粒细胞输注预防中性粒细胞减少症或中性粒细胞功能障碍患者感染
摘要
研究背景
尽管有现代抗菌药物和支持疗法，但细菌和真菌感染仍然是长期疾病相关或治疗相关中性粒细胞减少症患者的主要并发症。自20世纪90年代末以来，人们对捐赠的粒细胞输注的需求不断增加，以治疗或预防由于自身缺乏功能性粒细胞而引起的严重感染。这是对2009年首次发表的Cochrane系统综述的更新。
研究目的
确定与未接受该干预的对照人群相比，预防性粒细胞输注对预防中性粒细胞减少症或中性粒细胞功能紊乱患者的全因死亡率、感染死亡率和感染或任何其他原因感染的证据方面的有效性和安全性。
检索策略
我们在Cochrane对照试验中心注册库（Cochrane Central Register of Controlled Trials）( Cochrane图书馆（Cochrane Library） 2015年第3期)、MEDLINE（1946年起）、EMBASE（1974年起）、CINAHL（1937年起）、Transfusion Evidence Library(1980年起)和正在进行的试验数据库中检索了截至2015年4月20日的随机对照试验（Randomised Controlled Trials, RCTs）和半随机对照试验。
纳入排除标准
比较接受粒细胞输注以防止感染发生与不接受粒细胞输注的对照组的随机对照试验（RCTs）和半随机对照试验。新生儿是另一项Cochrane系统综述的研究对象，他们被排除在本系统综述之外。本系统综述没有对检测的结局进行限制，但侧重于死亡率、感染所致的死亡率和不良事件。
资料收集与分析
我们使用了Cochrane协作网推荐的标准方法学程序。
主要结果
十二项试验符合纳入标准。一项试验仍在进行中，余下11项试验合格，共涉及653名受试者。这些试验是于1978年至2006年间进行，并招募了来自相对可比患者群体的受试者。没有一项研究纳入中性粒细胞功能障碍患者。有十项研究仅包括成人，两项研究包括成人和儿童。其中十项研究包含了每个组单独的数据，并能够进行批判性地评价。一项研究对受试者再次进行了随机分配，因此无法进行定量分析。
总体而言，根据GRADE方法，不同结局的证据质量介于极低到低。这是因为许多研究存在高偏倚风险，而且许多结局估计并不精确。
九项研究（609名受试者）报告了全因死亡率。接受预防性粒细胞输注的受试者和未接受预防性粒细胞输注的受试者之间在30天后的全因死亡率方面没有差异（七项研究；437名受试者；RR=0.92, 95%CI [0.63, 1.36]； 极低质量证据 ）。
七项研究（398名受试者）报告了感染导致的死亡率。接受预防性粒细胞输注的受试者和未接受预防性粒细胞输注的受试者之间在30天后因感染导致的死亡率方面没有差异（六项研究；286名受试者；RR=0.69, 95%CI [0.33, 1.44]； 极低质量证据 ）。
九项研究（609名受试者）报告了局部或全身细菌或真菌感染的人数。粒细胞剂量亚组之间存在差异（亚组差异检验P=0.01）。在低剂量粒细胞组，接受预防性粒细胞输注的受试者与未接受预防性粒细胞输注的受试者之间在30天后感染的人数没有差异（每天粒细胞<1.0x10 10 ）（四项研究，204名受试者；RR=0.84, 95%CI [0.58, 1.20]； 极低质量证据 ）。在中等剂量粒细胞组中，接受预防性粒细胞输注的受试者在30天后感染的人数有所减少（每天粒细胞为1.0x10 10 至4.0x10 10 ）（4项研究；293名受试者；RR=0.40, 95%CI [0.26, 0.63]， 低质量证据 ）。
在接受预防性粒细胞输注的受试者中，患有菌血症和真菌血症的受试者数量有所减少（九项研究；609名受试者；RR=0.45, 95%CI [0.30, 0.65]， 低质量证据 ）。
在接受预防性粒细胞输注的受试者中，局部细菌或真菌感染的人数没有差异（六项研究；296名受试者；RR=0.75, 95%CI [0.50, 1.14]； 极低质量证据 ）。
仅报告接受粒细胞输注的受试者和粒细胞输注的捐赠者的严重不良事件。
作者结论
对于因骨髓抑制化疗或造血干细胞移植而导致中性粒细胞减少的人，有低质量证据表明预防性粒细胞输注可降低患菌血症或真菌血症的风险。有低质量证据表明，预防性粒细胞输注的效果可能呈剂量依赖性，每天至少1.0x10 10 的剂量能更有效地降低感染风险。没有足够的证据来确定在感染导致的死亡率、全因死亡率或严重不良事件方面的任何差异。
PICOs
简语概要
输注被称为粒细胞的白细胞，以预防缺乏功能性粒细胞的人感染
系统综述问题
我们评价了有关为预防感染而进行粒细胞输注是否安全以及是否能降低感染风险的证据。我们的目标人群是患中性粒细胞减少症（一种白细胞（嗜中性粒细胞）的数量极低，或白细胞功能不正常（嗜中性粒细胞功能障碍）的人。
系统综述背景
功能正常的白细胞，特别是粒细胞，对于对抗威胁生命的细菌和真菌感染很重要。多年来，一些医院的医生一直在给那些因疾病和/或治疗导致白细胞数量或功能减少而缺乏白细胞的人输注粒细胞。
自20世纪90年代以来，对粒细胞输注的需求呈稳步增长的趋势，这主要是由于引入了一种称为粒细胞集落刺激因子（Granulocyte Colony‐stimulating Factor, G‐CSF）的药物，如果将它给予捐赠者，会导致捐赠者血液中的中性粒细胞数量增加，并可能收集到比以前更大剂量的粒细胞。
研究特征
证据有效期截至2015年4月。本次更新确定了12项试验，比较了输注粒细胞以预防感染与不给予粒细胞以预防感染。一项试验尚未完成。评价了共包含653名受试者的十一项试验。这些试验是在1978年至2006年间进行的。一项试验的数据未包括在分析中，因为受试者不止一次被纳入试验。有十项研究仅包括成人，两项研究包括成人和儿童。
六项研究报告了他们的资金来源，并且全部由政府或慈善机构资助。
主要研究结果
给予粒细胞输注以预防感染并不影响因感染而死亡的风险，或因任何原因而死亡的风险。
给予粒细胞输注以预防感染减少了血液中出现细菌或真菌感染的人数，但并没有减少局部出现细菌或真菌感染的人数。
尚不清楚粒细胞输注是否会增加发生严重不良事件的风险，因为不良事件仅在接受粒细胞输注的人群中报告。
证据质量
大多数研究结果的证据质量低或极低。这是因为病人和他们的医生知道病人被分配到哪个研究组，而且其中两项研究不是真正的随机研究（如果病人有合适的粒细胞捐赠者，就被分配到粒细胞输注组）。
Authors' conclusions
Summary of findings
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Prophylactic granulocytes compared with no prophylactic granulocytes for preventing infection in people with neutropenia or neutrophil dysfunction |
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Patient or population: people with neutropenia or neutrophil dysfunction Settings: Hospital Intervention: prophylactic granulocytes Comparison: no prophylactic granulocytes |
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Outcomes |
Illustrative comparative risks* (95% CI) |
Relative effect
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No of Participants
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Quality of the evidence
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Comments |
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Assumed risk |
Corresponding risk |
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Control |
Prophylactic granulocytes |
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All‐cause mortality up to 30 days Follow‐up: median 30 days |
145 per 1000 |
134 per 1000 (91 to 198) |
RR 0.92 (0.63 to 1.36) |
437
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⊕⊝⊝⊝
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|
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Mortality due to infection up to 30 days Follow‐up: median 30 days |
98 per 1000 |
68 per 1000
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RR 0.69 (0.33 to 1.44) |
286
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⊕⊝⊝⊝
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People with localised or systemic bacterial or fungal infections ‐ low‐dose granulocyte transfusions Follow‐up: median 30 days |
374 per 1000 |
314 per 1000
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RR 0.84 (0.58 to 1.2) |
204
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⊕⊝⊝⊝
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People with localised or systemic bacterial or fungal infections ‐ Intermediate‐dose granulocyte transfusions Follow‐up: median 30 days |
376 per 1000 |
150 per 1000 (98 to 237) |
RR 0.4 (0.26 to 0.63) |
293
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⊕⊕⊝⊝
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People with bacteraemia or fungaemia Follow‐up: median 30 days |
249 per 1000 |
112 per 1000 (75 to 162) |
RR 0.45 (0.3 to 0.65) |
609
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⊕⊕⊝⊝
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People with localised bacterial or fungal infection Follow‐up: median 30 days |
271 per 1000 |
204 per 1000 (136 to 309) |
RR 0.75 (0.50 to 1.14) |
296
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⊕⊝⊝⊝
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People with serious adverse events |
See comment |
See comment |
See comment |
See comment |
See comment |
Adverse events were only reported for the groups receiving granulocyte transfusions |
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*The basis for the
assumed risk
(e.g. the median control group risk across studies) is provided in footnotes. The
corresponding risk
(and its 95% confidence interval) is based on the assumed risk in the comparison group and the
relative effect
of the intervention (and its 95% CI).
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GRADE Working Group grades of evidence
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1
Owing to the nature of the intervention (granulocyte transfusion) and difficulty blinding participants, physicians and outcome assessors studies were at high risk of performance and detection bias. We downgraded the evidence by 1 for risk of bias
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Background
Description of the condition
Functioning white blood cells are a vital component of the defence system against infection in humans. There are a variety of different white blood cells that work together and perform complementary roles. Granulocytes are white blood cells that contain granules which are directly visible when viewed through a light microscope. Neutrophils are a subtype of granulocytes and are the most numerous circulating white blood cells in healthy adults. Granulocytes in general and neutrophils in particular are crucial in protecting against bacterial and fungal infection. A persisting reduction in neutrophil numbers is called neutropenia, the severity of which has been classified by the World Health Organization ( WHO 1992 ): when the peripheral blood count of neutrophils is below a level of 0.5 x 10 9 /L there is an increased risk of severe infection (the normal neutrophil count ranges from 2 to 7.5 x 10 9 /L in adults). Idiosyncratic neutropenia occurs in the population with a frequency of 120 per million people per year ( van Staa 2003 ), but neutropenia is also an inevitable complication of chemotherapy for malignant diseases, as well as a presenting feature of many haematological disorders. Infection in people with neutropenia is associated with hospital admission, organ damage, and a significant number of deaths, despite the use of specific and appropriate antibiotic and antifungal drugs ( Klastersky 2001 ). Even with a normal number of neutrophils, other patients may suffer from a similar inability to fight infections adequately if there is an impairment in the function of their neutrophils ( Kuijpers 1999 ).
Description of the intervention
Published reviews have suggested that the efficacy of granulocyte transfusions in neutropenic people is proportional to the dose of granulocytes transfused, with an optimal level being at least 10 10 granulocytes or at least 10 10 granulocytes per metre squared of recipient body surface area per transfusion ( Engelfriet 2000 ; Vamvakas 1996 ). However, there are a number of technical problems that make it difficult to collect adequate granulocyte doses for transfusion. Granulocytes are difficult to separate from other blood cells, and in addition healthy donors do not have very high levels of circulating granulocytes in their peripheral blood. There are a number of different methods for collecting granulocytes for transfusion in humans. Apheresis is a favoured technique utilising equipment incorporating a centrifuge or filter to selectively remove white blood cells from the donor whilst returning other cellular and liquid components to the donor ( Freireich 1964 ).
In the early 1990s, growth factors such as granulocyte colony‐stimulating factor (G‐CSF) that stimulate the bone marrow to produce more white blood cells (particularly granulocytes) were developed for therapeutic use. These drugs allowed high peripheral blood white cell counts to be achieved in healthy donors. Steroids can also increase the white cell count, but alone they are not as effective as G‐CSF. Using this method, adequate doses of granulocytes can be produced for adults. The exposure of a healthy volunteer donor to any form of medication with potential side effects does however present ethical and safety issues ( Gutierrez 2001 ; Strauss 2003 ).
How the intervention might work
There is limited evidence by laboratory testing that donated granulocytes are functional ( Bashir 2003 ; Dale 1998 ). The ability to collect greater numbers of granulocytes has however generated renewed interest in the potential role of granulocyte transfusions, either as additional therapy for people with neutropenia and established infections or when given as prophylaxis to prevent severe or life‐threatening infections ( Dale 2000 ; Hubel 2001 ; Illerhaus 2002 ; Kerr 2003 ; Peters 1999 ; Price 2000 ). These advances have occurred in conjunction with advances in anti‐microbial therapy, including antifungal drugs, but the exact relative contributions of these agents in the context of more aggressive chemotherapy regimens and bone marrow transplants remains unclear.
Why it is important to do this review
This systematic review aimed to assess the effectiveness and safety of prophylactic granulocyte transfusions in people with neutropenia or neutrophil dysfunction. Previous Cochrane reviews have been performed with specific reference to neonatal practice and therapeutic granulocyte transfusion in adults ( Pammi 2011 ; Stanworth 2005 ). Using granulocyte transfusion as part of a strategy for prevention of infection in neutropenic people may be more effective than therapeutic transfusions in response to established infection. This systematic review would therefore complement the previous Cochrane reviews.
This is an update of a previous Cochrane review ( Massey 2009 ).
Objectives
To determine the effectiveness and safety of prophylactic granulocyte transfusions compared with a control population not receiving this intervention for preventing all‐cause mortality, mortality due to infection, and evidence of infection due to infection or due to any other cause in people with neutropenia or disorders of neutrophil function.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) and quasi‐RCTs. Quasi‐RCTs included those in which allocation to receive granulocyte transfusion was dependent upon the availability of suitably‐matched donors; this form of randomisation was referred to as quasi‐randomisation in the text.
Types of participants
People with neutropenia (whether due to treatment or disease, or whether reversible or irreversible) were considered. People with inherited disorders of neutrophil dysfunction were also eligible for inclusion. Studies with neonates were excluded as these trials have been appraised in another Cochrane Review ( Pammi 2011 ).
Types of interventions
Intervention
Granulocyte transfusions given as prophylaxis, prior to the development of documented infection. All sources of granulocytes, all doses, and different methods of collection were included.
Control
Prophylactic granulocyte transfusions not administered.
Types of outcome measures
Primary outcomes
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Death (from all causes)
Secondary outcomes
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Death due to infection
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Number of infections (whether systemic or at specific loci or microbiologically proven, with details of pathogens isolated)
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Numbers of days with fever
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Number of days on treatment with antimicrobials (or courses of treatment with antibiotics/antifungals)
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Increment of neutrophil count (x10 9 /L)
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Duration of neutropenia reversal after transfusion (neutropenia defined as count below 0.5 x 10 9 /L).
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Serious adverse events: resulting in death, requiring or prolonging hospitalisation, resulting in persistent or significant disability/incapacity, or life‐threatening
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Adverse events requiring discontinuation of intervention
Other factors which may influence the outcome of neutropenia were extracted and reported in Characteristics of included studies and discussed in Overall completeness and applicability of evidence . These included the following.
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Use of therapeutic granulocyte transfusion
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Use of colony‐stimulating factors in recipients, particularly G‐CSF
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Policies and use of prophylactic antibiotics and antifungals
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Method of preparation and source of granulocytes for transfusion
Search methods for identification of studies
Electronic searches
Bibliographic databases
We searched for randomised controlled trials (RCTs) in the following databases.
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CENTRAL ( Cochrane Library 2014, Issue 3 ) ( Appendix 1 )
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MEDLINE (Ovid, 1946 to April 20 2015) ( Appendix 2 )
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EMBASE (Ovid, 1974 to April 20 2015) ( Appendix 3 )
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CINAHL (EBSCOhost, 1937 to April 20 2015) ( Appendix 4 )
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Lilacs (BIREME/PAHO/WHO, 1982 to April 20 2015) ( Appendix 5 )
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KoreaMed (KAMJE, 1997 to April 20 2015) ( Appendix 6 )
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PakMediNet (2001 to April 20 2015) ( Appendix 6 )
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IndMed (ICMR‐NIC, 1986 to April 20 2015) ( Appendix 7 )
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Transfusion Evidence Library ( www.transfusionevidencelibrary.com ) (1980 to April 20 2015) ( Appendix 8 )
We updated searches from the original search in October 2008 ( Massey 2009 ). Searches in MEDLINE, EMBASE and CINAHL were combined with adaptations of the Cochrane RCT search filters, as detailed in the Cochrane Handbook for Systematic Reviews of Interventions ( Lefebvre 2011 ).
Databases of ongoing trials
We also searched ClinicalTrials.gov ( http://clinicaltrials.gov/ct2/search ) ( Appendix 9 ), the WHO International Clinical Trials Registry (ICTRP) ( http://apps.who.int/trialsearch/ ) ( Appendix 9 ), and the ISRCTN Register ( http://www.controlled‐trials.com/isrctn/ ) ( Appendix 10 ), in order to identify ongoing trials.
All new search strategies are presented as indicated in Appendices 1‐10. Search strategies for the original (2008) searches are presented in Appendix 11 .
Searching other resources
We augmented database searching with the following methods.
Handsearching of reference lists
We checked references of all included trials, relevant review articles and current treatment guidelines for further literature. These searches were limited to the 'first generation' reference lists.
Personal contacts
We contacted authors of relevant studies, study groups and experts worldwide known to be active in the field for unpublished material or further information on ongoing studies.
Data collection and analysis
Selection of studies
We updated the selection of studies from the selection of studies performed for the previous version of this review ( Massey 2009 ).
One review author (CD) excluded all duplicates and studies that were clearly irrelevant (e.g. non‐human) that had been identified by the review search strategy. Two review authors (LE, PB) independently screened all remaining electronically‐derived citations and abstracts of papers identified by the review search strategy for relevance. We excluded studies that were clearly irrelevant at this stage based on a review of the abstract. Two review authors (LE, PB) independently formally assessed the full texts of all potentially‐relevant trials for eligibility against the criteria outlined above. All disagreements were resolved by discussion without the need for a third review author (SS). We sought further information from study authors if the article contained insufficient data to make a decision about eligibility. A study eligibility form was designed for trials of granulocyte transfusion to help in the assessment of relevance, which included ascertaining whether the participants were neonates, and whether the two groups could be defined in the trial on the basis of a therapeutic‐only versus prophylactic granulocyte transfusion strategy. We recorded the reasons why potentially‐relevant studies failed to meet the eligibility criteria.
Data extraction and management
We updated the data extraction from the one used to extract data for the previous version of this review ( Massey 2009 ). This included data extraction for all new studies that have been included since the previous review and an updated 'Risk of bias' assessment for all included studies.
Two review authors (LE, PB) conducted the data extraction according to the guidelines proposed by The Cochrane Collaboration ( Higgins 2011a ). We resolved potential disagreements between the review authors by consensus. The review authors were not blinded to names of authors, institutions, journals, or the outcomes of the trials. Due to minor changes in the format, the data extraction forms were piloted on a further study, thereafter the two authors (LE, PB) extracted data independently for all the studies. The following data were extracted.
General information
Review author's name, date of data extraction, study ID, first author of study, author's contact address (if available), citation of paper, objectives of the trial.
Trial details
Trial design, location, setting, sample size, power calculation, treatment allocation, inclusion and exclusion criteria, reasons for exclusion, comparability of groups, length of follow‐up, stratification, stopping rules described, statistical analysis, results, conclusion, and funding.
Characteristics of participants
Age, gender, ethnicity, total number recruited, total number randomised, total number analysed, types of underlying disease, lost to follow‐up numbers, drop outs (percentage in each arm) with reasons, protocol violations, previous treatments, current treatment, prognostic factors.
Interventions
Experimental and control interventions, method of preparation and source of granulocytes for transfusion, timing of intervention, dosage of granulocyte given, compliance to interventions, any differences between interventions, and any additional interventions given, especially in relation to the use of therapeutic granulocyte transfusions, the use of colony‐stimulating factors in recipients, particularly G‐CSF and the use of prophylactic and therapeutic antibiotics and antifungals.
Assessment of bias
Sequence generation, allocation concealment, blinding (participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, other sources of bias.
Outcomes measured
Death (from all causes) . Death due to infection. Number of infections (whether systemic or at specific loci or microbiologically proven, with details of pathogens isolated). Numbers of days with fever. Number of days on treatment with antimicrobials (or courses of treatment with antibiotics/antifungals). Increment of neutrophil count (x10 9 /L). Duration of neutropenia reversal after transfusion (neutropenia defined as count below 0.5 x 10 9 /L). Serious adverse events: resulting in death, requiring or prolonging hospitalisation, resulting in persistent or significant disability/incapacity, or life‐threatening. Adverse events requiring discontinuation of intervention.
We used both full‐text versions and abstracts to retrieve the data. For publications reporting on more than one trial, we used one data extraction form for each trial. For trials reported in more than one publication, we extracted data using one form only. Where these sources did not provide sufficient information, we contacted authors and study groups for additional details.
One review author entered data into the software and a second review author checked for accuracy.
Assessment of risk of bias in included studies
We updated the 'Risk of bias' assessment from the 'Risk of bias' assessment performed for the previous version of this review ( Massey 2009 ).
Two review authors (LE, PB) assessed all included studies for possible risk of bias (as described in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011c ). The assessment included information about the design, conduct and analysis of the trial. Each criterion was evaluated on a three‐point scale: low risk of bias, high risk of bias, or unclear. To assess risk of bias, the following questions were included in the 'Risk of bias' table for each included study.
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Was the allocation sequence adequately generated?
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Was allocation adequately concealed?
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Was knowledge of the allocated intervention adequately prevented during the study (including an assessment of blinding of participants, personnel, and outcome assessors)?
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Were incomplete outcome data adequately addressed (for every outcome separately)?
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Are reports of the study free of selective outcome reporting?
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Was the study apparently free of other problems that could put it at risk of bias?
Measures of treatment effect
For dichotomous outcomes, we recorded the number of outcomes in the treatment and control groups and we estimated the treatment effect measures across individual studies as the relative effect measures (risk ratio (RR) with 95% confidence intervals (CIs)).
For continuous outcomes, we recorded the mean and standard deviations (SDs). For continuous outcomes measured using the same scale, the effect measure was the mean difference (MD) with 95% CIs, or the standardised mean difference (SMD) for outcomes measured using different scales.
For time‐to‐event outcomes, we planned to extract the hazard ratio (HR) from published data according to Parmar 1998 and Tierney 2007 . However, no time to event data were reported.
If the data available could not be reported in any of the formats described above, we reported the results narratively.
Unit of analysis issues
We did not pre‐specify in the protocol how we would deal with any unit of analysis issues. There were unit of analyses issues. In Mannoni 1979 participants were randomised more than once, 44 participants were included within the study but six participants were re‐randomised. Data for the first randomisation could not be extracted from the report, and further information from the authors was not available. Data from this study were therefore not incorporated into any meta‐analysis.
Dealing with missing data
We dealt with missing data according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions ( Higgins 2011b ). We contacted authors in order to obtain information that was missing or unclear in the published report. We contacted the authors of the Vij 2003 study, but no further analyses had been performed apart from the analyses in the primary paper.
Within an outcome, the preferred analysis was an intention‐to‐treat analysis (ITT). Where data were missing, we recorded the number of participants lost to follow‐up for each trial.
Assessment of heterogeneity
If studies were considered sufficiently homogenous in their study design, we conducted a meta‐analysis and assessed the statistical heterogeneity ( Deeks 2011 ). We assessed statistical heterogeneity of treatment effects between trials using a Chi 2 test with a significance level at P < 0.1. We used the I 2 statistic to quantify possible heterogeneity (I 2 > 50% moderate heterogeneity, I 2 > 80% considerable heterogeneity). We explored potential causes of heterogeneity by sensitivity and subgroup analyses if possible.
Assessment of reporting biases
We did not perform a formal assessment of potential publication bias (small trial bias) by generating a funnel plot and statistically test using a linear regression test ( Sterne 2011 ) as no meta‐analysis contained 10 or more studies.
Data synthesis
We performed analyses according to the recommendations of The Cochrane Collaboration ( Deeks 2011 ). We used aggregated data for analysis. For statistical analysis, we entered data into Review Manager 5.3 .
Where meta‐analysis was feasible, we used the fixed‐effect model for pooling the data. We used the Mantel‐Haenszel method for dichotomous outcomes or Peto method as necessary, and the inverse variance method for continuous outcomes. Even in the absence of statistical heterogeneity, we explored the robustness of any summary measures, particularly with respect to study methodological quality.
We planned to use the random‐effects model for sensitivity analyses as part of the exploration of heterogeneity. However, none of the analyses performed reported heterogeneity, as expressed by the I 2 above 50%, therefore only the fixed‐effect model was reported. If heterogeneity was found to be above 80%, we did not perform a meta‐analysis and results were commented on as a narrative.
'Summary of findings' table
We used GRADE to build a 'Summary of findings' table as suggested in the Cochrane Handbook for Systematic Reviews of Interventions ( Schünemann 2011 ). This included the following.
-
Death from all causes
-
Death due to infection
-
Number of infections (localised or systemic)
-
Number of infections (bacteraemia or fungaemia)
-
Number of infections (localised)
-
Number of serious adverse events
A GRADE assessment had not been pre‐specified in the protocol.
Subgroup analysis and investigation of heterogeneity
The only subgroup analysis pre‐specified in the previous version of this review (
Massey 2009
), was granulocyte dose.
We performed a subgroup analysis on granulocyte dose, classifying studies in to low dose (mean granulocyte dose less than 1 x 10
10
per day for an adult patient), intermediate dose (mean granulocyte dose 1 x 10
10
to 4 x 10
10
per day for an adult patient), and high dose (mean granulocyte dose greater than 4 x 10
10
per day for an adult patient).
We commented on differences between subgroups as a narrative.
Investigation of heterogeneity between studies also included, if appropriate, age of the study (as the treatment of neutropenic people has changed over the last 40 years).
Sensitivity analysis
We intend to assess the robustness of our findings by the following two sensitivity analyses.
-
Including only those trials at low risk of bias
-
Including only those trials in which 20% participants or less were lost to follow‐up.
A sensitivity analysis including only those studies at low risk of bias was not performed because none of the studies were at low risk of bias.
Results
Description of studies
See Characteristics of included studies ; Characteristics of excluded studies .
Results of the search
See PRISMA Flow Diagram Figure 1 .
Study flow diagram.
The original search (conducted 1st January 2009) identified a total of 1253 potentially relevant citations. There were 701 citations after duplicates were removed, 676 records were excluded on the basis of the abstract. The original systematic review identified 25 studies which appeared relevant on the basis of the their full text or abstract.
This updated search (conducted 20th April 2015) identified a total of 2188 potentially relevant citations. There were 1910 citations after duplicates were removed. We were able to exclude 1893 citations on the basis of the abstract by two out of three review authors (LE, CD, and PB). Two review authors (LE, PB) retrieved and assessed 10 full‐text articles for relevance.
The previous systematic review ( Massey 2009 ), identified 12 trials that compared prophylactic granulocyte transfusions versus no prophylactic platelet transfusions; 10 completed trials ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ), and two ongoing studies ( Price 2014 ; Seidel 2008 ), which are now excluded. This updated search identified two additional studies ( Vij 2003 ; NCT01204788 ). The study by Vij 2003 was not identified in the previous systematic review ( Massey 2009 ). This was because the search strategy we used for this update of the review was much more extensive than the previous search strategy ( see Search methods for identification of studies ).
In total, we assessed 12 studies and deemed them eligible for inclusion ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; NCT01204788 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Vij 2003 ; Winston 1980 ), however the NCT01204788 study is still ongoing.
Included studies
See Characteristics of included studies for full details of each study.
Twelve studies were eligible for inclusion in this review. Eleven studies have been completed ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Vij 2003 ; Winston 1980 ), and one study has been stopped early due to poor recruitment ( NCT01204788 ) but results have not been published.
Of the 11 completed studies, nine studies were randomly controlled studies ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ), and two studies allocated participants to the intervention arm on the basis of a suitable available granulocyte donor ( Oza 2006 ; Vij 2003 ).
Ongoing Studies
This updated review identified one ongoing study that was eligible for inclusion ( NCT01204788 ). This study has been completed but has not been published. The previous systematic review ( Massey 2009 ) identified two potentially relevant studies that have since been excluded because they were studying the wrong intervention ( Price 2014 ; Seidel 2008 ).
See Characteristics of ongoing studies for further details.
Studies contributing to this review
See Characteristics of included studies for full details of each study.
Study Design
There were five single‐centre parallel randomised controlled trials (RCTs) ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Schiffer 1979 ; Winston 1980 ); two single centre quasi‐randomised studies ( Oza 2006 ; Vij 2003 ); three multicentre parallel RCTs ( Petersen 1987 ; Strauss 1981 ; Sutton 1982 ) and one parallel RCT where the number of centres was unclear ( Mannoni 1979 ).
Study Size
The number of participants enrolled in all studies was small, ranging between 18 ( Schiffer 1979 ) and 225 ( Vij 2003 ) participants analysed. Most of the studies presented no or little information on sample sizes required to power the trial around a main outcome, and only one study made any attempt to justify the statistical analysis of the required size ( Oza 2006 ). All other trials should probably be considered more as hypothesis generating in respect of design.
Setting
The nine RCTs were published between 1978 and 1987 ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ), the two quasi‐randomised studies were published between 2003 and 2006 ( Oza 2006 ; Vij 2003 ). Seven studies were based in the United States ( Clift 1978 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Vij 2003 ; Winston 1980 ); one study was based in Canada ( Sutton 1982 ); one study was based in France ( Mannoni 1979 ); one study was based in Spain ( Gomez‐Villagran 1984 ); and one study was based in the United Kingdom ( Ford 1982 ).
Participants
The majority of participants were people with haematological malignancies receiving intensive chemotherapy or a haematopoietic stem cell transplant (HMST). Most studies included only adults. Two studies included children and adults ( Clift 1978 ; Gomez‐Villagran 1984 ).
Intervention
Average dose and range
The dose of granulocytes transfused varied between studies ( Table 1 ). The mean dose varied from 0.6 x 10 10 ( Strauss 1981 ) to 5.9 x 10 10 ( Oza 2006 ) ( Table 1 ). No dose was reported by two studies ( Petersen 1987 ; Vij 2003 ).
|
Study |
Mean dose of granulocyte transfusions |
Range of doses of granulocyte transfusions |
Frequency of transfusions |
Total number of transfusions per patient Mean/median and range |
|
0.6 x 10 10* |
Not reported |
Daily |
18.5 (mean) (3 to 28) |
|
|
0.9 x 10 10 |
0.2 to 2.5 x 10 10 |
Daily |
Not reported |
|
|
1.2 x 10 10 |
0.3 to 3.5 x 10 10 |
Daily |
23.4 mean (13 to 34) |
|
|
1.24 x 10 10 |
0.55 to 4.2 x 10 10 |
Daily |
6.16 (mean) (5 to 11) |
|
|
2.22 x 10 10 (leucofiltration) 1.57 x 10 10 (centrifugation) |
Not reported |
Daily |
12.4 (mean) (6 to 25) |
|
|
2.1 x 10 10 |
1.3 to 3.7 |
Daily |
12 (mean) (8 to 15) |
|
|
Not reported |
Not reported |
Daily |
12 (median) (6 to 27) |
|
|
1.15 x 10 10 |
0.34 to 2.4 x 10 10 |
4/7 days per week |
11 (mean) (3 to 19) |
|
|
1.45 x 10 10 |
0.28 to 3.45 |
Alternate days |
7 (median) (1 to 12) |
|
|
5.9 x 10 10 (first dose) 5.2 x 10 10 (second dose) |
0.02 to 15.5 (first dose) 0.02 to 21.0 ( second dose) |
Twice |
2 |
|
|
Not reported |
Not reported |
Twice |
2 |
* Strauss ( Strauss 1981 ) did not express the dose given in terms of absolute numbers of granulocytes but described the median dose as 0.34 x 10 10 per square metre of recipient body surface area. (This would approximate to a dose of 0.6 x 10 10 as all participants were over 12 years old).
Schedule for transfusion
Granulocyte transfusions were commenced when the recipient's neutrophil count fell below a pre‐defined value in eight of the 11 studies. This "trigger" neutrophil count was 0.2 x 10 9 /L for two studies ( Clift 1978 ; Petersen 1987 ), and 0.5 x10 9 /L for six studies ( Ford 1982 ; Gomez‐Villagran 1984 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ). In the Schiffer study, the granulocyte component contained a significant number of platelets and was therefore commenced if the patient needed platelet transfusion, even if the defined neutrophil count trigger had not been met Schiffer 1979 .
The other three studies started granulocyte transfusions at pre‐specified time points after treatment ( Mannoni 1979 ; Oza 2006 ; Vij 2003 ).
Once prophylactic granulocyte transfusions had commenced, daily transfusions were given in seven of the 11 studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Petersen 1987 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ) ( Table 1 ). Granulocyte transfusions were given on alternate days by one study ( Ford 1982 ), and for four days out of seven by one study ( Schiffer 1979 ). Two studies gave granulocyte transfusions on two occasions at fixed time points after HSCT ( Oza 2006 ; Vij 2003 ).
Granulocyte transfusions were discontinued when the recipient's neutrophil count rose above a pre‐defined value in eight of the 11 studies. This "trigger" neutrophil count was 0.2 x 10 9 /L for two studies ( Clift 1978 ; Petersen 1987 ), and 0.5 x10 9 /L for six studies ( Ford 1982 ; Gomez‐Villagran 1984 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ). Mannoni gave transfusions for a set period of 12 days but continued for 15 days in one case as there was evidence of infection at 12 days ( Mannoni 1979 ). Two studies gave granulocyte transfusions on two occasions at fixed time points after HSCT ( Oza 2006 ; Vij 2003 ).
Method of collection of granulocytes
The method of collection of granulocytes varied between trials. Nine studies used either intermittent or continuous flow centrifugation ( Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Vij 2003 ). One study used both filtration leucapheresis and continuous flow centrifugation ( Clift 1978 ). One study only used filtration leucapheresis ( Winston 1980 ). Methods of collection have developed considerably since these publications. Filtration leucapheresis is rarely used now, as despite possibly higher yields compared to continuous flow centrifugation, there are concerns about toxicity to the donor and recipient, in addition to evidence of poor increments and functionality of transfused granulocytes.
Premedication of donors
Four studies did not administer any form of medication to the donors to increase the granulocyte yield ( Clift 1978 ; Petersen 1987 ; Strauss 1981 ; Winston 1980 ).
Five studies gave donors steroids, either dexamethasone, hydrocortisone or prednisolone ( Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979; Schiffer 1979; Sutton 1982 ).
Donor selection
Human leucocyte (HLA)‐matched and ABO matched the granulocyte donor in two studies ( Oza 2006 ; Vij 2003 ); one study ensured that donor and recipient were HLA and ABO compatible ( Mannoni 1979 ). One study stated that family members were used as granulocyte donors and the HLA‐matched sibling donor was used whenever possible ( Petersen 1987 ).
Two studies used serological compatibility based upon leucocyte crossmatch (rather than HLA matching) ( Clift 1978 ; Gomez‐Villagran 1984 ), in which donor leucocytes were crossmatched against recipient serum/plasma by lymphocytotoxic (LCT) techniques prior to transfusion, and donors were ABO and Rh compatible.
Four studies did not HLA‐match the granulocyte donor ( Ford 1982 ; Schiffer 1979 ; Strauss 1981 ; Winston 1980 ). Schiffer 1979 discontinued unmatched transfusions if transfusion reactions or refractoriness to platelet transfusions occurred, at which point HLA‐matched donors were used if available. One study did not report whether any assessment of leucocyte compatibility was assessed ( Sutton 1982 ).
Co‐interventions and/or alternative interventions
Differences between the studies were also identified in the co‐interventions provided to participants. Specifically, this would include the diagnostic and therapeutic options available for anti‐microbial practice.
One study ( Petersen 1987 ) had an important difference in that there was an alternative intervention. Petersen 1987 randomised participants between two study arms. One arm received prophylactic granulocyte transfusions, the other arm received prophylactic broad‐spectrum antibiotics (vancomycin 2 g/24 hours, ticarcillin 300 mg/kg/24 hours (cefotaxime if allergic) and tobramycin 5 mg/kg/24 hours) ( Petersen 1987 ).
Four studies gave prophylactic antibiotics to all participants ( Ford 1982 ; Gomez‐Villagran 1984 ; Schiffer 1979 ; Winston 1980 ). Three studies did not give prophylactic antibiotics ( Mannoni 1979 ; Oza 2006 ; Strauss 1981 ). Three studies did not report whether prophylactic antibiotics were given ( Clift 1978 ; Sutton 1982 ; Vij 2003 ).
Five studies defined the empirical antibiotic treatment to be given if a patient had a febrile episode ( Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ; Strauss 1981 ; Winston 1980 ). Five studies did not specify the antibiotics to be given ( Clift 1978 ; Mannoni 1979 ; Schiffer 1979 ; Sutton 1982 ; Vij 2003 ).
Six studies gave therapeutic granulocyte transfusions to control participants ( Clift 1978 ; Mannoni 1979 ; Petersen 1987 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ). Two studies did not give therapeutic granulocyte transfusions to control participants ( Ford 1982 ; Gomez‐Villagran 1984 ). Three studies did not report whether therapeutic granulocyte transfusions were given ( Oza 2006 ; Schiffer 1979 ).
Specific regimens for antifungal diagnosis and therapy were not stated in any trial except for Oza 2006 who stated that Amphotericin B was used as therapy and Winston 1980 who stated that people remaining febrile for seven days and people with surveillance cultures that were positive for Candida or Aspergillus were eligible to receive amphotericin. Amphotericin B was the most widely used antifungal agent at the time of the other included studies.
Funding Sources
Six studies reported their funding sources, and all were funded by charities or governments ( Clift 1978 ; Ford 1982 ; Petersen 1987 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ).
Definition of infection (used to recruit uninfected people or identify those who became infected)
Studies also applied different criteria for definition of infection although defined in all studies on the basis of temperature, clinical signs and isolation of organisms.
Seven studies stated that patients with infections were excluded from the studies ( Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Winston 1980 ); the specific exclusion definitions varied (See Characteristics of included studies ).
Four studies did not specifically state whether infected patients were excluded from the studies ( Clift 1978 ; Oza 2006 ; Sutton 1982 ; Vij 2003 ), and in the Clift 1978 study it is clear in the analysis that some patients were on systemic antibiotics at enrolment.
Outcomes
Although few studies examined exactly the same range of outcomes, most trials reported mortality and survival (at different time points), information on fever (or days with fever), and information on episodes of infection (however defined), together with a measure of antibiotic use. (See Characteristics of included studies ).
Excluded studies
Twenty‐three studies within 27 citations did not meet the inclusion criteria for this review (See Characteristics of excluded studies ).
-
Twelve studies were excluded because they evaluated the therapeutic use of granulocyte transfusions ( Alavi 1977 ; Bow 1984 ; DRKS00000218 ; Herzig 1977 ; Higby 1975 ; Klastersky 2001 ; Price 2014 ; Scali 1978 ; Seidel 2008 ; Vogler 1977 ; Wheeler 1987 ; Winston 1982 )
-
Two studies evaluated the prophylactic use of granulocyte transfusions in neonates ( Baley 1987 ; Christensen 1982 )
-
Two studies compared two different types of granulocyte transfusions ( Ambinder 1981 ; Freireich 2013 )
-
Five studies were not randomised ( Altrichter 2011 ; Atay 2011 ; Ikemoto 2012 ; NCT01932710 ; UMIN000014777 )
-
One study included both randomised and allocated people, and the results of the study did not separate out these categories of enrolled participants.( Buckner 1983 )
-
One article study was a review ( Pammi 2011 )
Risk of bias in included studies
See Figure 2 and Figure 3 for visual representations of the assessments of risk of bias across all studies and for each item in the included studies. See the Characteristics of included studies section 'Risk of bias' table for further information about the bias identified within the individual studies.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Although nine of the 11 included studies were RCTs ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ), many of the studies had some threats to validity. The majority of these potential risks were due to a lack of detail on the specific criteria and were judged as "unclear risk" according to the Cochrane grading system. Two studies were quasi‐randomised studies that allocated participants to the intervention arm if they had a suitable donor ( Oza 2006 ; Vij 2003 ).
Allocation
We considered two studies to be at high risk of selection bias ( Oza 2006 ; Vij 2003 ). In Oza 2006 and Vij 2003 the recipient was "randomised" to the prophylactic granulocyte group if the donor who donated stem cells for the transplant was ABO‐matched and able to donate. Eight studies were at an unclear risk of bias because they did not report the methods of sequence generation or allocation concealment ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Petersen 1987 ; Schiffer 1979 ; Sutton 1982 ; Winston 1980 ). We considered one study ( Strauss 1981 ) to be at low risk of selection bias because it reported that separate randomisation schedules were prepared for each institute and stratum. An algorithm that ensured an approximate balance between treatment groups was used to generate each schedule. Participants were randomly assigned to receive daily granulocyte transfusions or not to receive them by a telephone call to the co‐ordinating centre.
Blinding
None of the studies provided any details on whether participants, investigators or outcome assessors were blinded to the intervention. For all subjective outcomes (all secondary outcomes of this review), we considered three studies to be at high risk of bias because they noted that the participants receiving prophylactic granulocyte transfusions did not require prophylactic platelet transfusions because of the number of platelets contained within the granulocyte transfusion ( Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ). Investigators would have been able to identify which participants were receiving prophylactic granulocyte transfusion even if they had been blinded to the intervention. We considered the other eight studies to be at an unclear risk of bias ( Clift 1978 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Vij 2003 ; Winston 1980 ).
Incomplete outcome data
We considered three studies to be at high risk of attrition bias due to the large number of participants who were randomised but not included in the final analysis ( Clift 1978 ; Ford 1982 ; Petersen 1987 ). Between 16% ( Petersen 1987 ) and 50% ( Ford 1982 ) of participants were randomised but not included within the analysis. In Clift 1978 and Petersen 1987 there was also a significant imbalance between the number of participants randomised and included within the study between those participants in the prophylactic granulocyte transfusion group and those in the control group.
Selective reporting
We could not assess this for any of the studies because protocols were not available to assess whether any pre‐specified outcomes were not reported or outcomes were reported that were not pre‐specified. We therefore classified all studies as at unclear risk of bias.
Other potential sources of bias
One study publication ( Vij 2003 ) was classified as an "advertisement" in accordance with 18 USC section 1734 because the publication costs of the article were defrayed in part by part charge payment, this study was classified as high risk because of this.
We classified the Mannoni 1979 study at high risk of bias because six participants had been re‐randomised within the study. We classified the Oza 2006 study at high risk of bias because people who were cytomegalovirus (CMV) mis‐matched with their donor were excluded from being in the prophylactic granulocyte transfusion group. This mis‐match may have increased the risk of CMV viraemia within the control group. We classified the Petersen 1987 study at high risk of bias because of the number of deviations from the original study design in the prophylactic granulocyte arm of the study.
The small numbers of participants in all the studies compromised the likelihood that there was equivalence in baseline and prognostic parameters. We therefore classified the seven other studies at unclear risk of bias ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ).
Effects of interventions
See: Summary of findings for the main comparison
See summary of findings Table for the main comparison .
The Vij 2003 study reported none of the outcomes pre‐specified in our review. We contacted the study authors who were unable to provide any additional data not reported in the original paper . Therefore, data were available for only 10 of the 11 included studies ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ).
All‐cause mortality (10 studies)
All‐cause mortality was reported by 10 studies ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ) ( Table 2 ). The time points for assessment of mortality varied between studies. Eight studies reported mortality up to 30 days ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Schiffer 1979 ; Strauss 1981 ; Winston 1980 ); one study reported mortality up to 100 days ( Petersen 1987 ); and one study reported mortality over 100 days ( Sutton 1982 ).
|
Study |
Number of participants randomised |
Number of participants analysed |
Prophylactic Granulocytes |
Control |
|
Mortality at up to 21 days |
||||
|
86 |
69 |
0/29 |
1/40 |
|
|
35 |
35 |
2/19 |
6/16 |
|
|
Mortality at up to 30 days |
||||
|
49 |
24 |
3/13 |
2/11 |
|
|
44 |
44 in 50 episodes of aplasia |
0/20 |
4/26 |
|
|
151 |
151 |
2/53 |
5/98 |
|
|
22 |
18 |
0/9 |
2/9 |
|
|
102 |
102 |
12/54 |
6/48 |
|
|
38 |
38 |
13/19 |
13/19 |
|
|
Mortality at up to 100 days |
||||
|
134 |
112 |
21/67 |
11/45 |
|
|
Mortality over 100 days |
||||
|
67 |
64 |
19/28 |
25/36 |
|
The Mannoni 1979 study re‐randomised six participants and the information was therefore not included within the meta‐analysis. Information on overall mortality was available and extracted from nine studies ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ).
Seven studies (437 participants) reported mortality up to 30 days ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ; Schiffer 1979 ; Strauss 1981 ; Winston 1980 ). A meta‐analysis showed no difference between participants receiving prophylactic granulocyte transfusions and those that did not (risk ratio (RR) 0.92; 95% confidence interval (CI) 0.63 to 1.36) ( Analysis 1.1 ), nor was any difference seen if only studies that gave a median granulocyte dose of over 1 x 10 10 /L per day were included (four studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Oza 2006 ; Winston 1980 ); 293 participants; RR 0.74; 95% CI 0.47 to 1.16) ( Analysis 1.1 ).
One study reported all‐cause mortality up to 100 days ( Petersen 1987 ). There was no difference in all‐cause mortality between participants receiving prophylactic granulocyte transfusions and those that did not (112 participants; RR 1.28; 95% CI 0.69 to 2.39) ( Analysis 1.2 ).
One study reported all‐cause mortality over 100 days ( Sutton 1982 ). There was no difference in all‐cause mortality between participants receiving prophylactic granulocyte transfusions and those that did not (65 participants; RR 0.94; 95% CI 0.67 to 1.33) ( Analysis 1.3 ).
Mortality due to infection (eight studies)
Mortality due to infection was reported by eight studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ) ( Table 3 ). The Mannoni 1979 study re‐randomised six participants and the information was therefore not included within the meta‐analysis.
|
Study |
Number of participants randomised |
Number of participants analysed |
Prophylactic Granulocytes |
Control |
|
Mortality at up to 21 days |
||||
|
86 |
69 |
0/29 |
1/40 |
|
|
35 |
35 |
0/19 |
4/16 |
|
|
Mortality at up to 30 days |
||||
|
49 |
24 |
1/13 |
1/11 |
|
|
44 |
44 in 50 episodes of aplasia |
0/20 |
2/26 |
|
|
22 |
18 |
0/9 |
2/0 |
|
|
102 |
102 |
8/54 |
4/48 |
|
|
38 |
38 |
1/19 |
2/19 |
|
|
Mortality at up to 100 days |
||||
|
134 |
112 |
3/67 |
2/45 |
|
Six studies (286 participants) reported mortality due to infection up to 30 days ( Clift 1978 ; Gomez‐Villagran 1984 ; Oza 2006 ; Schiffer 1979 ; Strauss 1981 ; Winston 1980 ). A meta‐analysis showed no difference between participants receiving prophylactic granulocyte transfusions and those that did not (RR 0.69; 95% CI 0.33 to 1.44) ( Analysis 1.4 ), nor was any difference seen if only studies that gave a median granulocyte dose of over 1 x 10 10 /L per day were included (three studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Winston 1980 ); 142 participants; RR 0.25; 95% CI 0.06 to 1.10) ( Analysis 1.4 ).
One study reported mortality due to infection up to 100 days ( Petersen 1987 ). There was no difference in mortality due to infection between participants receiving prophylactic granulocyte transfusions and those that did not (112 participants; RR 1.01; 95% CI 0.18 to 5.79) ( Analysis 1.5 ).
Number of infection episodes (10 studies)
The numbers of localised or systemic bacterial or fungal infections were reported by 10 studies. ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ) ( Table 4 ). The Mannoni 1979 study re‐randomised six participants and the information was therefore not included within the meta‐analysis.
|
Study |
Number of participants analysed |
Total number of participants with an infection |
Localised infections (excluding oral candida) |
Systemic infections (Bacteraemia or fungaemia) |
|||
|
Prophylactic Granulocytes |
Control |
Prophylactic Granulocytes |
Control |
Prophylactic Granulocytes |
Control |
||
|
69 |
2/29 |
17/40 |
2 participants 1 Candidal oesophagitis 1 Rhinitis due to coagulase positive staphylococcus |
7 participants |
0 participants |
10 participants 2 Escherichia coli 2 Pseudomonas aeruginosa 2 Corynebacteria 2 Beta‐haemolytic streptococci 1 Serratia 1 Enterobacter |
|
|
24 |
4/13 |
7/11 |
3 participants 1 Pneumonia 1 Cellulitis & Abscess 1 Enteritis |
5 participants 3 Pneumonia 1 Cellulitis & Abscess 1 Enteritis |
1 participant 1 Klebsiella pneumoniae |
3 participants 2 Staphylococcus aureus 1 Staphylococcus alba |
|
|
35 |
4/19 |
10/16 |
4 participants 1 Pneumonia 0 Cellulitis & Abscess 3 Pharyngitis |
6 participants 2 Pneumonia 2 Cellulitis & Abscess 2 Pharyngitis |
0 participants |
4 participants 2 Escherichia coli 1 Pseudomonas aeruginosa 1 Staphylococcus aureus |
|
|
44 (50 episodes of aplasia) |
1/20 |
11/26 |
1 episode 0 Pneumonia 1 Cellulitis & Abscess |
15 episodes 8 Pneumonia 4 Cellulitis & Abscess 3 Enteritis |
0 participants |
Not reported |
|
|
151 |
7/53 |
29/98 |
Not reported |
Not reported |
7 participants bacteraemia (not further defined) |
29 participants bacteraemia (not further defined) |
|
|
112 |
26/67 |
18/45 |
15 participants 0 Pneumonia 5 Colitis 1 Sinusitis 1 Mouth/throat 2 Urinary tract infection 4 RAC site 4 Other |
9 participants 2 Pneumonia 1 Colitis 2 Sinusitis 2 Mouth/throat 1 Urinary tract infection 1 RAC site 1 Other |
13 participants 10 Coagulase ‐ive Staphylococcus 1 Candida 2 Streptococcus 3 Gram ‐ive bacilli |
11 participants 4 Coagulase ‐ive Staphylococcus 4 Candida 0 Streptococcus 5 Gram ‐ive bacilli |
|
|
18 |
2/9 |
6/9 |
2 participants 1 Cellulitis 1 Sinusitis |
5 participants 2 Pulmonary aspergillosis 2 Cellulitis 1 Oesophagitis |
0 participants |
1 participant 1 T. glabrata |
|
|
102 |
25/54 |
20/48 |
12 Pneumonia 5 Cellulitis 3 Abscess 3 Urinary tract infection |
6 Pneumonia 3 Cellulitis 3 Abscess 1 Urinary tract infection |
8 episodes 2 Gram +ive septicaemia 3 Gram ‐ive septicaemia 3 fungal isolates |
14 episodes 8 Gram +ive septicaemia 8 Gram ‐ive septicaemia 1 fungal isolate |
|
|
60 |
3/29 |
4/31 |
Not reported |
Not reported |
3 episodes 1 Escherichia coli 1 Pseudomonas aeruginosa 1 Klebsiella pneumoniae |
4 episodes 1 Escherichia coli 1 Pseudomonas aeruginosa 2 Klebsiella pneumoniae |
|
|
38 |
7/19 |
9/19 |
7 participants 3 Pneumonia 4 Cellulitis & Abscess 0 Urinary tract infection |
6 participants 3 Pneumonia 3 Cellulitis & Abscess 0 Urinary tract infection |
0 participants |
3 participants 1 Streptococcus viridans 1 Staphylococcus epidermidis 1 Enterococcus |
|
* Data for this trial are for the first 30 days when participants were granulocytopenic prior to engraftment. Data are for a similar time period to the other studies.
RAC = right atrial catheter
Nine studies (609 participants) reported localised or systemic infections up to 30 days ( Clift 1978 ; Gomez‐Villagran 1984 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ). A meta‐analysis showed that there were significant differences between the granulocyte dose subgroups (test for subgroup differences: Chi² = 8.54, df = 2 (P = 0.01), I² = 76.6%) ( Analysis 1.6 ). We therefore did not perform an overall analysis.
In the intermediate granulocyte dose group, participants receiving prophylactic granulocyte transfusions had fewer infections (four studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Oza 2006 ; Winston 1980 ); 293 participants; RR 0.40; 95% CI 0.26 to 0.63) ( Analysis 1.6 ). In the low‐dose subgroup no difference was seen between those participants who received prophylactic granulocytes and those that did not (four studies ( Ford 1982 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ); 204 participants; RR 0.84; 95% CI 0.58 to 1.20) ( Analysis 1.6 ).
As there was clinical heterogeneity between studies in the types of infections reported, we performed separate meta‐analyses for systemic infections (bacteraemia and fungaemia) and localised infections (bacterial or fungal infections excluding oral candidaemia).
Nine studies (609 participants) reported systemic infections ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ). A meta‐analysis showed that overall, there was a reduction in the number of bacteraemias and fungaemias in the participants receiving granulocyte transfusions (RR 0.45; 95% CI 0.30 to 0.65) ( Analysis 1.7 ); this effect was most marked in those studies giving an intermediate dose of granulocytes (four studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Oza 2006 ; Winston 1980 ); 293 participants; RR 0.28; 95% CI 0.14 to 0.55) ( Analysis 1.7 ).
Excluding the data for the study that compared prophylactic granulocyte transfusions versus prophylactic antibiotics from the analysis had no effect on the overall result ( Petersen 1987 ), (RR 0.37; 95% CI 0.23 to 0.59) ( Analysis 1.8 ).
Six studies (296 participants) reported localised infections ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Petersen 1987 ; Schiffer 1979 ; Winston 1980 ). A meta‐analysis showed that overall, there was no difference in the number of localised infections between participants receiving prophylactic granulocyte transfusions and those that did not (RR 0.75; 95% CI 0.50 to 1.14) ( Analysis 1.9 ). There was also no difference seen when only those studies giving an intermediate dose of granulocytes were included in the analysis (three studies ( Clift 1978 ; Gomez‐Villagran 1984 ; Winston 1980 ); 142 participants; RR 0.71; 95% CI 0.38 to 1.31) ( Analysis 1.9 ).
Excluding the data for the study that compared prophylactic granulocyte transfusions versus prophylactic antibiotics from the analysis had no effect on the overall result ( Petersen 1987 ), (RR 0.62; 95% CI 0.37 to 1.02) ( Analysis 1.10 ).
Number of days with fever (five studies)
Five studies reported the number of days with fever ( Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ; Schiffer 1979 ; Winston 1980 ). These data were reported in different ways and could not be incorporated in to a meta‐analysis ( Table 5 ). There was no obvious trend in the number of days with fever between studies.
|
Study |
Number of participants analysed |
Number of days with fever |
Number of participants receiving antibiotics |
Number of days with antibiotics |
Number of participants receiving antifungal medication |
||||
|
Prophylactic granulocytes |
Control |
Prophylactic granulocytes |
Control |
Prophylactic granulocytes |
Control |
Prophylactic granulocytes |
Control |
||
|
31* |
Not reported |
Not reported |
9/16 |
13/15 |
Not reported |
Not reported |
Not reported |
Not reported |
|
|
19 # |
Median 4.5 (range 0 to 18) |
Median 9 (range 3 to 12) |
9/10 |
9/9 |
Median 8 (range 0 to 15) |
Median 10.5 (range 6 to 16) |
Not reported |
Not reported |
|
|
35 |
5.1 ± 3.5 |
6 ± 5.6 |
11/19 |
13/16 |
6.7 ± 4.4 |
7.8 ± 6.2 |
Not reported |
Not reported |
|
|
151 |
Median 2 (range 0 to 15) |
Median 2 (range 0 to 17) |
53/53 |
97/98 |
Median 9 (range 1 to 20) |
Median 11 (range 0 to 26) |
Not reported |
Not reported |
|
|
112 |
Not reported |
Not reported |
Not reported |
Not reported |
Not reported |
Not reported |
33 |
29 |
|
|
18 |
Mean 9 (range 2 to 16) |
Mean 9 (range 2 to 18) |
Not reported |
Not reported |
Mean 13 (range 7 to 25) |
Mean 13 (range 9 to 20) |
Not reported |
Not reported |
|
|
38 |
10.1 (SE 1.3) |
7.7 (SE 1.7) |
18 |
15 |
10.5 (SE 1.6) |
8.2 (SE 1.8) |
5 |
5 |
|
* Participants who were not on antibiotics at the start of the study
# Participants who did not die during the first 26 days of the study
SE = standard error
Number of days on treatment with antimicrobials (courses of treatment with antibiotics/antifungals) (five studies)
Five studies reported the number of days on treatment with antibiotics ( Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ; Schiffer 1979 ; Winston 1980 ). these data were reported in different ways and could not be incorporated in to a meta‐analysis ( Table 5 ). Three of the five studies showed a slightly lower number of days on antibiotics in the prophylactic granulocyte arm of the study ( Ford 1982 ; Gomez‐Villagran 1984 ; Oza 2006 ); one study showed no difference ( Schiffer 1979 ); and one study showed an increased number of days on antibiotics ( Winston 1980 ).
Increment of neutrophil count (x10 9 /L) (six studies)
Neutrophil increments were reported as an absolute rise in the peripheral blood neutrophil count, known as the count increment, or as a corrected count increment see Table 6 . The data could not be incorporated in to a meta‐analysis because of the different ways the data had been reported.
|
Study |
Total number of granulocyte transfusions |
1 hour absolute neutrophil increment |
1 hour corrected count increment |
Duration of neutropenia reversal |
|
|
On antibiotics |
Not on antibiotics |
||||
|
360 |
Not reported |
CFC Median 0.28 x 10 9 /L (Range 0 to 1.16) LF Median 0.06 x 10 9 /L (Range 0 to 0.49) |
CFC Median 0.38 x 10 9 /L (Range 0.1 to 1.32) LF Median 0.06 x 10 9 /L (Range 0 to 0.32) |
Not reported |
|
|
107 |
Median 0.32 x 10 9 /L |
Not reported |
Not reported |
||
|
254 |
Not reported |
Mean 0.41 x 10 9 /L (Range 0.04 to 1.15) |
Mean 0.50 x 10 9 /L (Range 0.19 to 1.14) |
Not reported |
|
|
Not reported |
Not reported |
Average 0.30 x 10 9 /L |
Not reported |
||
|
Not reported |
Most < 0.15 x 10 9 /L |
Not reported |
Not reported |
||
|
Not reported |
Not reported |
Mean 0.12 x 10 9 /L (range 0 to 0.66) |
Not reported |
||
CFC = continuous flow centrifugation
LF = leucofiltration
Six studies report the count increment or corrected count increment ( Clift 1978 ; Ford 1982 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Schiffer 1979 ; Winston 1980 ). Two studies reported the count increment, and it varied from a median of < 0.15 x 10 9 /L to 0.32 x 10 9 /L ( Ford 1982 ; Schiffer 1979 ). Four studies reported the corrected count increment ( Clift 1978 ; Gomez‐Villagran 1984 ; Mannoni 1979 ; Winston 1980 ), and it varied from a median of 0.06 x 10 9 /L ( Clift 1978 ) to a mean of 0.5 x 10 9 /L ( Gomez‐Villagran 1984 ).
Duration of neutropenia reversal after transfusion (neutropenia defined as count below 0.5 x 10 9 /L)
None of the studies reported the duration of neutropenia reversal after transfusion.
Serious adverse events: resulting in death, requiring or prolonging hospitalisation, resulting in persistent or significant disability/incapacity, or life‐threatening (four studies)
Serious adverse events were reported by four studies ( Table 7 ). One study reported a donor event ( Clift 1978 ), and three studies reported recipient events ( Ford 1982 ; Gomez‐Villagran 1984 ; Sutton 1982 ).
|
Study |
Number of participants receiving granulocyte transfusions |
Number of granulocyte transfusions |
Donor events |
Recipient events |
|
29 prophylactic 16 therapeutic |
360 |
1 1 ‐ haemodynamic compromise |
0 |
|
|
13 prophylactic |
107 |
0 |
1 1 ‐ TA GvHD |
|
|
19 prophylactic |
254 |
Not reported |
7 1 ‐ haemolysis 6 ‐ dyspnoea & cyanosis |
|
|
29 prophylactic 2 therapeutic |
Not reported |
Not reported |
3 3 ‐ dyspnoea and wheeze |
TA GvHD = Transfusion‐associated Graft versus Host Disease
Clift 1978 described an episode of haemodynamic compromise due to loss of blood after a section of tubing was accidentally disconnected.
Ford 1982 described one death due to transfusion‐associated graft versus host disease in a participant who had received 10 granulocyte transfusions that had not been irradiated from related donors.
Gomez‐Villagran 1984 described one case of haemolysis due to passive transfer of anti‐A , and six pulmonary reactions (dyspnoea, cyanosis, but no pulmonary infiltrates on chest X‐ray).
Sutton 1982 described severe dyspnoea and wheezing in three participants.
Adverse events requiring discontinuation of intervention (six studies)
Adverse events requiring discontinuation of the granulocyte transfusions were reported for six studies ( Clift 1978 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ) (See Table 8 ). Two studies reported donor events ( Clift 1978 ; Petersen 1987 ) and six studies reported recipient events ( Clift 1978 ; Petersen 1987 ; Schiffer 1979 ; Strauss 1981 ; Sutton 1982 ; Winston 1980 ).
|
Study |
Number of participants receiving granulocyte transfusions |
Total number of granulocyte transfusions |
Donor events |
Recipient events |
|
29 prophylactic 16 therapeutic |
360 |
4 1 ‐ haemodynamic compromise 1 ‐ abdominal cramps 2 ‐ recurrent blocking of port |
0 |
|
|
67 prophylactic 4 therapeutic |
Not reported |
6 1 ‐ low platelet count 1 ‐ bleeding from arterio‐venous shunt 4 ‐ obstruction of lumen of shunt or catheter |
13 5 ‐ transfusion reactions 3 ‐ no increment in granulocyte count 5 ‐ donor required for platelet transfusions |
|
|
10 prophylactic 0 therapeutic |
Not reported |
Not reported |
1 1 ‐ diffuse pulmonary infiltrate |
|
|
54 prophylactic |
987 |
Not reported |
6 (not further defined) |
|
|
29 prophylactic 2 therapeutic |
Not reported |
Not reported |
5 (not further defined) |
|
|
19 prophylactic 6 therapeutic |
Not reported |
Not reported |
0 |
Discussion
Summary of main results
This Cochrane review aimed to evaluate the literature on the effectiveness and safety of prophylactic granulocyte transfusions. This review should be read in conjunction with another review undertaken to evaluate the randomised trial evidence base for the use of therapeutic granulocyte transfusions ( Stanworth 2005 ).
We identified 12 randomised and quasi‐randomised trials that met our inclusion criteria; one of which is still ongoing ( NCT01204788 ). Eleven trials were included in this review containing a total of 653 participants. These trials were conducted between 1978 and 2006 and enrolled participants from fairly comparable patient populations. None of the studies included people with neutrophil dysfunction. Ten of these studies contained separate data for each arm and were able to be critically appraised. One study re‐randomised participants and therefore quantitative analysis was unable to be performed.
The findings of the review led to the following main conclusions.
-
There was insufficient evidence to detect a difference in all‐cause mortality between people receiving prophylactic granulocyte transfusions and those that did not. This was measured over 30 days in seven studies (437 participants; RR 0.92, 95% CI 0.63 to 1.36).
-
There was insufficient evidence to detect a difference in mortality due to infection between people receiving prophylactic granulocyte transfusions and those that did not. This was measured over 30 days in six studies (286 participants; RR 0.69, 95% CI 0.33 to 1.44).
-
There were differences between the granulocyte dose subgroups (test for subgroup differences P = 0.01) in the number of people with localised or systemic bacterial or fungal infections. There was no difference in the number of people with infections in the low‐dose granulocyte group (< 1.0 x 10 10 granulocytes per day) between people receiving prophylactic granulocyte transfusions and those that did not (four studies, 204 participants; RR 0.84, 95% CI 0.58 to 1.20). There was a decreased number of people with infections over 30 days in the people receiving prophylactic granulocyte transfusions in the intermediate‐dose granulocyte group (1.0 x 10 10 to 4.0 x 10 10 granulocytes per day) (4 studies; 293 participants; RR 0.4, 95% CI 0.26 to 0.63). There was a decreased number of people with bacteraemia and fungaemia in the people receiving prophylactic granulocyte transfusions (nine studies; 609 participants; RR 0.45, 95% CI 0.30 to 0.65). There was no difference in the number of people with localised bacterial or fungal infection in the people receiving prophylactic granulocyte transfusions (six studies; 296 participants; RR 0.75, 95% CI 0.50 to 1.14).
-
There was insufficient evidence to detect a difference in the number of serious adverse events between people receiving prophylactic granulocyte transfusions and those that did not. This was because serious adverse events were only reported for people receiving granulocyte transfusions and donors of granulocyte transfusions.
-
There was no obvious trend in the number of days with fever, or number of days with antibiotics between people receiving prophylactic granulocyte transfusions and those that did not.
-
None of the studies reported the duration of neutropenia reversal.
Overall completeness and applicability of evidence
This review provides the most up‐to‐date assessment of the effectiveness and safety of a prophylactic granulocyte transfusion policy compared with not administering prophylactic granulocyte transfusions. This updated review identified one additional quasi‐randomised trial ( Vij 2003 ). This review provides some low‐quality evidence that prophylactic granulocytes decrease the risk of developing a bacterial or fungal infection.
However, the results of this review should not be interpreted without considering the impact of the following factors.
-
The studies included in this review range over a 28‐year period (1978 to 2006) during which chemotherapy protocols, predicted survival rates, supportive care, including antibiotics and antifungal medication, have changed substantially. Newer less toxic antifungal drug options are now available.
-
None of the studies reported on quality control measures operating for blood components, including granulocytes, and current blood components may be manufactured to a higher specification than in the time period of these studies.
-
Only two of the studies gave granulocyte colony‐stimulating factor (G‐CSF) to the granulocyte donors ( Oza 2006 ; Vij 2003 ).
-
None of the studies assessed the use of granulocytes derived from whole blood donations ( Bashir 2008 ). This component has been assessed in a small safety study ( Massey 2012 ). The process of obtaining granulocyte collections from directed G‐CSF and/or steroid‐stimulated donors who are 'family and friends' of patients or unrelated donors involves multiple steps. It is important that family and 'friends' of patients are given time and adequate explanation of the small risks to which they are exposed by both taking specific drugs (steroids or G‐CSF, or both) to mobilise granulocytes into the peripheral blood and by undergoing an apheresis procedure. To date, most of these risks have been theoretical or weak associations only but posterior capsular cataracts, splenic rupture and venous thrombosis have been described ( Bennett 2006 ; Ghodsi 2001 ; Goldman 2006 ; Gutierrez 2001 ). There are also a number of potentially important constraints that can limit provision of apheresis products on a regular and timely basis; e.g. hospitals in Europe managing granulocyte collections by apheresis now have a requirement for meeting 'blood establishment status' according to EU legislation.
-
One study ( Petersen 1987 ), compared prophylactic granulocyte transfusions with prophylactic broad‐spectrum antibiotics. Data from this study were only incorporated into meta‐analyses for two outcomes, people with bacteraemia of fungaemia and people with localised bacterial or fungal infection. There was no significant difference to the overall analysis when results from this study were excluded.
-
Not all end points from the studies could be analysed due to varying methods of reporting the outcomes. This was true for: numbers of days with fever; number of days on treatment with antimicrobials (or courses of treatment with antibiotics/antifungals); and increment of neutrophil count (x10 9 /L).
-
In three of the studies many of the participants enrolled were not included in the final analysis ( Clift 1978 ; Ford 1982 ; Petersen 1987 ). Between 16% ( Petersen 1987 ) and 50% ( Ford 1982 ) of participants were randomised but not included within the analysis.
Quality of the evidence
Overall, the quality of the evidence was rated as very low to low across different outcomes according to GRADE methodology ( summary of findings Table for the main comparison ). This was due to many of the studies being at high risk of bias, and many of the outcome estimates being imprecise.
Two outcomes were considered low‐grade quality evidence according to GRADE methodology due to the very serious risk of bias of the included studies.
-
People with localised or systemic bacterial or fungal infections ‐ Intermediate‐dose granulocyte transfusions.
-
People with bacteraemia or fungaemia.
This was because of: a high risk of selection bias because two studies were quasi‐randomised; a high risk of attrition bias because three studies did not include a significant proportion of randomised people in the analysis; and a high risk of performance bias and detection bias due to the nature of the intervention (granulocyte transfusion) and difficulty blinding participants, physicians and outcome assessors.
Four outcomes were considered very low‐grade quality evidence according to GRADE methodology due to the very serious risk of bias of the included studies (see above) and the serious imprecision of the estimates.
-
All‐cause mortality.
-
Mortality due to infection.
-
People with localised or systemic bacterial or fungal infections ‐ low‐dose granulocyte transfusions.
-
People with localised bacterial or fungal infection.
The reason for the imprecision is because of the small number of participants within the trials and the low number of events. For example, if we assume an all‐cause mortality rate of 14.5% (overall rate within the included studies within this review up to 30 days), we need a sample size of approximately 15,000 participants to be able to detect with 90% power the ability to save two extra lives per 100 people within a 30‐day period.
See Figure 2 and Figure 3 for visual representations of the assessments of risk of bias across all studies and for each item in the individual studies.
Potential biases in the review process
To our knowledge, our review process is free from bias. We conducted a comprehensive search; searching data sources (including multiple databases, and clinical trial registries) to ensure that all relevant trials would be captured. There were no restrictions for the language in which the paper was originally published. The relevance of each paper was carefully assessed and all screening and data extractions were performed in duplicate. We pre‐specified all outcomes and subgroups prior to analysis. There were insufficient numbers of included studies within the meta‐analyses for us to use a funnel plot to examine the risk of publication bias.
Agreements and disagreements with other studies or reviews
We know of no other recent systematic reviews on the use of prophylactic granulocyte transfusions in people with neutropenia or neutrophil dysfunction. The last review on this subject was the previous version of this review ( Massey 2009 ). Although the methodology of the review has changed in this update of the review to conform to current Cochrane Collaboration recommendations, the overall message of the review is unaltered.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 1 All‐cause mortality up to 30 days.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 2 All‐cause mortality up to 100 days.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 3 All‐cause mortality over 100 days.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 4 Mortality due to infection up to 30 days.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 5 Mortality due to infection up to 100 days.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 6 People with localised or systemic bacterial or fungal infections.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 7 People with bacteraemia or fungaemia.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 8 People with bacteraemia or fungaemia (excluding study that compared prophylactic granulocyte transfusions versus prophylactic broad‐spectrum antibiotics).
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 9 People with localised bacterial or fungal infection.
Comparison 1 Prophylactic granulocytes versus no prophylactic granulocytes, Outcome 10 People with localised bacterial or fungal infection (excluding study that compared prophylactic granulocyte transfusions versus prophylactic broad‐spectrum antibiotics).
|
Prophylactic granulocytes compared with no prophylactic granulocytes for preventing infection in people with neutropenia or neutrophil dysfunction |
||||||
|
Patient or population: people with neutropenia or neutrophil dysfunction Settings: Hospital Intervention: prophylactic granulocytes Comparison: no prophylactic granulocytes |
||||||
|
Outcomes |
Illustrative comparative risks* (95% CI) |
Relative effect
|
No of Participants
|
Quality of the evidence
|
Comments |
|
|
Assumed risk |
Corresponding risk |
|||||
|
Control |
Prophylactic granulocytes |
|||||
|
All‐cause mortality up to 30 days Follow‐up: median 30 days |
145 per 1000 |
134 per 1000 (91 to 198) |
RR 0.92 (0.63 to 1.36) |
437
|
⊕⊝⊝⊝
|
|
|
Mortality due to infection up to 30 days Follow‐up: median 30 days |
98 per 1000 |
68 per 1000
|
RR 0.69 (0.33 to 1.44) |
286
|
⊕⊝⊝⊝
|
|
|
People with localised or systemic bacterial or fungal infections ‐ low‐dose granulocyte transfusions Follow‐up: median 30 days |
374 per 1000 |
314 per 1000
|
RR 0.84 (0.58 to 1.2) |
204
|
⊕⊝⊝⊝
|
|
|
People with localised or systemic bacterial or fungal infections ‐ Intermediate‐dose granulocyte transfusions Follow‐up: median 30 days |
376 per 1000 |
150 per 1000 (98 to 237) |
RR 0.4 (0.26 to 0.63) |
293
|
⊕⊕⊝⊝
|
|
|
People with bacteraemia or fungaemia Follow‐up: median 30 days |
249 per 1000 |
112 per 1000 (75 to 162) |
RR 0.45 (0.3 to 0.65) |
609
|
⊕⊕⊝⊝
|
|
|
People with localised bacterial or fungal infection Follow‐up: median 30 days |
271 per 1000 |
204 per 1000 (136 to 309) |
RR 0.75 (0.50 to 1.14) |
296
|
⊕⊝⊝⊝
|
|
|
People with serious adverse events |
See comment |
See comment |
See comment |
See comment |
See comment |
Adverse events were only reported for the groups receiving granulocyte transfusions |
|
*The basis for the
assumed risk
(e.g. the median control group risk across studies) is provided in footnotes. The
corresponding risk
(and its 95% confidence interval) is based on the assumed risk in the comparison group and the
relative effect
of the intervention (and its 95% CI).
|
||||||
|
GRADE Working Group grades of evidence
|
||||||
|
1
Owing to the nature of the intervention (granulocyte transfusion) and difficulty blinding participants, physicians and outcome assessors studies were at high risk of performance and detection bias. We downgraded the evidence by 1 for risk of bias
|
||||||
|
Study |
Mean dose of granulocyte transfusions |
Range of doses of granulocyte transfusions |
Frequency of transfusions |
Total number of transfusions per patient Mean/median and range |
|
0.6 x 10 10* |
Not reported |
Daily |
18.5 (mean) (3 to 28) |
|
|
0.9 x 10 10 |
0.2 to 2.5 x 10 10 |
Daily |
Not reported |
|
|
1.2 x 10 10 |
0.3 to 3.5 x 10 10 |
Daily |
23.4 mean (13 to 34) |
|
|
1.24 x 10 10 |
0.55 to 4.2 x 10 10 |
Daily |
6.16 (mean) (5 to 11) |
|
|
2.22 x 10 10 (leucofiltration) 1.57 x 10 10 (centrifugation) |
Not reported |
Daily |
12.4 (mean) (6 to 25) |
|
|
2.1 x 10 10 |
1.3 to 3.7 |
Daily |
12 (mean) (8 to 15) |
|
|
Not reported |
Not reported |
Daily |
12 (median) (6 to 27) |
|
|
1.15 x 10 10 |
0.34 to 2.4 x 10 10 |
4/7 days per week |
11 (mean) (3 to 19) |
|
|
1.45 x 10 10 |
0.28 to 3.45 |
Alternate days |
7 (median) (1 to 12) |
|
|
5.9 x 10 10 (first dose) 5.2 x 10 10 (second dose) |
0.02 to 15.5 (first dose) 0.02 to 21.0 ( second dose) |
Twice |
2 |
|
|
Not reported |
Not reported |
Twice |
2 |
|
|
* Strauss ( Strauss 1981 ) did not express the dose given in terms of absolute numbers of granulocytes but described the median dose as 0.34 x 10 10 per square metre of recipient body surface area. (This would approximate to a dose of 0.6 x 10 10 as all participants were over 12 years old). |
||||
|
Study |
Number of participants randomised |
Number of participants analysed |
Prophylactic Granulocytes |
Control |
|
Mortality at up to 21 days |
||||
|
86 |
69 |
0/29 |
1/40 |
|
|
35 |
35 |
2/19 |
6/16 |
|
|
Mortality at up to 30 days |
||||
|
49 |
24 |
3/13 |
2/11 |
|
|
44 |
44 in 50 episodes of aplasia |
0/20 |
4/26 |
|
|
151 |
151 |
2/53 |
5/98 |
|
|
22 |
18 |
0/9 |
2/9 |
|
|
102 |
102 |
12/54 |
6/48 |
|
|
38 |
38 |
13/19 |
13/19 |
|
|
Mortality at up to 100 days |
||||
|
134 |
112 |
21/67 |
11/45 |
|
|
Mortality over 100 days |
||||
|
67 |
64 |
19/28 |
25/36 |
|
|
Study |
Number of participants randomised |
Number of participants analysed |
Prophylactic Granulocytes |
Control |
|
Mortality at up to 21 days |
||||
|
86 |
69 |
0/29 |
1/40 |
|
|
35 |
35 |
0/19 |
4/16 |
|
|
Mortality at up to 30 days |
||||
|
49 |
24 |
1/13 |
1/11 |
|
|
44 |
44 in 50 episodes of aplasia |
0/20 |
2/26 |
|
|
22 |
18 |
0/9 |
2/0 |
|
|
102 |
102 |
8/54 |
4/48 |
|
|
38 |
38 |
1/19 |
2/19 |
|
|
Mortality at up to 100 days |
||||
|
134 |
112 |
3/67 |
2/45 |
|
|
Study |
Number of participants analysed |
Total number of participants with an infection |
Localised infections (excluding oral candida) |
Systemic infections (Bacteraemia or fungaemia) |
|||
|
Prophylactic Granulocytes |
Control |
Prophylactic Granulocytes |
Control |
Prophylactic Granulocytes |
Control |
||
|
69 |
2/29 |
17/40 |
2 participants 1 Candidal oesophagitis 1 Rhinitis due to coagulase positive staphylococcus |
7 participants |
0 participants |
10 participants 2 Escherichia coli 2 Pseudomonas aeruginosa 2 Corynebacteria 2 Beta‐haemolytic streptococci 1 Serratia 1 Enterobacter |
|
|
24 |
4/13 |
7/11 |
3 participants 1 Pneumonia 1 Cellulitis & Abscess 1 Enteritis |
5 participants 3 Pneumonia 1 Cellulitis & Abscess 1 Enteritis |
1 participant 1 Klebsiella pneumoniae |
3 participants 2 Staphylococcus aureus 1 Staphylococcus alba |
|
|
35 |
4/19 |
10/16 |
4 participants 1 Pneumonia 0 Cellulitis & Abscess 3 Pharyngitis |
6 participants 2 Pneumonia 2 Cellulitis & Abscess 2 Pharyngitis |
0 participants |
4 participants 2 Escherichia coli 1 Pseudomonas aeruginosa 1 Staphylococcus aureus |
|
|
44 (50 episodes of aplasia) |
1/20 |
11/26 |
1 episode 0 Pneumonia 1 Cellulitis & Abscess |
15 episodes 8 Pneumonia 4 Cellulitis & Abscess 3 Enteritis |
0 participants |
Not reported |
|
|
151 |
7/53 |
29/98 |
Not reported |
Not reported |
7 participants bacteraemia (not further defined) |
29 participants bacteraemia (not further defined) |
|
|
112 |
26/67 |
18/45 |
15 participants 0 Pneumonia 5 Colitis 1 Sinusitis 1 Mouth/throat 2 Urinary tract infection 4 RAC site 4 Other |
9 participants 2 Pneumonia 1 Colitis 2 Sinusitis 2 Mouth/throat 1 Urinary tract infection 1 RAC site 1 Other |
13 participants 10 Coagulase ‐ive Staphylococcus 1 Candida 2 Streptococcus 3 Gram ‐ive bacilli |
11 participants 4 Coagulase ‐ive Staphylococcus 4 Candida 0 Streptococcus 5 Gram ‐ive bacilli |
|
|
18 |
2/9 |
6/9 |
2 participants 1 Cellulitis 1 Sinusitis |
5 participants 2 Pulmonary aspergillosis 2 Cellulitis 1 Oesophagitis |
0 participants |
1 participant 1 T. glabrata |
|
|
102 |
25/54 |
20/48 |
12 Pneumonia 5 Cellulitis 3 Abscess 3 Urinary tract infection |
6 Pneumonia 3 Cellulitis 3 Abscess 1 Urinary tract infection |
8 episodes 2 Gram +ive septicaemia 3 Gram ‐ive septicaemia 3 fungal isolates |
14 episodes 8 Gram +ive septicaemia 8 Gram ‐ive septicaemia 1 fungal isolate |
|
|
60 |
3/29 |
4/31 |
Not reported |
Not reported |
3 episodes 1 Escherichia coli 1 Pseudomonas aeruginosa 1 Klebsiella pneumoniae |
4 episodes 1 Escherichia coli 1 Pseudomonas aeruginosa 2 Klebsiella pneumoniae |
|
|
38 |
7/19 |
9/19 |
7 participants 3 Pneumonia 4 Cellulitis & Abscess 0 Urinary tract infection |
6 participants 3 Pneumonia 3 Cellulitis & Abscess 0 Urinary tract infection |
0 participants |
3 participants 1 Streptococcus viridans 1 Staphylococcus epidermidis 1 Enterococcus |
|
|
* Data for this trial are for the first 30 days when participants were granulocytopenic prior to engraftment. Data are for a similar time period to the other studies. RAC = right atrial catheter |
|||||||
|
Study |
Number of participants analysed |
Number of days with fever |
Number of participants receiving antibiotics |
Number of days with antibiotics |
Number of participants receiving antifungal medication |
||||
|
Prophylactic granulocytes |
Control |
Prophylactic granulocytes |
Control |
Prophylactic granulocytes |
Control |
Prophylactic granulocytes |
Control |
||
|
31* |
Not reported |
Not reported |
9/16 |
13/15 |
Not reported |
Not reported |
Not reported |
Not reported |
|
|
19 # |
Median 4.5 (range 0 to 18) |
Median 9 (range 3 to 12) |
9/10 |
9/9 |
Median 8 (range 0 to 15) |
Median 10.5 (range 6 to 16) |
Not reported |
Not reported |
|
|
35 |
5.1 ± 3.5 |
6 ± 5.6 |
11/19 |
13/16 |
6.7 ± 4.4 |
7.8 ± 6.2 |
Not reported |
Not reported |
|
|
151 |
Median 2 (range 0 to 15) |
Median 2 (range 0 to 17) |
53/53 |
97/98 |
Median 9 (range 1 to 20) |
Median 11 (range 0 to 26) |
Not reported |
Not reported |
|
|
112 |
Not reported |
Not reported |
Not reported |
Not reported |
Not reported |
Not reported |
33 |
29 |
|
|
18 |
Mean 9 (range 2 to 16) |
Mean 9 (range 2 to 18) |
Not reported |
Not reported |
Mean 13 (range 7 to 25) |
Mean 13 (range 9 to 20) |
Not reported |
Not reported |
|
|
38 |
10.1 (SE 1.3) |
7.7 (SE 1.7) |
18 |
15 |
10.5 (SE 1.6) |
8.2 (SE 1.8) |
5 |
5 |
|
|
* Participants who were not on antibiotics at the start of the study # Participants who did not die during the first 26 days of the study SE = standard error |
|||||||||
|
Study |
Total number of granulocyte transfusions |
1 hour absolute neutrophil increment |
1 hour corrected count increment |
Duration of neutropenia reversal |
|
|
On antibiotics |
Not on antibiotics |
||||
|
360 |
Not reported |
CFC Median 0.28 x 10 9 /L (Range 0 to 1.16) LF Median 0.06 x 10 9 /L (Range 0 to 0.49) |
CFC Median 0.38 x 10 9 /L (Range 0.1 to 1.32) LF Median 0.06 x 10 9 /L (Range 0 to 0.32) |
Not reported |
|
|
107 |
Median 0.32 x 10 9 /L |
Not reported |
Not reported |
||
|
254 |
Not reported |
Mean 0.41 x 10 9 /L (Range 0.04 to 1.15) |
Mean 0.50 x 10 9 /L (Range 0.19 to 1.14) |
Not reported |
|
|
Not reported |
Not reported |
Average 0.30 x 10 9 /L |
Not reported |
||
|
Not reported |
Most < 0.15 x 10 9 /L |
Not reported |
Not reported |
||
|
Not reported |
Not reported |
Mean 0.12 x 10 9 /L (range 0 to 0.66) |
Not reported |
||
|
CFC = continuous flow centrifugation LF = leucofiltration |
|||||
|
Study |
Number of participants receiving granulocyte transfusions |
Number of granulocyte transfusions |
Donor events |
Recipient events |
|
29 prophylactic 16 therapeutic |
360 |
1 1 ‐ haemodynamic compromise |
0 |
|
|
13 prophylactic |
107 |
0 |
1 1 ‐ TA GvHD |
|
|
19 prophylactic |
254 |
Not reported |
7 1 ‐ haemolysis 6 ‐ dyspnoea & cyanosis |
|
|
29 prophylactic 2 therapeutic |
Not reported |
Not reported |
3 3 ‐ dyspnoea and wheeze |
|
|
TA GvHD = Transfusion‐associated Graft versus Host Disease |
||||
|
Study |
Number of participants receiving granulocyte transfusions |
Total number of granulocyte transfusions |
Donor events |
Recipient events |
|
29 prophylactic 16 therapeutic |
360 |
4 1 ‐ haemodynamic compromise 1 ‐ abdominal cramps 2 ‐ recurrent blocking of port |
0 |
|
|
67 prophylactic 4 therapeutic |
Not reported |
6 1 ‐ low platelet count 1 ‐ bleeding from arterio‐venous shunt 4 ‐ obstruction of lumen of shunt or catheter |
13 5 ‐ transfusion reactions 3 ‐ no increment in granulocyte count 5 ‐ donor required for platelet transfusions |
|
|
10 prophylactic 0 therapeutic |
Not reported |
Not reported |
1 1 ‐ diffuse pulmonary infiltrate |
|
|
54 prophylactic |
987 |
Not reported |
6 (not further defined) |
|
|
29 prophylactic 2 therapeutic |
Not reported |
Not reported |
5 (not further defined) |
|
|
19 prophylactic 6 therapeutic |
Not reported |
Not reported |
0 |
|
Outcome or subgroup title |
No. of studies |
No. of participants |
Statistical method |
Effect size |
|
1 All‐cause mortality up to 30 days Show forest plot |
7 |
437 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.92 [0.63, 1.36] |
|
1.1 Low‐dose granulocytes |
3 |
144 |
Risk Ratio (M‐H, Fixed, 95% CI) |
1.32 [0.64, 2.72] |
|
1.2 Intermediate‐dose granulocytes |
4 |
293 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.74 [0.47, 1.16] |
|
2 All‐cause mortality up to 100 days Show forest plot |
1 |
Risk Ratio (M‐H, Fixed, 95% CI) |
Totals not selected |
|
|
2.1 Granulocyte dose unknown |
1 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.0 [0.0, 0.0] |
|
|
3 All‐cause mortality over 100 days Show forest plot |
1 |
Risk Ratio (M‐H, Fixed, 95% CI) |
Totals not selected |
|
|
3.1 Low‐dose granulocytes |
1 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.0 [0.0, 0.0] |
|
|
4 Mortality due to infection up to 30 days Show forest plot |
6 |
286 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.69 [0.33, 1.44] |
|
4.1 Low‐dose granulocytes |
3 |
144 |
Risk Ratio (M‐H, Fixed, 95% CI) |
1.14 [0.46, 2.86] |
|
4.2 Intermediate‐dose granulocytes |
3 |
142 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.25 [0.06, 1.10] |
|
5 Mortality due to infection up to 100 days Show forest plot |
1 |
Risk Ratio (M‐H, Fixed, 95% CI) |
Totals not selected |
|
|
5.1 Granulocyte dose unknown |
1 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.0 [0.0, 0.0] |
|
|
6 People with localised or systemic bacterial or fungal infections Show forest plot |
9 |
Risk Ratio (M‐H, Fixed, 95% CI) |
Subtotals only |
|
|
6.1 Low‐dose granulocyte transfusions |
4 |
204 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.84 [0.58, 1.20] |
|
6.2 Intermediate‐dose granulocyte transfusions |
4 |
293 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.40 [0.26, 0.63] |
|
6.3 Unknown dose of granulocyte transfusion |
1 |
112 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.97 [0.61, 1.55] |
|
7 People with bacteraemia or fungaemia Show forest plot |
9 |
609 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.45 [0.30, 0.65] |
|
7.1 Low‐dose granulocyte transfusions |
4 |
204 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.51 [0.27, 0.96] |
|
7.2 Intermediate‐dose granulocyte transfusions |
4 |
293 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.28 [0.14, 0.55] |
|
7.3 Unknown dose of granulocyte transfusions |
1 |
112 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.79 [0.39, 1.61] |
|
8 People with bacteraemia or fungaemia (excluding study that compared prophylactic granulocyte transfusions versus prophylactic broad‐spectrum antibiotics) Show forest plot |
8 |
497 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.37 [0.23, 0.59] |
|
8.1 Low‐dose granulocyte transfusions |
4 |
204 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.51 [0.27, 0.96] |
|
8.2 Intermediate‐dose granulocyte transfusions |
4 |
293 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.28 [0.14, 0.55] |
|
9 People with localised bacterial or fungal infection Show forest plot |
6 |
296 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.75 [0.50, 1.14] |
|
9.1 Low‐dose granulocyte transfusions |
2 |
42 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.46 [0.19, 1.11] |
|
9.2 Intermediate‐dose granulocyte transfusions |
3 |
142 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.71 [0.38, 1.31] |
|
9.3 Unknown dose of granulocyte transfusions |
1 |
112 |
Risk Ratio (M‐H, Fixed, 95% CI) |
1.12 [0.54, 2.33] |
|
10 People with localised bacterial or fungal infection (excluding study that compared prophylactic granulocyte transfusions versus prophylactic broad‐spectrum antibiotics) Show forest plot |
5 |
184 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.62 [0.37, 1.02] |
|
10.1 Low‐dose granulocyte transfusions |
2 |
42 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.46 [0.19, 1.11] |
|
10.2 Intermediate‐dose granulocyte transfusions |
3 |
142 |
Risk Ratio (M‐H, Fixed, 95% CI) |
0.71 [0.38, 1.31] |