Colony stimulating factors as adjunctive therapy in neonatal sepsis
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《美国医学杂志》
Department of Paediatrics, Pt . BD Sharma, Post Graduate Institute of Medical Sciences, Rohtak, India
Compared to adults, the unique susceptibility of neonates to sepsis associated neutropenia is due to a smaller neutrophil storage pool, a reduced capacity for neutrophil mobilization from bone marrow reserves and a slower regeneration of neutrophils in the bone marrow.[1] Additionally, neutrophil abnormalities like impairment of chemotaxis, adherence, deformability, polarization, superoxide anion generation and bacterial killing etc may exist and predispose the neonates to an impaired immune response during overwhelming bacterial sepsis.[2],[3]
Proliferation and differentiation of myeloid progenitor cells is controlled by a family of hematopoietic growth factors called colony stimulating factors (CSF). Four CSFsGranulocyte CSF (G-CSF), Granulocyte Monocyte CSF (GM-CSF), Monocyte CSF (M-CSF) and interleukin-3 have been isolated and characterized. However only G-CSF and GM-CSF are available commercially and have gained access into daily clinical routine. G-CSF has been shown to specially promote granulocyte development and maturation by stimulating myeloid progenitor proliferation, increasing bone marrow neutrophil storage pool, including peripheral neutrophilia and enhancing mature neutrophil effector functions. GM-CSF, on the other hand, acts on multiple cell lineages such as macrophages, eosinophils and on neutrophils.[4] Also GM-CSF seems to be more potent than G-CSF in neutrophil cell chemotaxis. GM-CSF and G-CSF gene expression is significantly decreased in neonates.[5]
The first report of G-CSF administration to a 654g SGA neonate with persistent neutropenia and multiple episodes of neonatal sepsis was published 10 years ago.[6] Since then a number of clinical studies have demonstrated the role of colony stimulating factors' application in neonates.
Initial evaluation of rhGM-CSF or rhG-CSF use were largely phase I/II type trials that sought to identify any clinical side effects while establishing a proper dosing range for newborns. Several of these trials revealed that G-CSF and GMCSF were safe and effectively increased ANC in septic neonates with neutropenia.[5],[7],[8],[9]
Kocherlakota et al[9] administered an I/Vinfusion of rhG-CSF (10mg/Kg/d for 3 days) to 14 septic neutropenic neonates. Results were compared with a conventional therapy group. Absolute Neutrophil Count (ANC) was significantly increased to more than baseline in rhG-CSF treated group. Thirteen patients of the 14 in the treated group and 5 of the conventionally treated group survived to 28 days after the onset of sepsis. The same authors in yet another study demonstrated that GCSF administration decreased the incidence of neonatal sepsis in critically ill ventillated neonates with preclampsia associated neutropenia [10]
Russel et al[11] studied 28 neonates with birth weight of 500-1500 grams, ANC ￡5000/cmm and clinical evidence of sepsis. They were randomly assigned to receive either rhG-CSF (10mg/Kg/d)I/V (n=13) or placebo (n=15) for a maximum of 14 days. There was a significantly more rapid increase in ANC in rhG-CSF treated group (p<0.001). The number of deaths were also significantly fewer in the group receiving rhG-CSF.
Drossou et al[12] studied the effects of treatment with recombinant human G-CSF on the neutrophil count and function of preterm neonates with documented sepsis. They reported that the administration of rhG-CSF to septic neonates significantly increased the absolute granulocyte count and enhaced the neutrophil respiratory burst and beta 2 integrin expression. Similar results have been reported by other authors.[13],[14]
Miura et al[15] performed a randomized, double masked, parallelgroup, placebo controlled trial of rhG-CSF administration to 44 preterm septic neonates, who were <5 days old, weighing 500-2000 g. The results revealed that the mortality rate was not different between treatment and placebo groups. However, the occurence of a subsequent nosocomial infection was lower in the rhG-CSF recipients.
A meta analysis[16] of reports on neutropenic neonates examined five different studies and could not demonstrate more then a trend towards reduced mortality rates in rhG-CSF treated patients (odds ratio 0.43,95% confidence interval 0.14-1.23, p￡0.13). The meta -analysis identified neonates with birth weight <2000 g to be preferential candidates. It is tempting to conclude that G-CSF administration reduced mortality for neonates with sepsis and neutropenia. However neutropenia was not defined consistently in the studies. Russel et al[11] used "relative neutropenia"i.e. ANC <5000/ml, where as others used a definition of <1500/mL. The reduction in mortality was not significant in neutropenic neonates. This was possibly because of a very high reported mortality in neonates with sepsis accompanied by neutropenia.
Serious side effects of G/GM-CSF application have not been reported. Initial concerns about associated thrombocytopenia in one early report using rhG-CSF was in an uncontrolled pilot study [17]. In further studies by the same workers, no evidence of rhG- CSF related thrombocytopenia was noted. Antibodies have been reported for recombinant erythropoietin and are considered to be causative of a form of red cell aplasia. This can occur in the case of G-CSF and GM- CSF also. There is only one study of long term outcome after rhGCSF application in neonates in which no adverse hematologic, immunologic or developmental effects were found in a two year follow up[18]. In cases of unexplained neutropenia during a course of G/GM-CSF, the presence of neutralizing antibodies should be excluded. Further trials are required for long term outcomes.
Existing clinical trials of Colony Stimulating Factor administration in neonates have demonstrated safety and feasibility of these adjuncts in the therapy of neonatal sepsis. However on long term effects, data is not sufficient. The preferential group defined is low birth weight septic neonates with neutropenia. Further studies are required before recommending G/GM-CSF routinely in neonatal sepsis.
References
1. Banerjee MC, Speer CP. The current role of colony stimulating factors in prevention and treatment of neonatal sepsis. Semin Neonatol 2002; 7 : 335-349.
2. Cairo MS. Cytokines: A new immunotherapy. Clinics in Perinatol 1991; 81 : 343-355.
3. Cairo MS, Ellis R. Results of phase I/II trial of rhGM_CSF in VLBW neonates; significant induction of circulating neutrophils,monocytes, platelets and bone marrow neutrophils. Blood 1995; 86 : 2509-2515.
4. Rodwell RL, Taylor K. Hematologic scoring system in early diagnosis of sepsis in neutropenic newborns. Pediatr Infectious Dis J 1993; 12 : 372-376.
5. Schibler KR, White WL. Production of G-CSF in vitro by monocytes from preterm and term neonates. Blood 82: 2478-2484.
6. Roberts RL, Szelc CM, Scates SM . Neutropenia in an extremely premature infant treated with rhG-CSF. Am J Dis Child 1991; 145 : 803-812.
7. Gillan ER, Christensen RD, Suen YU, Elis R, deVen CV, Cario SM. A randomized placebo controlled trial of rhG-CSF administration in newborn infants with presumed sepsis : significant induction of peripheral and bone marrow neutrophilia. Blood 1994; 84 : 1427-1433.
8. Barak Y, Leibovitz E, Mogilner B, Amitay M, Bullin A, Koren A. The in vivo effect of recombinant human G_CSF in neutropenic neonates with sepsis. Eur J Pediatr 1997; 156 : 643-646.
9. Kocherlakota P, La Gamma E. Human G-CSF may improve outcome attributable to neonatal sepsis complicated by neutropenia. Pediatrics 1997; 100 : 6-8.
10. Kocherlakota P, La Gamma EF. Preliminary report: rhGCSF may reduce the incidence of neonatal sepsis in prolonged pre eclampsia associated neutropenia. Pediatrics 1998; 102 : 1107-1111.
11. Russel B, Emmerson N, Wilkinson N, Chant T, Sweet DG, Halliday HL. A trial ofsrhG-CSF for the treatment of VLBW infants with presumed sepsis and neutropenia. Arch Dis Child Fetal Neonatal Ed 2001; 84: F7 2-6.
12. Drossou AV, Kanakoudi T, Kremenopoulous G. Administration of rhG_CSF to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and b2 integrin expression. Results of a randomized controlled trial. Eur J Pediatr 1998; 157 : 583-588.
13. Bilgin K,Yarami A,Haspolat K, Alitas M,Gunbey S,Derman O. A randomized trial of GM-CSF in neonates with sepsis and neutropenia. Pediatrics 2001; 107 : 36-41.
14. Ahmad A, LaboradaG, Bussel J, NesinM. Comparision of rh-GCSF and placebo for treatment of septic preterm infants. Pediatr Infect Dis J 2002; 21 : 1061-1065.
15. Miura E, Procianoy RS, Miura CS, Miura MS, Mello C, Christensen RD. A randomized, double masked, placebo controlled trial of rG-CSF administration to preterm infants with the clinical diagnosis of early onset sepsis. Pediatrics 2001; 107 : 30-35.
16. Bernstein HM, Poolock BH, Calboun DA, Christemen RD. Administration of G-CSF to neonates with septicaemia: A metaanalysis. J Pediatr 2001; 138 : 917-920.
17. Russel B, Davis EG. rhG-CSF treatment for neonatal neutropenia. Arch Dis Child 1995; F53-4.
18. Rosenthal MD, Healy MS, Gillina E. Astwo years follow up of neonates with presumed sepsis treated with rhG-CSF factor during the first week of life. J Pediatr 1996; 128 : 135-1357.(Gathwala Geeta, Bala Hars)
Compared to adults, the unique susceptibility of neonates to sepsis associated neutropenia is due to a smaller neutrophil storage pool, a reduced capacity for neutrophil mobilization from bone marrow reserves and a slower regeneration of neutrophils in the bone marrow.[1] Additionally, neutrophil abnormalities like impairment of chemotaxis, adherence, deformability, polarization, superoxide anion generation and bacterial killing etc may exist and predispose the neonates to an impaired immune response during overwhelming bacterial sepsis.[2],[3]
Proliferation and differentiation of myeloid progenitor cells is controlled by a family of hematopoietic growth factors called colony stimulating factors (CSF). Four CSFsGranulocyte CSF (G-CSF), Granulocyte Monocyte CSF (GM-CSF), Monocyte CSF (M-CSF) and interleukin-3 have been isolated and characterized. However only G-CSF and GM-CSF are available commercially and have gained access into daily clinical routine. G-CSF has been shown to specially promote granulocyte development and maturation by stimulating myeloid progenitor proliferation, increasing bone marrow neutrophil storage pool, including peripheral neutrophilia and enhancing mature neutrophil effector functions. GM-CSF, on the other hand, acts on multiple cell lineages such as macrophages, eosinophils and on neutrophils.[4] Also GM-CSF seems to be more potent than G-CSF in neutrophil cell chemotaxis. GM-CSF and G-CSF gene expression is significantly decreased in neonates.[5]
The first report of G-CSF administration to a 654g SGA neonate with persistent neutropenia and multiple episodes of neonatal sepsis was published 10 years ago.[6] Since then a number of clinical studies have demonstrated the role of colony stimulating factors' application in neonates.
Initial evaluation of rhGM-CSF or rhG-CSF use were largely phase I/II type trials that sought to identify any clinical side effects while establishing a proper dosing range for newborns. Several of these trials revealed that G-CSF and GMCSF were safe and effectively increased ANC in septic neonates with neutropenia.[5],[7],[8],[9]
Kocherlakota et al[9] administered an I/Vinfusion of rhG-CSF (10mg/Kg/d for 3 days) to 14 septic neutropenic neonates. Results were compared with a conventional therapy group. Absolute Neutrophil Count (ANC) was significantly increased to more than baseline in rhG-CSF treated group. Thirteen patients of the 14 in the treated group and 5 of the conventionally treated group survived to 28 days after the onset of sepsis. The same authors in yet another study demonstrated that GCSF administration decreased the incidence of neonatal sepsis in critically ill ventillated neonates with preclampsia associated neutropenia [10]
Russel et al[11] studied 28 neonates with birth weight of 500-1500 grams, ANC ￡5000/cmm and clinical evidence of sepsis. They were randomly assigned to receive either rhG-CSF (10mg/Kg/d)I/V (n=13) or placebo (n=15) for a maximum of 14 days. There was a significantly more rapid increase in ANC in rhG-CSF treated group (p<0.001). The number of deaths were also significantly fewer in the group receiving rhG-CSF.
Drossou et al[12] studied the effects of treatment with recombinant human G-CSF on the neutrophil count and function of preterm neonates with documented sepsis. They reported that the administration of rhG-CSF to septic neonates significantly increased the absolute granulocyte count and enhaced the neutrophil respiratory burst and beta 2 integrin expression. Similar results have been reported by other authors.[13],[14]
Miura et al[15] performed a randomized, double masked, parallelgroup, placebo controlled trial of rhG-CSF administration to 44 preterm septic neonates, who were <5 days old, weighing 500-2000 g. The results revealed that the mortality rate was not different between treatment and placebo groups. However, the occurence of a subsequent nosocomial infection was lower in the rhG-CSF recipients.
A meta analysis[16] of reports on neutropenic neonates examined five different studies and could not demonstrate more then a trend towards reduced mortality rates in rhG-CSF treated patients (odds ratio 0.43,95% confidence interval 0.14-1.23, p￡0.13). The meta -analysis identified neonates with birth weight <2000 g to be preferential candidates. It is tempting to conclude that G-CSF administration reduced mortality for neonates with sepsis and neutropenia. However neutropenia was not defined consistently in the studies. Russel et al[11] used "relative neutropenia"i.e. ANC <5000/ml, where as others used a definition of <1500/mL. The reduction in mortality was not significant in neutropenic neonates. This was possibly because of a very high reported mortality in neonates with sepsis accompanied by neutropenia.
Serious side effects of G/GM-CSF application have not been reported. Initial concerns about associated thrombocytopenia in one early report using rhG-CSF was in an uncontrolled pilot study [17]. In further studies by the same workers, no evidence of rhG- CSF related thrombocytopenia was noted. Antibodies have been reported for recombinant erythropoietin and are considered to be causative of a form of red cell aplasia. This can occur in the case of G-CSF and GM- CSF also. There is only one study of long term outcome after rhGCSF application in neonates in which no adverse hematologic, immunologic or developmental effects were found in a two year follow up[18]. In cases of unexplained neutropenia during a course of G/GM-CSF, the presence of neutralizing antibodies should be excluded. Further trials are required for long term outcomes.
Existing clinical trials of Colony Stimulating Factor administration in neonates have demonstrated safety and feasibility of these adjuncts in the therapy of neonatal sepsis. However on long term effects, data is not sufficient. The preferential group defined is low birth weight septic neonates with neutropenia. Further studies are required before recommending G/GM-CSF routinely in neonatal sepsis.
References
1. Banerjee MC, Speer CP. The current role of colony stimulating factors in prevention and treatment of neonatal sepsis. Semin Neonatol 2002; 7 : 335-349.
2. Cairo MS. Cytokines: A new immunotherapy. Clinics in Perinatol 1991; 81 : 343-355.
3. Cairo MS, Ellis R. Results of phase I/II trial of rhGM_CSF in VLBW neonates; significant induction of circulating neutrophils,monocytes, platelets and bone marrow neutrophils. Blood 1995; 86 : 2509-2515.
4. Rodwell RL, Taylor K. Hematologic scoring system in early diagnosis of sepsis in neutropenic newborns. Pediatr Infectious Dis J 1993; 12 : 372-376.
5. Schibler KR, White WL. Production of G-CSF in vitro by monocytes from preterm and term neonates. Blood 82: 2478-2484.
6. Roberts RL, Szelc CM, Scates SM . Neutropenia in an extremely premature infant treated with rhG-CSF. Am J Dis Child 1991; 145 : 803-812.
7. Gillan ER, Christensen RD, Suen YU, Elis R, deVen CV, Cario SM. A randomized placebo controlled trial of rhG-CSF administration in newborn infants with presumed sepsis : significant induction of peripheral and bone marrow neutrophilia. Blood 1994; 84 : 1427-1433.
8. Barak Y, Leibovitz E, Mogilner B, Amitay M, Bullin A, Koren A. The in vivo effect of recombinant human G_CSF in neutropenic neonates with sepsis. Eur J Pediatr 1997; 156 : 643-646.
9. Kocherlakota P, La Gamma E. Human G-CSF may improve outcome attributable to neonatal sepsis complicated by neutropenia. Pediatrics 1997; 100 : 6-8.
10. Kocherlakota P, La Gamma EF. Preliminary report: rhGCSF may reduce the incidence of neonatal sepsis in prolonged pre eclampsia associated neutropenia. Pediatrics 1998; 102 : 1107-1111.
11. Russel B, Emmerson N, Wilkinson N, Chant T, Sweet DG, Halliday HL. A trial ofsrhG-CSF for the treatment of VLBW infants with presumed sepsis and neutropenia. Arch Dis Child Fetal Neonatal Ed 2001; 84: F7 2-6.
12. Drossou AV, Kanakoudi T, Kremenopoulous G. Administration of rhG_CSF to septic neonates induces neutrophilia and enhances the neutrophil respiratory burst and b2 integrin expression. Results of a randomized controlled trial. Eur J Pediatr 1998; 157 : 583-588.
13. Bilgin K,Yarami A,Haspolat K, Alitas M,Gunbey S,Derman O. A randomized trial of GM-CSF in neonates with sepsis and neutropenia. Pediatrics 2001; 107 : 36-41.
14. Ahmad A, LaboradaG, Bussel J, NesinM. Comparision of rh-GCSF and placebo for treatment of septic preterm infants. Pediatr Infect Dis J 2002; 21 : 1061-1065.
15. Miura E, Procianoy RS, Miura CS, Miura MS, Mello C, Christensen RD. A randomized, double masked, placebo controlled trial of rG-CSF administration to preterm infants with the clinical diagnosis of early onset sepsis. Pediatrics 2001; 107 : 30-35.
16. Bernstein HM, Poolock BH, Calboun DA, Christemen RD. Administration of G-CSF to neonates with septicaemia: A metaanalysis. J Pediatr 2001; 138 : 917-920.
17. Russel B, Davis EG. rhG-CSF treatment for neonatal neutropenia. Arch Dis Child 1995; F53-4.
18. Rosenthal MD, Healy MS, Gillina E. Astwo years follow up of neonates with presumed sepsis treated with rhG-CSF factor during the first week of life. J Pediatr 1996; 128 : 135-1357.(Gathwala Geeta, Bala Hars)