Elsevier

Cytotherapy

Volume 19, Issue 11, November 2017, Pages 1256-1269
Cytotherapy

Review Articles
Granulocyte transfusions: A concise review for practitioners

https://doi.org/10.1016/j.jcyt.2017.08.012Get rights and content

Abstract

Granulocyte transfusions (GTXs) have been used to treat and prevent infections in neutropenic patients for more than 40 years, despite persistent controversy regarding their efficacy. This narrative review attempts to complement recent systematic reviews by the Cochrane Collaboration and provide both historical context and critical assessment of the most significant clinical studies published over the years. The data suggest that properly collected and promptly infused granulocytes are active against infections, both bacterial and fungal. The most important question that remains unanswered is in which patients the administration of granulocytes will be beneficial. The preponderance of evidence suggests that granulocyte transfusions may be efficacious in few select cases as a temporizing measure to control an infection that is expected (or proven) to be refractory to optimal antimicrobial treatment, and that could otherwise be controlled by marrow recovery, which is expected to happen. In this regard, they are best considered a “bridge” that grants enough time for the recipient to develop their own response to the infection. The challenges to use GTXs successfully are both clinical, in terms of timely identifying the patients who may benefit, and logistical, in terms of optimal selection of donors and collection technique.

Introduction

There are many more published reviews on GTXs than clinical trials: a simple PubMed search with the words “granulocyte transfusion” OR “granulocyte transfusions” in the “Title” field shows 47 Clinical Trials and 85 Reviews (search performed May 8, 2017). The aim of the current addition to the already overcrowded literature is to provide practicing clinicians with a succinct critical assessment of the data from the standpoint of an Infectious Disease practitioner who has worked for more than two decades in one of the institutions that pioneered this therapeutic modality.

Unbiased, systematic reviews have recently been published by the Cochrane Collaboration on the use of GTXs for prophylaxis and treatment. The conclusions were that there is low quality evidence suggesting GTX may work for prophylaxis [1] and that there is not enough evidence to decide on treatment efficacy [2]. These systematic reviews include, for methodological reasons, only 12 and 10 articles, respectively. In this review I will comment on most controlled trials on GTX, starting with the most recent ones, as well as on some case series that provide additional information. After discussing efficacy I will address toxicity. Finally, I will try to make recommendations for use and for research based on the evidence presented.

Section snippets

Brief history of GTXs

GTXs may be considered the oldest form of cell therapy. Injection of “buffy coat” preparations to treat neutropenic states was initially reported back in 1934 [3]. Subsequent studies showed that granulocytes infused into aplastic dogs migrated to sites of infection [4]. Animal models showed that GTXs could help in the management of bacterial infections [5]. However, obtaining enough neutrophils from healthy donors to produce a measurable increase in absolute neutrophil count (ANC) was

Technical considerations

There is general agreement that at least 1 × 1010 granulocytes (or 1.5 × 108 granulocytes/kg) should be given per transfusion to expect efficacy, although there is only scant clinical evidence that this is the case. Many experts believe that even higher numbers are necessary or desirable —at least 4 × 1010. The term “high-dose” granulocyte transfusion has been used to refer to ≥0.6 × 109 granulocytes/kg (which, in a 70 kg recipient, would give the 4 × 1010 mentioned above) [20]. The usual

GTX in current clinical practice: case report

Figure 1 illustrates the effect of GTXs on a proven invasive fungal infection that seemed to be progressing on antifungal therapy. A 9-year-old child with severe aplastic anemia presented with fever, positive blood cultures for Fusarium solani and a wedge-shaped, dense pulmonary infiltrate that showed branching septate hyphae on a fine-needle aspirate. The apparent lack of response of the infection to the combination of voriconazole and amphotericin B and the subsequent resolution after a few

Controlled studies: no evidence of efficacy

There are only three controlled studies of GTXs obtained by stimulating donors with G-CSF: a single-center case-control study [30] and two randomized, multicenter phase 3 trials, one from Europe [31] and the other from the US [20] (Table I). The three studies found no evidence of effectiveness of GTX, but they have different limitations that may make their conclusions less than definitive.

GTX for treatment of infection: summary of older studies

A review of the early studies of GTX (Table II) is necessary for two reasons. First, some of these [9], [10], [11] are the only controlled studies that have shown efficacy—without them there would be no question about GTX, as all subsequent controlled studies have been negative. Second, they involve mainly patients with gram-negative bacterial infections treated with relatively ineffective antibiotics, and in the current era of multidrug-resistant pathogens this use may become relevant again.

GTX for prophylaxis of infection

Two early trials of prophylactic GTX showed decreased frequency of infection, but no survival benefit [54], [55]. Subsequent studies confirmed the lack of effect on overall outcome but did not show the decreased infection risk [56], [57], [58], [59] and highlighted complications of the procedure, including cytomegalovirus (CMV) infection [56], [57], pulmonary reactions [57] and transfusion reactions with alloimmunization [60]. The largest study showed lower frequency of septicemia in the

Toxicity of GTXs

The main complications of GTX include fever, Human Leukocyte Antigen (HLA) sensitization, pulmonary reactions and (if CMV+ donors are used) CMV infection.

Conclusion

Transfused granulocytes have activity against infectious agents, but may cause transfusion reactions (including severe, even fatal, pulmonary reactions), alloimmunization that could contribute to rejection of a subsequent HCT and (unless they are obtained from CMV-seronegative donors) CMV infection. Regarding prevention of infection, there is enough (low quality, but consistent) evidence to suggest that prophylactic GTXs may result in decreased infection, but there is no evidence they would be

Acknowledgments

Disclosure of interest: The author has no commercial, proprietary, or financial interest in the products or companies described in this article.

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