Estcourt Lise J, Stanworth Simon J, Hopewell Sally, Doree Carolyn, Trivella Marialena, Massey Edwin
Haematology/Transfusion Medicine, NHS Blood and Transplant, Level 2, John Radcliffe Hospital, Headington, Oxford, UK, OX3 9BQ.
Cochrane Database Syst Rev. 2016 Apr 29;4(4):CD005339. doi: 10.1002/14651858.CD005339.pub2.
Despite modern antimicrobials and supportive therapy bacterial and fungal infections are still major complications in people with prolonged disease-related or treatment-related neutropenia. Transfusions of granulocytes have a long history of usage in clinical practice to support and treat severe infection in high-risk groups of patients with neutropenia or neutrophil dysfunction. However, there is considerable current variability in therapeutic granulocyte transfusion practice, and uncertainty about the beneficial effect of transfusions given as an adjunct to antibiotics on mortality. This is an update of a Cochrane review first published in 2005.
To determine the effectiveness and safety of granulocyte transfusions compared to no granulocyte transfusions as adjuncts to antimicrobials for treating infections in people with neutropenia or disorders of neutrophil function aimed at reducing mortality and other adverse outcomes related to infection.
We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 2). MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 11 February 2016.
RCTs comparing people with neutropenia or disorders of neutrophil dysfunction receiving granulocyte transfusions to treat infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, language or publication status.
We used standard methodological procedures expected by the Cochrane Collaboration.
We identified 10 trials that met the inclusion criteria with a total of 587 participants. We also identified another ongoing trial. These trials were conducted between 1975 and 2015. None of the studies included people with neutrophil dysfunction. The studies differed in the type of infections they included. Six studies included both children and adults, however data were not reported separately for children and adults. The two newest studies gave granulocyte colony stimulating factor (G-CSF) to donors; both were stopped early due to lack of recruitment. Three studies re-randomised participants and therefore quantitative analysis was unable to be performed.Overall the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcomes being imprecise.There may be no difference in all-cause mortality over 30 days between participants receiving therapeutic granulocyte transfusions and those that did not (six studies; 321 participants; RR 0.75, 95% CI 0.54 to 1.04; very low-quality evidence). There were no differences between the granulocyte dose subgroups (< 1 x 10(10) per day versus ≥ 1 x 10(10) per day) (test for subgroup differences P = 0.39). There was a difference in all-cause mortality between the studies based on the age of the study (published before 2000 versus published 2000 or later) (test for subgroup differences P = 0.03). There was no difference in all-cause mortality between participants receiving granulocyte transfusions and those that did not in the newest study (one study; 111 participants; RR 1.10, 95% CI 0.70 to 1.73, low-quality evidence). There may be a reduction in all-cause mortality in participants receiving granulocyte transfusions compared to those that did not in studies published before the year 2000 (five studies; 210 participants; RR 0.53, 95% CI 0.33 to 0.85; low-quality evidence).There may be no difference in clinical reversal of concurrent infection between participants receiving therapeutic granulocyte transfusions and those that did not (five studies; 286 participants; RR 0.98, 95% CI 0.81 to 1.19; low-quality evidence).There is insufficient evidence to determine whether there is a difference in pulmonary serious adverse events (1 study; 24 participants; RR 0.85, 95% CI 0.38 to 1.88; very low-quality evidence).None of the studies reported number of days on therapeutic antibiotics, number of adverse events requiring discontinuation of treatment, or quality of life.Six studies reported their funding sources and all were funded by governments or charities.
AUTHORS' CONCLUSIONS: In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is insufficient evidence to determine whether granulocyte transfusions affect all-cause mortality. To be able to detect a decrease in all-cause mortality from 35% to 30% would require a study containing at least 2748 participants (80% power, 5% significance). There is low-grade evidence that therapeutic granulocyte transfusions may not increase the number of participants with clinical resolution of an infection.
尽管有现代抗菌药物和支持性治疗，但细菌和真菌感染仍是疾病相关或治疗相关的长期中性粒细胞减少患者的主要并发症。粒细胞输注在临床实践中有很长的使用历史，用于支持和治疗中性粒细胞减少或中性粒细胞功能障碍的高危患者群体中的严重感染。然而，目前治疗性粒细胞输注的实践存在很大差异，并且对于作为抗生素辅助治疗的输注对死亡率的有益效果存在不确定性。这是2005年首次发表的Cochrane系统评价的更新版。
确定与不进行粒细胞输注相比，粒细胞输注作为抗菌药物辅助治疗中性粒细胞减少或中性粒细胞功能障碍患者感染的有效性和安全性，旨在降低与感染相关的死亡率和其他不良结局。
我们在Cochrane对照试验中心注册库（CENTRAL）（Cochrane图书馆2016年第2期）、MEDLINE（1946年起）、Embase（1974年起）、CINAHL（1937年起）、输血证据图书馆（1980年起）以及截至2016年2月11日的正在进行的试验数据库中检索随机对照试验（RCT）。
RCT，比较接受粒细胞输注治疗感染的中性粒细胞减少或中性粒细胞功能障碍患者与不接受粒细胞输注的对照组。新生儿是另一项Cochrane系统评价的主题，本评价将其排除。对所检查的结局、语言或发表状态没有限制。
我们采用了Cochrane协作网期望的标准方法程序。
我们识别出10项符合纳入标准的试验，共587名参与者。我们还识别出另一项正在进行的试验。这些试验在1975年至2015年间进行。没有一项研究纳入中性粒细胞功能障碍患者。这些研究纳入的感染类型不同。6项研究纳入了儿童和成人，但未分别报告儿童和成人的数据。两项最新的研究给供者使用了粒细胞集落刺激因子（G-CSF）；两项均因招募不足而提前终止。3项研究对参与者进行了重新随机分组，因此无法进行定量分析。根据GRADE方法，总体而言，不同结局的证据质量非常低至低。这是由于许多研究存在高偏倚风险，且许多结局不精确。接受治疗性粒细胞输注的参与者与未接受输注的参与者在30天全因死亡率上可能没有差异（6项研究；321名参与者；RR 0.75，95%CI 0.54至1.04；极低质量证据）。粒细胞剂量亚组（每天<1×10¹⁰与≥1×10¹⁰）之间没有差异（亚组差异检验P = 0.39）。根据研究发表年份（2000年之前发表与2000年或之后发表），研究之间的全因死亡率存在差异（亚组差异检验P = 0.03）。在最新的研究中，接受粒细胞输注的参与者与未接受输注的参与者在全因死亡率上没有差异（1项研究；111名参与者；RR 1.10，95%CI 0.70至1.73，低质量证据）。与2000年之前发表的研究中未接受粒细胞输注的参与者相比，接受粒细胞输注的参与者全因死亡率可能降低（5项研究；210名参与者；RR 0.53，95%CI 0.33至0.85；低质量证据）。接受治疗性粒细胞输注的参与者与未接受输注的参与者在并发感染的临床逆转方面可能没有差异（5项研究；286名参与者；RR 0.98，95%CI 0.81至1.19；低质量证据）。没有足够的证据确定肺部严重不良事件是否存在差异（1项研究；24名参与者；RR 0.85，95%CI 0.38至1.88；极低质量证据）。没有一项研究报告治疗性抗生素使用天数、需要停止治疗的不良事件数量或生活质量。6项研究报告了其资金来源，全部由政府或慈善机构资助。
对于因骨髓抑制性化疗或造血干细胞移植导致中性粒细胞减少的患者，没有足够的证据确定粒细胞输注是否会影响全因死亡率。要能够检测到全因死亡率从35%降至30%，需要一项至少包含2748名参与者的研究（80%的检验效能，5%的显著性水平）。有低质量证据表明治疗性粒细胞输注可能不会增加感染临床缓解的参与者数量。
