Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction
The Cochrane Database of Systematic Reviews. 2016;((4)):CD005339.
BACKGROUND Despite modern antimicrobials and supportive therapy bacterial and fungal infections are still major complications in people with prolonged disease-related or treatment-related neutropenia. Transfusions of granulocytes have a long history of usage in clinical practice to support and treat severe infection in high-risk groups of patients with neutropenia or neutrophil dysfunction. However, there is considerable current variability in therapeutic granulocyte transfusion practice, and uncertainty about the beneficial effect of transfusions given as an adjunct to antibiotics on mortality. This is an update of a Cochrane review first published in 2005. OBJECTIVES To determine the effectiveness and safety of granulocyte transfusions compared to no granulocyte transfusions as adjuncts to antimicrobials for treating infections in people with neutropenia or disorders of neutrophil function aimed at reducing mortality and other adverse outcomes related to infection. SEARCH METHODS We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 2). MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1980) and ongoing trial databases to 11 February 2016. SELECTION CRITERIA RCTs comparing people with neutropenia or disorders of neutrophil dysfunction receiving granulocyte transfusions to treat infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS We identified 10 trials that met the inclusion criteria with a total of 587 participants. We also identified another ongoing trial. These trials were conducted between 1975 and 2015. None of the studies included people with neutrophil dysfunction. The studies differed in the type of infections they included. Six studies included both children and adults, however data were not reported separately for children and adults. The two newest studies gave granulocyte colony stimulating factor (G-CSF) to donors; both were stopped early due to lack of recruitment. Three studies re-randomised participants and therefore quantitative analysis was unable to be performed.Overall the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcomes being imprecise.There may be no difference in all-cause mortality over 30 days between participants receiving therapeutic granulocyte transfusions and those that did not (six studies; 321 participants; RR 0.75, 95% CI 0.54 to 1.04; very low-quality evidence). There were no differences between the granulocyte dose subgroups (< 1 x 1010 per day versus ≥ 1 x 1010 per day) (test for subgroup differences P = 0.39). There was a difference in all-cause mortality between the studies based on the age of the study (published before 2000 versus published 2000 or later) (test for subgroup differences P = 0.03). There was no difference in all-cause mortality between participants receiving granulocyte transfusions and those that did not in the newest study (one study; 111 participants; RR 1.10, 95% CI 0.70 to 1.73, low-quality evidence). There may be a reduction in all-cause mortality in participants receiving granulocyte transfusions compared to those that did not in studies published before the year 2000 (five studies; 210 participants; RR 0.53, 95% CI 0.33 to 0.85; low-quality evidence).There may be no difference in clinical reversal of concurrent infection between participants receiving therapeutic granulocyte transfusions and those that did not (five studies; 286 participants; RR 0.98, 95% CI 0.81 to 1.19; low-quality evidence).There is insufficient evidence to determine whether there
Neutrophil/granulocyte transfusions collected from G-CSF + dexamethasone-stimulated donors
Current Opinion in Hematology. 2015;22((6)):565-7.
PURPOSE OF REVIEW The purpose of this review is to report a recently completed multicenter randomized controlled trial of neutrophil/granulocyte transfusions collected from G-CSF + dexamethasone donors to treat neutropenic infections in oncology and transplant patients, within the context of other historic and current clinical trials.The multicenter trial (RING Study) was funded by the NHLBI transfusion medicine/hemostasis clinical trials network. RECENT FINDINGS There was no significant benefit of therapeutic neutrophil/granulocyte transfusions versus antibiotics per intention to treat analysis, but 32% of patients received substandard neutrophil doses. Separate analysis suggested patients given a higher neutrophil doses had better outcomes. SUMMARY Efficacy of 'high-dose' therapeutic neutrophil/granulocyte transfusions remains unproven, but promising.
Role of granulocyte transfusions in invasive fusariosis: systematic review and single-center experience
BACKGROUND Invasive Fusarium infection is relatively refractory to available antifungal agents. Invasive fusariosis (IF) occurs almost exclusively in the setting of profound neutropenia and/or systemic corticosteroid use. Treatment guidelines for IF are not well established, including the role of granulocyte transfusions (GTs) to counter neutropenia. STUDY DESIGN AND METHODS We conducted a systematic review, identifying IF cases where GTs were used as adjunctive therapy to antifungal agents and also report a single-center case series detailing our experience (1996-2012) of all IF cases treated with antifungal agents and GTs. In the systematic review cases, GTs were predominantly collected from nonstimulated donors whereas, in the case series, they were universally derived from dexamethasone- and granulocyte-colony-stimulating factor-stimulated donors. RESULTS Twenty-three patients met inclusion criteria for the systematic review and 11 for the case series. Response rates after GTs were 30 and 91% in the review and case series, respectively. Survival to hospital discharge remained low at 30 and 45%, respectively. Ten patients in the systematic review and three in the case series failed to achieve hematopoietic recovery and none of these survived. In the case series, donor-stimulated GTs generated mean "same-day" neutrophil increments of 3.35 x 10(9) +/-1.24 x 10(9) /L and mean overall posttransfusion neutrophil increments of 2.46 x 10(9) +/-0.85 x 10(9) /L. Progressive decrements in neutrophil response to GTs in two cases were attributed to GT-related HLA alloimmunization. CONCLUSION In patients with IF, donor-stimulated GTs may contribute to high response rates by effectively bridging periods of neutropenia or marrow suppression. However, their utility in the absence of neutrophil recovery remains questionable.Copyright Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
A prospective, randomized, double-blind study, comparing unirradiated to irradiated white blood cell transfusions in acute leukemia patients
A prospective, randomized double-blind study comparing the effects of irradiated and unirradiated white blood cells was conducted in 108 acute leukemia patients with life-threatening infections, refractory to antibiotics. The study demonstrated no significant improvement in 30-day survival or overall survival. Transfusion of unirradiated white cells did not compromise the patient's opportunity to undergo allogeneic stem cell transplant, nor the success rate or overall survival after allogeneic transplant. The important positive finding in this study was that the unirradiated white cells produced a significantly higher increment in circulating granulocytes and in a higher proportion of patients granulocyte count exceeded 1000 per microliter, approaching normal concentrations. The increase in the number and the improved survival of the unirradiated granulocytes suggest that this procedure might potentially be a method to improve the utility of granulocyte transfusions and merits further investigation. The study demonstrated non-inferiority for unirradiated white cells. There were no harmful effects such as graft-versus-host disease, indicating that such studies would be safe to conduct in the future.
Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction
Cochrane Database of Systematic Reviews. 2009;((1):):CD005341.
BACKGROUND Since the late 1990s there has been increasing demand for donated granulocyte transfusions to treat or prevent severe infections in patients who lack their own functional granulocytes. Other than in neonates, no systematic reviews have been performed for over 10 years relating to the efficacy of prophylactic granulocyte transfusions. OBJECTIVES To determine the effectiveness and safety of granulocyte transfusions compared with a control population not receiving this intervention for preventing mortality due to infection or due to any other cause in patients with neutropenia or disorders of neutrophil function. SEARCH STRATEGY We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2008, MEDLINE, EMBASE and other specialised databases up to October 2008. We also searched reference lists of articles and contacted experts in the field. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing patients receiving granulocyte transfusions to prevent the development of infection with a control group receiving no granulocyte transfusions. Neonates have been the subject of a recent review and were excluded. There was no restriction by outcomes examined, but this review focuses on mortality, mortality due to infection and adverse events. DATA COLLECTION AND ANALYSIS Two review authors independently assessed potentially relevant studies for inclusion. Data were extracted by two review authors and the methodological quality was examined. Data were analysed using random and fixed effects models. MAIN RESULTS Ten trials met the inclusion criteria. Allocation in all trials was random, with the control arm receiving no prophylactic therapy, except one trial in which the control group received specific prophylactic antibiotics. One study reported biological randomisation based upon the availability of suitably matched, related donors rather than strict randomisation. All trials were conducted over twenty years ago with one exception, a study from 2006 in which donors were pre-medicated with granulocyte colony stimulating factor (G-CSF) resulting in significantly higher mean doses of granulocytes collected for transfusion. Different policies otherwise applied for the schedule for transfusion, method of granulocyte procurement and criteria for defining infection. Combining the results showed a relative risk (RR) for mortality of 0.94 (95% confidence intervals (CI) 0.71 to 1.25). Exclusion of the two trials which reported transfusion of an average number of granulocytes below 1 x 1010 indicated a summary RR for mortality and mortality due to infection of 0.89 (CI 0.64 to 1.24) and 0.36 (0.14 to 0.96) respectively. AUTHORS' CONCLUSIONS Implications for clinical practice: The controlled trials that have been identified raise the possibility that prophylactic granulocyte transfusions at a dose of at least 1 x 1010 may reduce the risk of mortality from infection. Overall mortality was not affected. However, the majority of studies were performed decades ago, and standards of supportive care have advanced considerably. These earlier trials were also based on transfusing lower yields of collected granulocytes than currently recommended. It is difficult to recommend prophylactic granulocyte transfusions outside the setting of ongoing controlled trials, given the resource and cost implications.Implications for research: Larger trials are needed to establish the validity of the potential benefits raised by this review, in view of the methodological limitations, the small sample sizes and the heterogeneous definitions of infection that were encountered in the included studies.
Randomized phase III study of granulocyte transfusions in neutropenic patients
Bone Marrow Transplantation. 2008;42((10):):679-84.
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 x 10(6)/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.
Granulocyte transfusions in neutropaenic children: a systematic review of the literature
European Journal of Cancer. 2007;43((14):):2082-92.
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.
Prevention of nosocomial infections in marrow transplant patients: a prospective randomized comparison of systemic antibiotics versus granulocyte transfusions
Infection Control. 1986;7((12):):586-92.
One hundred twelve patients with hematologic malignancies underwent marrow transplantation from HLA-matched sibling donors and were randomized to receive either prophylactic granulocyte transfusions (PG, 67 patients) or prophylactic systemic antibiotics (PSA, 45 patients) as prophylaxis against nosocomial infections. Patients were treated in conventional hospital rooms and studied until day 100 post-transplant. For the entire study period, 26 patients (39%) in the PG group developed septicemia compared to 15 patients (33%) in the PSA group. Twenty-eight patients (42%) in the PG group developed local major infections compared to 19 patients (42%) in the PSA group. Ten patients (15%) in the PG group developed viral interstitial pneumonitis compared to 6 patients (13%) in the PSA group. None of these differences were statistically significant. There was no difference in the incidence of bacterial or fungal infections or viral interstitial pneumonitis between the two groups during the granulocytopenic or post-engraftment period. There was no difference in the incidence and severity of graft-versus-host-disease (GVHD). Inability to carry out the prophylaxis was frequent in the PG group, with complications necessitating discontinuance of transfusion in 24% of the recipients and 13% of the donors. The use of PG as an infection prophylaxis modality in marrow transplantation is not supported by this study, as it is difficult to carry out and because PG did not show any advantage over the use of PSA in preventing nosocomial infections.
A controlled trial of prophylactic granulocyte transfusions during induction chemotherapy for acute nonlymphoblastic leukemia
Thirty-five noninfected patients undergoing induction chemotherapy for acute nonlymphoblastic leukemia (ANLL) were randomized to either receive (19 patients) or not receive (16 control patients) prophylactic granulocyte transfusions (PGT) when their granulocyte count fell below 0.5 X 10(9)/1. Both groups received identical anti-infectious and supportive care except for granulocyte transfusions. The authors found a nonstatistically significant decrease of the infection rate in the prophylactic group. However, the bacteriologically documented infections and septicemia incidence was significantly higher in the control than in the prophylactic group (P less than 0.05). In the control group they observed in 8 of 16 cases life-threatening infections in contrast with only 1 case in the prophylactic group (P less than 0.01). A significant reduction of deaths due to infectious causes in the prophylactic versus control group were also found (P less than 0.05). The authors did not find an increase of pneumonia or pulmonary infiltrates in the patients belonging to prophylactic in comparison to control group.
Pulmonary complications in patients receiving granulocyte transfusions and amphotericin B
Canadian Medical Association Journal. 1984;130((5):):593-7.
To evaluate the possibility that in febrile granulocytopenic patients amphotericin B given along with granulocyte transfusions could increase the incidence of pulmonary complications, we studied 43 severely granulocytopenic patients during 46 episodes of fever. Granulocytes were administered as part of the clinical protocol to all 19 patients who had clinically or microbiologically documented infection; the other 24 patients were randomly allocated to treatment with granulocytes (13 patients) or without granulocytes (11 patients). In all, 32 patients received granulocyte transfusions during 35 episodes of fever. Pulmonary complications developed in six patients in each of the two randomized groups. The incidence of pulmonary complications was not influenced by the number of granulocyte transfusions or by the number of granulocytes per transfusion. Pulmonary complications were significantly more likely to occur in patients with fungal infections. Amphotericin B was given according to clinical indications; 21 patients in all received it. Survival was significantly poorer in patients with pulmonary complications, but the administration of amphotericin B was not related either to survival or to the incidence of pulmonary complications. We conclude that pulmonary complications and poor prognosis are related to underlying pulmonary fungal infection and not to any interaction between amphotericin B and granulocyte transfusions.