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Background: Granulocyte transfusions for patients with prolonged neutropenia and severe infections has been a controversial practice. Previous studies suggest a benefit of high‐dose granulocyte transfusions (≥0.6 × 109/kg), although, until recently, the consistent production of high‐dose units has been challenging. Here, we present our experience and results utilizing high‐dose granulocyte transfusions at a large, tertiary academic medical center for the treatment of infections in adult, neutropenic patients. Study Design/Methods: A retrospective chart review (2018–2021) was conducted for all patients who received high‐dose granulocyte transfusions from donors stimulated with granulocyte colony‐stimulating factor (G‐CSF) and dexamethasone. Gathered parameters included patient demographics, clinical history, infection status, dose, clinical outcomes, pre‐ and post‐absolute neutrophil count (ANC), and transfusion times including time between granulocyte collection, administration, and posttransfusion ANC count. Gathered parameters were summarized using descriptive statistics, outcomes were assessed utilizing Kaplan–Meier curves/log‐rank/regression testing. Results: Totally 28 adult, neutropenic patients refractory to antimicrobial agents and/or G‐CSF received a total of 173 granulocyte concentrates. Median ANC increased from 0.7 × 109/L pre‐transfusion to 1.6 × 109/L posttransfusion. The mean granulocyte yield was 77.4 × 109 resulting in an average dose per kilogram of 0.90 × 109 ± 0.30 × 109 granulocytes. Composite day 42 survival and microbial response was 42.9% (n = 12/28) without significant adverse reactions. Discussion: Here, we demonstrate the successful and safe implementation of high‐dose granulocyte transfusions for neutropenic patients. Given the rapid and consistent production, distribution, and improved granulocyte quality, further investigations to determine the clinical efficacy of G‐CSF primed granulocyte transfusions is now possible. [ABSTRACT FROM AUTHOR]

Granulocyte transfusions are sometimes used as adjunctive therapy for the treatment of infection in patients with chronic granulomatous disease (CGD). However, granulocyte transfusions can be associated with a high rate of alloimmunization, and their role in CGD patients undergoing hematopoietic cell transplantation (HCT) or gene therapy (GT) is unknown. We identified 27 patients with CGD who received granulocyte transfusions pre- (within 6 months) and/or post-HCT or GT in a retrospective survey. Twelve patients received granulocyte transfusions as a bridge to cellular therapy. Six (50%) of these patients had a complete or partial response. However, six of 10 (60%) patients for whom testing was performed developed anti-HLA antibodies, and three of the patients also had severe immune-mediated cytopenia within the first 100 days post-HCT or GT. Fifteen patients received granulocyte transfusions post-HCT only. HLA antibodies were not checked for any of these 15 patients, but there were no cases of early immune-mediated cytopenia. Out of 25 patients who underwent HCT, there were 5 (20%) cases of primary graft failure. Three of the patients with primary graft failure had received granulocyte transfusions pre-HCT and were subsequently found to have anti-HLA antibodies. In this small cohort of patients with CGD, granulocyte transfusions pre-HCT or GT were associated with high rates of alloimmunization, primary graft failure, and early severe immune-mediated cytopenia post-HCT or GT. Granulocyte transfusions post-HCT do not appear to confer an increased risk of graft failure.

Background: Hemato‐oncologic patients receiving intensive chemotherapy may develop severe neutropenia and serious bacterial and/or fungal infections. Granulocyte transfusions (GTs) may be beneficial as a bridging therapy in hemato‐oncologic patients with febrile neutropenia. Aim: To evaluate the clinical effectiveness of GTs in hemato‐oncologic patients with febrile neutropenia. Materials and Methods: This retrospective study evaluated the effectiveness of 150 GTs in 88 hemato‐oncologic patients. Donors were mobilized with granulocyte colony‐stimulating factors and dexamethasone. Patients' hematological parameters (pre‐ and post‐GT) and safety and effectiveness of GTs were analyzed. Results: The safety and effectiveness of GTs were assessed in the patients with various underlying conditions, including 78% with acute myeloid leukemia. In total, 150 GTs were administered, mostly during the chemotherapy induction phase. The GTs were well‐tolerated by the patients, and a significant increment in white blood cell count and absolute neutrophil count (ANC) was noticed in 95% of patients after the transfusion. The granulocyte dose was positively correlated with ANC after the transfusion. The average time to neutrophil recovery from the last day of GT was 6.7 days, and the 30‐day survival rate was 77%. The donors were all men, and a significant increase in WBC count was observed post‐mobilization. The median granulocyte yield was 2.28 × 1010/unit. All granulocyte products were crossmatched and irradiated before the transfusion. Conclusion: GTs can be a useful adjunctive treatment for febrile neutropenia in hemato‐oncologic patients with multidrug‐resistant sepsis. However, additional studies are required for confirming their effectiveness and establishing guidelines for their use. [ABSTRACT FROM AUTHOR]

Human neutrophils exert a well-known role as efficient effector cells to kill pathogenic micro-organisms. Apart from their role in innate immunity, neutrophils also have the capacity to suppress T cell-mediated immune responses as so-called granulocyte-myeloid-derived suppressor cells (g-MDSCs), impacting the clinical outcome of various disease settings such as cancer. Patients undergoing chemotherapy because of an underlying malignancy can develop prolonged bone marrow suppression and are prone to serious infections because of severe neutropenia. Concentrates of granulocytes for transfusion (GTX) constitute a therapeutic tool and rescue treatment to fight off these serious bacterial and fungal infections when antimicrobial therapy is ineffective. GTX neutrophils are mobilized by overnight G-CSF and/or Dexamethasone stimulation of healthy donors. Although the phenotype of these mobilized neutrophils differs from the circulating neutrophils under normal conditions, their anti-microbial function is still intact. In contrast to the unaltered antimicrobial effector functions, G-CSF/Dexamethasone-mobilized neutrophils were found to lack suppression of the T cell proliferation, whereas G-CSF-mobilized or Dexamethasone-mobilized neutrophils could still suppress the T cell proliferation upon cell activation equally well as control neutrophils. Although the mechanism of how G-CSF/Dex mobilization may silence the g-MDSC activity of neutrophils without downregulating the antimicrobial activity is presently unclear, their combined use in patients in the treatment of underlying malignancies may be beneficial—irrespective of the number of circulating neutrophils. These findings also indicate that MDSC activity does not fully overlap with the antimicrobial activity of human neutrophils and offers the opportunity to elucidate the feature(s) unique to their T-cell suppressive activity.

Granulocyte transfusions have been administered to patients with life-threatening infections for more than five decades. However, to what extent this should be the case is far from established. On the one hand, the clinical effects of these transfusions are difficult to prove in clinical studies, and the donors of granulocytes may be exposed to certain risks. On the other hand, clinical experience seems to support the idea that granulocyte transfusions do play an important role for severely ill patients, and the donors are primarily motivated by altruistic reasons. In this paper, we first discuss the ethical issues that arise from the fact that there is a conflict between clinical experience and the results from the attempts to perform randomized control trials, and second, the risk/benefit assessment that has to be made between two different parties, namely the recipient and the donor of granulocyte transfusions. [ABSTRACT FROM AUTHOR]

Human neutrophils exert a well-known role as efficient effector cells to kill pathogenic micro-organisms. Apart from their role in innate immunity, neutrophils also have the capacity to suppress T cell-mediated immune responses as so-called granulocyte-myeloid-derived suppressor cells (g-MDSCs), impacting the clinical outcome of various disease settings such as cancer. Patients undergoing chemotherapy because of an underlying malignancy can develop prolonged bone marrow suppression and are prone to serious infections because of severe neutropenia. Concentrates of granulocytes for transfusion (GTX) constitute a therapeutic tool and rescue treatment to fight off these serious bacterial and fungal infections when antimicrobial therapy is ineffective. GTX neutrophils are mobilized by overnight G-CSF and/or Dexamethasone stimulation of healthy donors. Although the phenotype of these mobilized neutrophils differs from the circulating neutrophils under normal conditions, their anti-microbial function is still intact. In contrast to the unaltered antimicrobial effector functions, G-CSF/Dexamethasone-mobilized neutrophils were found to lack suppression of the T cell proliferation, whereas G-CSF-mobilized or Dexamethasone-mobilized neutrophils could still suppress the T cell proliferation upon cell activation equally well as control neutrophils. Although the mechanism of how G-CSF/Dex mobilization may silence the g-MDSC activity of neutrophils without downregulating the antimicrobial activity is presently unclear, their combined use in patients in the treatment of underlying malignancies may be beneficial—irrespective of the number of circulating neutrophils. These findings also indicate that MDSC activity does not fully overlap with the antimicrobial activity of human neutrophils and offers the opportunity to elucidate the feature(s) unique to their T-cell suppressive activity. [ABSTRACT FROM AUTHOR]

Background/Aims: Despite limited evidence for efficacy, granulocyte transfusions (GTX) are used to prevent and treat opportunistic infections in patients with neutropenia. Methods: Three hundred and seventy-three GTX given to 74 patients were assessed retrospectively. Results: GTX were discontinued because of clinical improvement more often in patients with severe infections than in patients without severe infections (27 vs. 12%; p ≤ 0.002), whereas deaths resulted in discontinuation of GTX therapy less often in patients with severe infections than without (8 vs. 39%; p ≤ 0.002). Patients who died by 12 weeks after GTX initiation were more likely to have leukemia (p = 0.03), not to have recovery of neutrophil counts (p < 0.0001), and to have started GTX during a critical care unit stay (p < 0.001). Uses of granulocyte colony-stimulating factor (p ≤ 0.02) and interferon-γ (p ≤ 0.04) were more common in patients who survived. In patients with comorbidities (31%; odds ratio, OR, 12.6; 95% confidence interval, CI, 2.4-65.7; p ≤ 0.003), GTX was started in the critical care unit (OR 8.8; 95% CI 2.5-30.9; p < 0.001), and a high total bilirubin level at the end of GTX (OR 2.1; 95% CI 1.1-4.2; p = 0.03) had a higher probability of death 12 weeks after GTX therapy commenced. Conclusions: The possibility that a niche population may benefit from GTX requires further assessment. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background Granulocyte transfusions (GTXs) have been used successfully as an adjunctive treatment option for invasive infections in some neutropenic patients with underlying hematologic malignancy (HM). Patients and methods We sought to determine the impact of GTX as an adjunct to antifungal therapy in 128 patients with HM and prolonged neutropenia (≥14 days) with a proven or probable invasive aspergillosis (IA) infection by retrospectively reviewing our institutional database. Results Fifty-three patients received GTX and 75 did not. By univariate analysis, patients with invasive pulmonary aspergillosis who received GTX were less likely to respond to antifungal therapy (P = 0.03), and more likely to die of IA (P = 0.009) when compared with the non-GTX group. Among patients who received GTX, 53% developed a pulmonary reaction. Furthermore, IA-related death was associated with the number of GTX given (P = 0.018) and the early initiation of GTX within 7 days after starting antifungal therapy (P = 0.001). By multivariate competing risk analysis, patients who received GTX were more likely to die of IA than patients who did not receive GTX (P = 0.011). Conclusions Our study suggests that GTX does not improve response to antifungal therapy and is associated with worse outcomes of IA infection in HM patients, particularly those with pulmonary involvement. [ABSTRACT FROM PUBLISHER]

Abstract: The data of 10 children who developed 13 high-risk febrile neutropenia with/without microbiologically documented severe infection, while being treated for a hematologic disorder were investigated retrospectively. The 24th hour post-transfusion neutrophil and platelet counts increased significantly, compared to the baseline values (p =0.034, p =0.025). Except three granulocyte transfusions (GTs) after which oliguria and/or mild respiratory distress developed, the transfusions were well tolerated. The clinical response, hematologic response and infection related mortality rates were 69.2%, 53.8% and 30.8%, respectively. Although our study includes limited number of patients, we can conclude that GT seems beneficial for children with severe sepsis during neutropenia. [Copyright &y& Elsevier]

Infections continue to be a serious problem for severely neutropenic oncology and haematopoietic progenitor cell ( HPC) transplant patients. Although it is now possible to collect much larger numbers of neutrophils ( PMNs) from donors stimulated with granulocyte colony-stimulating factor + corticosteroids, the efficacy of these 'modern' granulocyte/ PMN transfusions, with higher doses of PMNs, has not been established by convincing randomized control trials. Accordingly, they cannot be recommended for standard therapy at this time. [ABSTRACT FROM AUTHOR]

Despite antibiotics, antifungals and haematopoietic growth factors, infections remain a major threat to neutropenic patients. To determine the role of granulocyte transfusions (GTs) in anti-infective therapy during neutropenia, GT administration was randomized in 74 adults with haematological or malignant diseases, febrile neutropenia and pulmonary or soft-tissue infiltrates after conventional or high-dose chemotherapy, a majority of them after allo-SCT (n=39). Neutrophil reconstitution was equal in the treatment and control arm. GT toxicity was minimal. The probability of 28-day survival after randomization was >80% in both groups, and no effect of GT on survival until day 100 could be detected in patients with fungal (n=55), bacterial or unknown infection (n=17) and various levels of neutropenia (ANC <500 vs >500 × 106/l). These findings can be attributed primarily to procedural obstacles, such as long delay from randomization to first GT, low cell content and slow sequence of GT, difficulties in randomizing a safe and potentially life-saving treatment in severely endangered individuals, and a large proportion of rapidly recovering patients in both arms. The requirement of another trial in a more specific patient population with daily transfusions of sufficient numbers of granulocytes to support or refute the empirically acknowledged benefits of GT is discussed.Bone Marrow Transplantation (2008) 42, 679–684; doi:10.1038/bmt.2008.237; published online 11 August 2008 [ABSTRACT FROM AUTHOR]

Due to unacceptably high mortality, invasive fungal infections (IFI) have long been considered a contraindication against allogeneic stem cell transplantation. Despite severe immunosuppression an 11-year-old girl requiring allogeneic bone marrow transplant (BMT) for relapsed acute lymphoblastic leukemia was cured of a concurrent invasive pulmonary aspergillosis. Treatment comprised combinations of liposomal amphotericin B, caspofungin and voriconazole with donor granulocyte transfusions. This therapeutic regimen, including the choice of reduced intensity conditioning (RIC), allowed the patient to receive an allogeneic BMT. In hematological remission the child later developed fatal chronic graft-versus-host disease. Combined antifungal treatment and granulocyte support allow for effective management of IFI even in allogeneic stem cell transplant recipients. However, short-term benefits of RIC may be outweighed by late complications. [ABSTRACT FROM AUTHOR]

Abstract: Background: Granulocyte transfusions (GTX) have been used for decades in paediatric neutropaenic patients, but uncertainty remains regarding their effectiveness. We reviewed all the paediatric data available on GTX, to gain a insight in to the indications for use, favourable effects and side effects in patients and donors. Methods: A comprehensive search was done in MEDLINE, EMBASE, LILACS and CENTRAL (1966 until 2006). All studies including children (1–18 years) who received GTX were included. Results: A total of 66 observational studies were included:Seven using prophylactic and 59 therapeutic GTX. Of the therapeutic studies 55 reported a proven sepsis caused by Gram-negative bacteria (34%) or fungal disease (48%) as the indication for GTX. Concerning effectiveness 70% survival was reported, but no controlled studies were identified. Side effects were mentioned in 27 studies including mild respiratory symptoms, allergic reactions and infection related complications (CMV). Side effects in the donor were mainly flu-like illness. Discussion: In this first review covering 30 years of experience on the use of GTX in children, we found no randomised evidence showing a positive benefit risk ratio. The available case reports and cohort studies alert us as to the potential benefits and harms of the use of GTX in neutropaenic children and provides the basis for a well designed trial in children. [Copyright &y& Elsevier]

Summary:The efficacy of granulocytes transfusions (GTX) in either the prevention or treatment of neutropenic sepsis has been a controversial issue. Early studies employing steroid mobilised GTX showed variable, dose-dependent results and significant pulmonary toxicity was reported. With the introduction of the recombinant myeloid growth factor, granulocyte-colony stimulating factor (G-CSF), the quantity of granulocytes that could be harvested was substantially increased leading to renewed interest in the clinical application of GTX. The administration of G-CSF to normal donors leads to significantly higher pre-harvest neutrophil counts and consequently larger granulocyte harvests. Infusion of G-CSF stimulated GTX results in measurable increases in the recipients'neutrophil count and may reduce the duration and severity of neutropenia. However, the efficacy of these GTX in treating or preventing established neutropenic sepsis remains to be established in prospective controlled clinical trials.Bone Marrow Transplantation (2004) 34, 839-846. doi:10.1038/sj.bmt.1704630 Published online 26 July 2004 [ABSTRACT FROM AUTHOR]

Summary. The predictable neutropenia that follows allogeneic stem cell transplantation (ASCT) may be associated with recurrence of previous life-threatening infection. We describe nine patients with either previous invasive aspergillosis (IA) or considered to be at high risk of developing IA who underwent ASCT with prophylactic granulocyte transfusions. The study group, when compared with a control group, had a significant reduction in the incidence and duration of fevers (P < 0·05) and maximum C-reactive protein (P < 0·05). There were significantly fewer days of neutropenia (P < 0·05). There was also radiological improvement of pulmonary infiltrates in four out of seven assessable patients. No serious toxicity was encountered in donors or recipients. We conclude that prophylactic granulocyte donations can be given safely, and that they significantly reduce the number of days of neutropenia. Further investigation is warranted to determine whether granulocyte donations can prevent the recurrence of IA in patients at risk of fungal infection. [ABSTRACT FROM AUTHOR]

Background High cell counts in granulocyte colony-stimulating factor (G-CSF)-mobilized granulocytes are detrimental to concentrate storage. An eightfold dilution with autologous plasma improves storage, but this method is impractical. The purpose of this study was to identify an infusible solution that could be used in place of autologous plasma to dilute and store granulocytes. Materials and Methods Granulocytes collected from donors given dexamethasone (8 mg per os) and/or G-CSF (5 µg/kg subcutaneously [SQ]) were diluted eightfold in the following cell culture media: X-Vivo 10, Dulbecco’s modified Eagle’s minimal essential medium (DMEM) or Iscoves modified Dulbecco’s medium (IMDM); or in the following infusible solutions: Plasma-Lyte A; Normosol R; lactated ringers, supplemented with 1% human serum albumin and 50 mm histidine (LRAH); or Plasma-Lyte A supplemented with 50 mm histidine buffer or 25 mm HEPES buffer plus 1% human serum albumin. The granulocytes were stored for 48 h at room temperature. White blood cell (WBC) counts, WBC viability and pH were measured after ≈ 2 h, 24 h and 48 h of storage. Results Cell counts, viability and pH were maintained after 2 h, 24 h and 48 h in cells stored in the three cell culture media. The pH fell slightly after 48 h to 6·86 ± 0·10 in granulocyte concentrates diluted in LRAH, but fell to a greater extent after 24 h and 48 h, to 6·36 ± 0·23 (48-h value) in granulocyte concentrates diluted in Plasma-Lyte A and to 6·40 ± 0·19 (48-h value) in granulocyte concentrates diluted in Normosol R. The cell counts of concentrates diluted in LRAH were stable for 48 h, but fell in granulocyte concentrates stored in Plasma-Lyte A and Normosol R. Plasma-Lyte A supplemented with histidine maintained the pH of diluted granulocyte concentrates better than Plasma-Lyte A supplemented with HEPES; 6·91 ± 0·10 and 6·65 ± 0·11, respectively, after 24 h. Cell counts were maintained best in granulocyte concentrates diluted in Plasma-Lyte A supplemented with albumin and one or both of the buffers. Conclusions Culture media were best for granulocyte storage, but they are not approved for in vivo use. Infusible solutions are not buffered adequately and lack sufficient protein, but infusible solutions, such as lactated Ringer’s solution or Plasma-Lyte A supplemented with buffers and albumin, hold promise as effective and licensable solutions for granulocyte storage. [ABSTRACT FROM AUTHOR]

Fifteen children with haematological diseases received an average of 10 granulocyte transfusions each, with 4.7×10 granulocytes per m body surface area (BSA) per transfusion. All patients except one had less than 100 granulocytes per μl blood combined with aplasia or hypoplasia of granulopoiesis. Thirteen patients were transfused therapeutically because of fever and/or severe local lesions unresponsive to antibiotic therapy. Two patients, who were transfused prophylactically after bone-marrow transplantation (BMT), were in excellent clinical condition during the entire period of granulocyte transfusions in spite of severe granulocytopenia. All patients except one showed definite clinical benefit from granulocyte transfusions. The non-responding patient had leukocyte antibodies. [ABSTRACT FROM AUTHOR]

In this article, the author reflects on respiratory complications in patients suffering with pulmonary aspergillosis along with the treatment by echinocandins. Topics discussed include issues in the usefulness of granulocyte transfusions (GTX) for the treatment of invasive pulmonary aspergillosis (IPA), alteration in the fungal cell wall while the exposure of Aspergillus to echinocandins and the risk of immune reconstitution inflammatory syndrome (IRIS).

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Introduction: The rapid spread of severe infections mainly due to resistant pathogens, justifies the search for therapies aiming to restore immune functions severely compromised in patients with hematologic malignancies. Areas covered: The present review summarizes the current knowledge on the role of granulocyte transfusions and colony-stimulating factors as treatment strategy for hematologic patients with serious infectious complications. In addition, a survey among 21 hematologic centers, to evaluate the clinical practice for the use of G-CSF originator and biosimilars was performed. Expert commentary: Granulocyte transfusions with a target dose of at least 1.5-3 × 10 8 cells/kg, may be considered as an approach to bridge the gap between marrow suppression and recovery of granulocytes. G-CSF shortens the period of neutropenia, the hospitalization, the use of antibiotics and the rate of febrile neutropenia (FN) in adult and pediatric patients with non-Hodgkin lymphoma, and in adults with acute myeloid leukemia where these advantages nevertheless, did not translate into a clinical benefit. G-CSF biosimilar showed equivalence or non-inferiority to filgrastim. There are no data supporting the use of GM-CSF, eltrombopag and erythropoietin for preventing or treating infectious complications in patients with hematologic disorders.