G-CSF and GM-CSF for treating or preventing neonatal infections
Editorial Group: Cochrane Neonatal Group
Published Online: 21 JUL 2003
Assessed as up-to-date: 27 APR 2003
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Carr R, Modi N, Doré CJ. G-CSF and GM-CSF for treating or preventing neonatal infections. Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No.: CD003066. DOI: 10.1002/14651858.CD003066.
- Publication Status: Edited (no change to conclusions)
- Published Online: 21 JUL 2003
The colony stimulating factors (CSFs), granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF), are naturally occurring cytokines that stimulate the production and antibacterial function of neutrophils and monocytes. Two strategies have been adopted for exploring whether CSFs can provide clinical benefit for preterm infants. The first has investigated their use as a treatment to improve outcome in established systemic infection, especially when complicated by a low neutrophil count. The alternative strategy has been to use CSFs prophylactically, to prevent sepsis prospectively through stimulation of neutrophil production and bactericidal function.
To determine the efficacy and safety of the haemopoietic colony stimulating factors (G-CSF or GM-CSF) in newborn infants, when used for:
a) treatment of suspected or proven systemic infection to reduce mortality, or
b) prophylaxis, to prevent systemic infection in infants at high risk of nosocomial infection.
To determine, in subgroup analysis, the influence of pre-existing or high risk of neutropenia on the outcome of therapy.
PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003) were searched in April 2003 using the keywords: G-CSF, GM-CSF, infant newborn, with and without the limit Clinical Trial. In addition, reference lists of identified RCTs, meta-analyses and personal files were searched.
The criteria used to select studies for inclusion were:
Subjects: Newborn infants in intensive care.
Interventions: G-CSF or GM-CSF given as treatment in conjunction with antibiotics for suspected or microbiologically proven systemic infection. G-CSF or GM-CSF given as prophylaxis with the aim of reducing the incidence of systemic infection.
Outcomes: Treatment studies reporting all cause mortality. Prophylaxis studies reporting subsequent incidence of sepsis and / or mortality.
Data collection and analysis
Relative risks (RR) and risk differences (RD) with 95% confidence intervals (CI) using the fixed effect model are reported. Number needed to treat (NNT) was calculated for the outcomes that showed a statistically significant reduction in RR.
Seven treatment studies of 257 infants with suspected systemic bacterial infection and three prophylaxis studies comprising 359 neonates are analysed.
Treatment studies: There is no evidence that the addition of G-CSF or GM-CSF to antibiotic therapy in preterm infants with suspected systemic infection reduces immediate all cause mortality. No significant survival advantage was seen at 14 days from the start of therapy [typical RR 0.71 (95% CI 0.38,1.33); typical RD -0.05 (95% CI -0.14, 0.04)]. However all seven of the treatment studies were small, the largest recruiting only 60 infants.
The subgroup analysis of 97 infants from three treatment studies who, in addition to systemic infection, had clinically significant neutropenia (< 1.7 x 10
Prophylaxis studies have not demonstrated a significant reduction in mortality in neonates receiving GM-CSF [RR 0.59 (95% CI 0.24,1.44); RD -0.03 (95% CI -0.08,0.02)]. The identification of sepsis as the primary outcome of prophylaxis studies has been hampered by inadequately stringent definitions of systemic infection. However, data from one study suggest that prophylactic GM-CSF may provide protection against infection when given to preterm infants who are neutropenic or at high risk of developing postnatal neutropenia.
There is currently insufficient evidence to support the introduction of either G-CSF or GM-CSF into neonatal practice, either as treatment of established systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high risk neonates. No toxicity of CSF use was reported in any study included in this review. The limited data suggesting that CSF treatment may reduce mortality when systemic infection is accompanied by severe neutropenia should be investigated further in adequately powered trials which recruit sufficient infants infected with organisms associated with a significant mortality risk.
Plain language summary
G-CSF and GM-CSF for treating or preventing neonatal infections
Infants born before 32 weeks and infants that are small for their gestational age are at high risk of developing infections while in hospital. These infections can cause death, disability (including cerebral palsy) as a result of damage to nervous tissue as well as contributing to chronic lung disease. Infection-related deaths have remained constant for two decades and antibiotic resistance is increasing, emphasising the need for new ways to prevent infection.
The haemopoietic colony stimulating factors (CSFs), granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) are naturally occurring substances (cytokines) that can increase circulating white blood cells (neutrophils) and their ability to destroy bacteria. Common minor side effects are low grade fever and skeletal pain. The review authors identified seven treatment studies of 257 premature infants with suspected systemic bacterial infection. Adding G-CSF or GM-CSF to antibiotic therapy did not improve survival, overall. It may be, however, that infants who had clinically low neutrophils at the start of treatment did show some reduction in number of deaths by day 14 (taken from three studies). In three studies in which 359 low birthweight or premature neonates were treated preventatively (prophylaxis) no reduction in deaths was evident in those neonates receiving GM-CSF. GM-CSF was well tolerated with no adverse reactions in these small studies.
血球生長因子 (CSFs) 、顆粒球巨噬細胞血球生長因子 (GMCSF) 和顆粒球生長因子 (GCSF) 是自然生成的細胞激素，可以促進中性球和單核球的生成和抗細菌功能。用兩種搜尋策略來探討CSFs是否能夠給予早產嬰兒臨床上的好處。第一點是在有全身性感染，尤其併有中性球低下時，應用於治療能不能改善預後。另一點是CSFs的預防性應用，藉由刺激中性球生長和殺菌功能，以求預防敗血症的發生。
評估於新生兒利用血球生長因子 (GCSF或GMCSF) 的效果和安全性。用於a) 治療疑似或證實為敗血症來降低死亡率；或b) 用於預防院內感染高風險嬰兒的全身性感染。於次群體分析，已是中性球低下或屬中性球低下高危群對使用CSF治療的影響。
使用關鍵字：GCSF、GMCSF、新生兒，有或無限定臨床試驗，在2003年4月搜尋PubMed、 EMBASE、MEDLINE和Cochrane Central Register of Controlled Trials。除此之外，搜尋出的隨機控制試驗、整合分析和個人的檔案所列的參考文獻表單，也被加以搜尋。
用固定效果模式是計算相對危險 (RR) 和危險差異 (RD) ，採95% 信賴區間 (CI) 。以統計學上明顯降低RR來計算需治療的數目 (NNT) 。
7個治療研究，共257個疑有全身細菌感染的嬰兒及3個預防研究，共359個新生兒納入分析。治療研究：沒有證據顯示於疑有全身性感染的早產兒，抗生素治療合併GCSF或GMCSF會減少所有原因立即的死亡。開始治療14天後，沒有明顯生存優勢[typical RR 0.71 (95% CI 0.38,1.33); typical RD −0.05 (95% CI −0.14, 0.04)]。雖然所有7個治療研究，但規模都不大，其中最大規模只有60個嬰兒。次群分析3個治療研究共97個嬰兒，有全身性感染併有臨床明顯中性球低下 (<1.7 x 109/l) ，確實在第14天時有明顯減少死亡率[RR 0.34 (95% CI 0.12, 0.92); RD −0.18 (95% CI −0.33, −0.03); NNT 6 (95% CI 3 – 33)]。預防研究沒有顯示接受GMCSF的新生兒可明顯減少死亡率[RR 0.59 (95% CI 0.24,1.44); RD −0.03 (95% CI −0.08,0.02)]。以敗血症為預防研究的預後結果會被不明確全身性感染定義所限制。然而，從另一研究顯示預防使用GMCSF可以保護有中性球低下或具高危險性發生產後中性球低下的早產兒免於感染。
此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。