from degradation, and 3) it is likely that the G-CSF present in human milk is biologically available to the neonate.     

Rebirth of granulocyte transfusions: should it involve pediatric oncology and transplant patients?

Several methodologic advances, particularly use of recombinant granulocyte colony stimulating factor to stimulate donors, have made it possible to collect extraordinarily large numbers of normal neutrophils for transfusion into neutropenic patients with life-threatening infections. Because larger doses of neutrophils can be transfused, renewed interest has arisen in the use of neutrophil (granulocyte) transfusions to treat adult oncology patients and progenitor cell transplant recipients, in whom neutropenia complicated by severe infections persists as a significant problem, despite combination antibiotic therapy, recombinant cytokines, myeloid growth factors, and use of mobilized peripheral blood progenitor cells. In this commentary, consideration is given as to whether pediatric oncology and transplant patients might benefit from modern granulocyte transfusion therapy. If children are found to experience significant morbidity or mortality from neutropenic infections despite modern supportive care, it is logical to explore the efficacy, potential toxicity, and cost-effectiveness of granulocyte transfusion therapy by properly designed, randomized clinical trials.