Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction Stable (no update expected for reasons given in 'What's new')

Abstract

Despite modern antimicrobials and supportive therapy, bacterial and fungal infections are still major complications in people with prolonged disease‐related or therapy‐related neutropenia. Since the late 1990s there has been increasing demand for donated granulocyte transfusions to treat or prevent severe infections in people who lack their own functional granulocytes. This is an update of a Cochrane review first published in 2009.

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.

We searched for randomised controlled trials (RCTs) and quasi‐RCTs in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), CINAHL (from 1937), theTransfusion Evidence Library (from 1980) and ongoing trial databases to April 20 2015.

Randomised controlled trials (RCTs) and quasi‐RCTs comparing people receiving granulocyte transfusions to prevent the development of infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, but this review focuses on mortality, mortality due to infection and adverse events.

We used standard methodological procedures expected by The Cochrane Collaboration.

Twelve trials met the inclusion criteria. One trial is still ongoing, leaving a total of 11 trials eligible involving 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 studies included only adults, and two studies included children and adults. Ten of these studies contained separate data for each arm and were able to be critically appraised. One study re‐randomised people and therefore quantitative analysis was unable to be performed.

Overall, the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcome estimates being imprecise.

All‐cause mortality was reported for nine studies (609 participants). There was no difference in all‐cause mortality over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (seven studies; 437 participants; RR 0.92, 95% CI 0.63 to 1.36, very low‐quality evidence).

Mortality due to infection was reported for seven studies (398 participants). There was no difference in mortality due to infection over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (six studies; 286 participants; RR 0.69, 95% CI 0.33 to 1.44, very low‐quality evidence).

The number of people with localised or systemic bacterial or fungal infections was reported for nine studies (609 participants). There were differences between the granulocyte dose subgroups (test for subgroup differences P = 0.01). There was no difference in the number of people with infections over 30 days between people receiving prophylactic granulocyte transfusions and those that did not in the low‐dose granulocyte group (< 1.0 x 1010 granulocytes per day) (four studies, 204 participants; RR 0.84, 95% CI 0.58 to 1.20; very low‐quality evidence). 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 1010 to 4.0 x 1010 granulocytes per day) (4 studies; 293 participants; RR 0.40, 95% CI 0.26 to 0.63, low‐quality evidence).

There was a decreased number of participants with bacteraemia and fungaemia in the participants receiving prophylactic granulocyte transfusions (nine studies; 609 participants; RR 0.45, 95% CI 0.30 to 0.65, low‐quality evidence).

There was no difference in the number of participants with localised bacterial or fungal infection in the participants receiving prophylactic granulocyte transfusions (six studies; 296 participants; RR 0.75, 95% CI 0.50 to 1.14; very low‐quality evidence).

Serious adverse events were only reported for participants receiving granulocyte transfusions and donors of granulocyte transfusions.

In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is low‐grade evidence that prophylactic granulocyte transfusions decrease the risk of bacteraemia or fungaemia. There is low‐grade evidence that the effect of prophylactic granulocyte transfusions may be dose‐dependent, a dose of at least 1.0 x 1010 per day being more effective at decreasing the risk of infection. There is insufficient evidence to determine any difference in mortality rates due to infection, all‐cause mortality, or serious adverse events.

Author(s)

Lise J Estcourt, Simon J Stanworth, Carolyn Doree, Patricia Blanco, Sally Hopewell, Marialena Trivella, Edwin Massey

Abstract

Transfusions of white blood cells called granulocytes for preventing infections in people who lack functioning granulocytes 

Review question 
 We evaluated the evidence about whether granulocyte transfusions given to prevent infection are safe and decrease the risk of infection. Our target population was people with neutropenia (a very low count of a type of white blood cell (neutrophil), or white blood cells that did not function properly (neutrophil dysfunction).

Background 
 Functioning white blood cells, in particular granulocytes, are important for fighting life‐threatening bacterial and fungal infections. For many years, some hospital physicians have been giving granulocyte transfusions to people who lack white cells as a result of disease and/or treatment that has reduced their number or function.

The demand for granulocytes for transfusion has shown a steady increase since the 1990s mainly as a result of the introduction of a drug called granulocyte colony‐stimulating factor (G‐CSF) which, if given to donors, leads to increased granulocyte numbers in the donor's blood and the collection of a larger dose of granulocytes than was previously possible.

Study characteristics 
 The evidence is current to April 2015. In this update, 12 trials were identified that compared giving granulocyte transfusions to prevent infections compared to not giving granulocytes to prevent infection. One trial has not yet been completed. Eleven trials containing a total of 653 participants were reviewed. These trials were conducted between 1978 and 2006. Data from one trial were not included in the analyses because patients were included within the trial more than once. Ten studies included only adults, and two studies included children and adults.

Six studies reported their funding sources, and all were funded by charities or governments.

Key results 
 Giving granulocyte transfusions to prevent infections did not affect the risk of death due to infection, or the risk of death due to any cause.

Giving granulocyte transfusions to prevent infections decreased the number of people who had a bacterial or fungal infection in the blood, but did not decrease the number of people having a localised bacterial or fungal infection.

It is unknown whether granulocyte transfusions increased the risk of having a serious adverse event because adverse events were only reported in people receiving granulocyte transfusions.

Quality of the evidence 
 The evidence for most of the findings was of very low or low quality. This was because patients and their doctors knew which study arm the patient had been allocated to and two of the studies were not true randomised studies (patients were allocated to the granulocyte transfusion arm if they had a suitable granulocyte donor).

Author(s)

Lise J Estcourt, Simon J Stanworth, Carolyn Doree, Patricia Blanco, Sally Hopewell, Marialena Trivella, Edwin Massey

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

The review has identified low‐quality evidence that prophylactic granulocyte transfusion lead to a reduction in the number of people developing a bacterial or fungal infection, especially if the dose is at least 1.0 x 1010 per day. It would however, be premature to conclude that the use of granulocytes as prophylaxis in people with neutropenia would improve outcomes and prove cost‐effective as the potential harms of the intervention could not be fully assessed. Supportive therapy in this setting has changed since most of the reviewed studies were performed. None of the studies in this review specifically evaluated people with congenital disorders of neutrophil function or production. None of the studies in this review assessed the use of blood product‐derived granulocytes. In keeping with the conclusions from the systematic review of the use of granulocyte transfusions for therapeutic indications, the use of granulocyte transfusions should still be regarded as investigational and should ideally be conducted in the context of ongoing prospective trials designed to answer the question of effectiveness.

Implications for research 

Contemporary well‐designed prospective trials of sufficient power are required to evaluate the effectiveness of granulocyte transfusions as prophylaxis. The design of trials needs to consider multiple factors. Most importantly, the power calculations should be based upon the outcome measures currently encountered with standard therapy in the population selected. If mortality rate is to be used as an outcome measure that may be improved by granulocyte transfusion then populations with a higher mortality rate may be more amenable to show evidence of benefit.

All systematic reviews performed to date have suggested that the dose transfused is important although the exact minimal effective dose remains uncertain. Such a dose could be consistently obtained by secondary processing of "buffy coat" granulocytes or by administering G‐CSF and steroids to ABO‐compatible apheresis donors. The schedule for administration of granulocyte transfusions in the identified studies varied considerably, and would need to be standardised. However, the frequency of transfusion is to a major part also governed by logistical issues and therefore it is likely that the schedule will continue to be dictated by availability of donors and facilities.

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