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   

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     

Treatment of chemotherapy-Induced Neutropenia in Children with Subcutaneously Administered Recombinant Human Granulocyte Colony-Stimulating Factor

Fifty-six children with various malignancies were treated subcutaneously with recombinant human granulocyte colony-stimulating factor (rhG-CSF, KRN 8601) for neutropenia induced by cancer chemotherapy. Patients the first chemotherapy without rhG-CSF (control course). In the second course, rhG-CSF was given once daily, starting 3 days after completion of identical chemotherapy (day 3) and continuing until day 12. At day 12, the white blood counts and neutrophil counts were found to be 6.8 and 30 times higher in the rhG-CSF course than in the control course (P 0001). Nadirs of white blood counts and neutrophils were significantly elevated in the rhG-CSF course (P 003 and . 0001, respectively). rhG-CSF administration shortened the neutropenic period in the majority of patients. Children tolerated the rhG-CSF administration well and we have hereby confirmed that rhG-CSF administration is useful for proceeding with chemotherapy in children with cancer.     

Sequential administration of interleukin-6 and granulocyte-colony stimulating factor in newborn rats: modulation of newborn granulopoiesis and thrombopoiesis.

During states of increased demand, neonatal host defense is characterized by dysregulation of granulopoiesis, resulting in a high incidence of neutropenia. This study investigated the modulation of neonatal rat hematopoiesis by 14-d administration of recombinant human (rh) IL-6, rh-granulocyte-colony stimulating factor (G-CSF), or sequential combination of rhIL-6 and rhG-CSF. Specifically, newborn Sprague-Dawley rats were treated with either rhIL-6 (5 micrograms/kg/d for 14 d), rhG-CSF (5 micrograms/kg/d for 14 d), rhIL-6 for 7 d followed by rhG-CSF for 7 d, PBS/BSA for 7 d followed by rhG-CSF for 7 d, or PBS/BSA for 14 d. RhIL-6 alone significantly increased the peripheral platelet count during the latter part of the 2nd wk of administration (d 13: 980 +/- 42 versus 716 +/- 23 x 10(3)/mm3) (p = less than 0.001) (mean +/- SEM). Treatment with rhIL-6 for 7 d followed by rhG-CSF significantly increased the peripheral neutrophil count compared with 7 d of PBS/BSA and 7 d of G-CSF (d 14 absolute neutrophil count 4888 +/- 12 versus 2720 +/- 317/mm3) (p = less than 0.05). Similarly, sequential rhIL-6/rhG-CSF significantly increased the d-14 bone marrow neutrophil storage pool (9873 +/- 882 versus 3564 +/- 159/mm3) (p = less than 0.005). Lastly, sequential rhIL-6/rhG-CSF induced the highest increase in bone marrow (p less than 0.01) and liver/spleen CFU-GM pool (p less than 0.001) compared with any other treatment group. These studies suggest that rhIL-6 alone is associated with a significant increase in the neonatal platelet count.(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoimmune neutropenia in infancy due to anti-NA1 antibody: detection of antibody with immunofluorescence and agglutination test

The sera from two patients with chronic neutropenia in infancy were examined for the presence of antineutrophil antibodies and their specificity against neutrophil antigen by using granulocyte indirect immunofluorescence test and microleukocyte agglutination test. In the microleukocyte agglutination test, the patients' sera reacted with neutrophils from their parents and normal unrelated donors having the neutrophil antigen NA1, but not with neutrophils from NA1- donors. After the absorption of patients' sera with NA1+ neutrophils, the antibody activity was completely abolished, resulting in the confirmation of the anti-NA1 antibody. In contrast, the granulocyte indirect immunofluorescence test showed positive reactions against both NA1+ and NA1- neutrophils, and the specificity for anti-NA1 was found in the results of the sera absorbed with NA1+ neutrophils. This suggested that the absorption experiment might be necessary to determine the specificity of the antibody for neutrophil antigen. Thus, we confirmed two cases with autoimmune neutropenia caused by anti-NA1 antibody. A combination of agglutination and immunofluorescence techniques would be recommended for investigation of neutrophil antibodies against the neutrophil-specific antigen.     

Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis

Neonatal thrombocytopenia or neutropenia may result from passive transfusion of maternally derived antibodies. Antibodies against platelet antigens are commonly associated with neonatal alloimmune thrombocytopenia (NAIT), and anti‐neutrophil antibodies are frequently identified in alloimmune neonatal neutropenia (ANN). Combined alloimmune cytopenias in the newborn are rarely reported; even fewer reports document human leukocyte antigen (HLA) antibodies as a potential cause of neonatal thrombocytopenia or neutropenia. We describe neutropenia and thrombocytopenia in a newborn associated with markedly elevated maternal HLA antibodies in the absence of anti‐neutrophil or anti‐platelet antibodies to highlight consideration of HLA antibodies in the pathogenesis of ANN and NAIT. Pediatr Blood Cancer 2009;53:97–99. © 2009 Wiley‐Liss, Inc.     

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.     

Autoimmune neutropenia of infancy

Neutrophil antibodies were demonstrated in 119 of 121 infants and young children with chronic neutropenia, establishing the diagnosis of autoimmune neutropenia of infancy. The median age at diagnosis was 8 months (range 3 to 30 months), and the female/male ratio was 6:4. Autoimmune neutropenia of infancy was manifested by recurrent fever and infection. All patients had selective neutropenia (absolute neutrophil count 0 to 500), and many had monocytosis. Fifteen of 16 patients tested failed to respond to epinephrine and hydrocortisone stimulation. Bone marrow had myeloid hyperplasia and reduced mature neutrophils. Recovery occurred in all 81 patients who passed the age of 5 years, except for one patient who is recovering at 6 1/2 years. The median age at recovery was 30 months; 95% recovered before 4 years. The estimated median duration of disease was 20 months. Neutrophil antibodies were detected early in the neutropenic phase by a combination of immunofluorescence and agglutination tests. Ten percent of these antibodies had specificity for NA1 or NA2. Ten of the 12 serum samples with a strong reaction in the flow cytometer reacted only with neutrophils. Two also reacted with an unidentified subpopulation (30%) of lymphocytes. Lymphocyte subsets were normal in 10 patients investigated, and abnormal levels of circulating immune complexes were detected in sera from 11 of 25 (44%) patients tested. Temporary remission was induced in all of eight patients who received intravenous IgG therapy. Autoimmune neutropenia of infancy is probably the most common cause of chronic neutropenia in infancy and early childhood, can be diagnosed by immunologic techniques, and requires only conservative management; spontaneous cure appears to be the rule.     

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.     

Alloimmune neonatal neutropenia

In three neonates, the diagnosis of anti-NA1 alloimmune neutropenia related to maternal immunization against fetal polymorphonuclear leukocytes (PMN) antigens was achieved by serum antibody screening and PMN phenotyping. All the children were small for date and exhibited bacterial infection within days 2-13. Neutropenia persisted until days 20-50. High-dose intravenous immunoglobulin G (IVIgG) was ineffective. In one case, NA1-negative PMN collected from a normal donor were infused because of infection after thoracic surgery and resulted in a sharp but transient increase in PMN counts with resolution of infection. The natural history and the management of alloimmune neonatal neutropenia are discussed.     

The neonatal blood count in health and disease. I. Reference values for neutrophilic cells.

Reference ranges for absolute total neutrophils/mm3, absolute immature neutrophils/mm3, and the fraction of immature to total neutrophils (I:T proportion) during the first 28 days of life are developed from 585 peripheral blood counts obtained from 304 normal neonates and 320 counts obtained from 130 neonates with perinatal complications demonstrated to have no statistically significant effect on neutrophil dynamics. Perinatal factors other than bacterial disease which significantly alter neutrophil dynamics include maternal hypertension, maternal fever prior to delivery, hemolytic disease, and periventricular hemorrhage. The predictive value of these reference ranges in identifying bacterial disease in the first week of age varies with the neutrophil factor evaluated and the clinical setting. Neutropenia in the presence of respiratory distress in the first 72 hours had an 84% likelihood of signifying bacterial disease, whereas neutropenia in the presence of asphyxia had a 68% likelihood of signifying bacterial disease. An abnormal I:T proportion had an accuracy of 82% and 61%, respectively, in the same clinical settings. Elevations of either immature or total neutrophils were less specific. Interpretation of abnormal neutrophil factors must include consideration of both infectious and noninfectious perinatal events.     

Modulation of neonatal rat myeloid kinetics resulting in peripheral neutrophilia by single pulse administration of Rh granulocyte-macrophage colony-stimulating factor and Rh granulocyte colony-stimulating factor.

Rh granulocyte-macrophage (GM) colony-stimulating factor (CSF) and rh granulocyte (G) CSF have been demonstrated to induce proliferation and maturation of myeloid stem cells and release of mature polymorphonucleocytes (PMNs) from human and animal adult bone marrows. Unfortunately, reduced bone marrow progenitor cells, neutrophil storage pool (NSP) depletion and peripheral neutropenia are characteristic of human and animal newborn bone marrows. We investigated the effect of administering intraperitoneal rhGM-CSF and rhG-CSF to Sprague-Dawley newborn rats (less than 36 h). Newborn rats treated with intraperitoneal CSF (3.0 micrograms/kg) demonstrated significant leukocytosis at 6 and 24 h: rhGM-CSF vs. control, WBC (10(3)/mm3), at 6 h, 8.0 +/- 0.5 vs 4.3 +/- 0.9 (p less than or equal to 0.003), and at 24 h, 7.7 +/- 1.7 vs. 3.8 +/- 0.2 (p less than or equal to 0.008); rhG-CSF vs. control WBC (10(3)/mm3) at 6 h, 6.6 +/- 1.2 vs 4.3 +/- 0.1 (p less than or equal to 0.03), and at 24 h, 8.1 +/- 0.2 vs. 3.75 +/- 0.2 (p less than or equal to 0.003). The absolute neutrophil count was also significantly elevated at 6 h following intraperitoneal CSF (3.0 micrograms/kg): RhGM-CSF vs. control 1,827 +/- 25 vs. 379 +/- 10 (p less than or equal to 0.001); rhG-CSF vs. control, 1,698 +/- 40 vs. 371 +/- 10.1 (p less than or equal to 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Detection and clinical evaluation of antineutrophil antibodies in neonates who had a blood transfusion or exchange transfusion

BACKGROUND: The aim of this study was to detect and investigate the clinical effects of antineutrophil antibodies in neonates who had received a blood transfusion or exchange transfusion. METHODS: Venous blood samples were drawn from 34 neonates at pretransfusion (sample 0), immediately after transfusion (sample 1), 2-3 weeks (sample 2) and 8-12 weeks (sample 3) after transfusion. Ten healthy neonates were in the control group. Antineutrophil antibodies were detected using flow cytometric assay. RESULTS: Antineutrophil antibody was detected in the sera of 20 (58.8%) neonates in the study group. Of these 20 neonates, nine had antineutrophil antibodies in serum samples 0, 1 and 2, which were probably due to the passive transfer of maternal antibodies. Nine neonates had antineutrophil antibodies in serum samples 1 and 2, which were probably due to neutrophil antibodies being present in the donor's blood. In two neonates, antineutrophil antibodies were not detected in samples 0 and 1, but appeared in sample 2, which were probably actively produced by the neonates. All of the antineutrophil antibodies disappeared in the serum samples, except in one neonate. Only one preterm newborn developed neutropenia, which resolved spontaneously in a week. The presence of antineutrophil antibody in transfused neonates was significantly higher than in non-transfused neonates. CONCLUSIONS: The presence of neutrophil specific antibodies in transfused neonates is not rare and antineutrophil antibodies may be found more often in transfused neonates compared to non-transfused neonates. The clinical significance of those antibodies needs to be assessed since they are transient and their clinical effects are not evident.     

Granulocyte colony-stimulating factor-responsive chronic neutropenia in cartilage-hair hypoplasia

: Chronic neutropenia is common in children with cartilage-hair hypoplasia (CHH). The authors describe a 6-year-old with severe CHH, moderate neutropenia associated with serum IgG antibodies directed against Fcgamma-RIIIb (NA1/2), and frequent bacterial infections. In this patient, long-term administration of granulocyte colony-stimulating factor increased peripheral neutrophil counts and prevented recurrent hospitalizations for bacterial lower respiratory tract infections.     

Recombinant human granulocyte colony-stimulating factor therapy for cyclic neutropenia associated with common variable immunodeficiency

A 14 year old boy with common variable immunodeficiency (CVID) had regularly recurring episodes of severe infections independently of the serum γ-globulin level. Serial blood counts revealed that this patient also had cyclic neutropenia. Recently, recombinant human granulocyte colony-stimulating factor (rhG-CSF) was reported to be an effective treatment for this disease. We tried rhG-CSF therapy for this patient and a prompt increase in the neutrophil count was noted. However, the cyclic alterations and duration of the nadir of the neutrophil count were not altered, which suggested that rhG-CSF has a variable efficacy in at least some patients with cyclic neutropenia.     

Use of myeloid colony-stimulating factors in neonates with septicemia

Bacterial sepsis is a major cause of neonatal morbidity and mortality. Successful management of neonatal sepsis requires early diagnosis, appropriate antimicrobial treatment, and aggressive intensive care. However, even when steps are taken appropriately, mortality rates can be high, particularly among certain subgroups, such as extremely preterm neonates and neonates with neutropenia. Multiple factors contribute to the increased susceptibility of neonates to infection, including developmental quantitative and qualitative neutrophil defects. Studies of infected animal and human neonates suggest that the use of recombinant human granulocyte colony stimulating factor (rhG-CSF) or recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) can partially counterbalance these defects and thereby reduce morbidity and mortality. However, the body of clinical evidence is currently not sufficient to recommend rhG-CSF or rhGM-CSF administration confidently as routine adjunctive treatment for neonates with sepsis.     

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.     

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.     

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.