Receiving Granulocyte Transfusions Research Articles

Granulocyte Transfusions in Neutropenic Infections: Insights From a Single-Center Study.

Introduction Despite the development of modern antibiotic and antifungal therapies, neutropenic infections remain life-threatening. Granulocyte transfusion (GTX) is a less frequently used treatment modality in patients with refractory neutropenic infections. The role of donor GTX remains controversial, partly because of the lack of proper clinical trials. This study aimed to contribute to the literature by evaluating the efficacy and side effects of granulocyte transfusions in our center. Methods Eight febrile neutropenic patients with confirmed infections received granulocyte transfusions from ABO-compatible related and unrelated donors. Donors received filgrastim and dexamethasone stimulation, and granulocyte suspensions were irradiated and administered within six hours. Monitoring, antibiotic therapy, and granulocyte colony-stimulating factor (G-CSF) support were maintained. Results Our study observed a 28-day survival rate of 25%, which was lower than that reported in previous literature. The median number of transfusions was 3, with an average eight-day duration post-infection diagnosis, and no side effects were observed. Conclusion While some patients benefited from GTX, overall survival rates remained modest, indicating the need for further research. Prospective, well-powered randomized controlled trials are essential to address patient selection, dosing, and duration to determine the clinical utility of GTX. This study underscores the complexity of GTX in real-world clinical practice and provides insight into the ongoing debate regarding its efficacy in treating severe neutropenic infections.

Outcomes of Neutropenic Patients with Severe Infections Treated with Granulocyte Transfusions: The USC Experience

Introduction Despite major progress in antimicrobial and supportive measures, prolonged disease-associated or treatment-related neutropenia is a leading cause of mortality and morbidity in patients after stem cell transplantation or with hematologic malignancies or bone marrow failure. Intuitively, a granulocyte transfusion should be as effective as a platelet or red cell transfusion. However, efforts to prove the effectiveness of granulocyte transfusions have been disappointing. Due to the lack of adequately powered randomized controlled trials, it is difficult to prove or refute the effectiveness of granulocyte transfusions in neutropenic patients. Therefore, they are likely underutilized or used inappropriately as a last resort. To better understand the utility of this treatment modality, we reviewed the outcomes of patients with hematologic conditions who received granulocyte transfusions at our institutions during the treatment of neutropenic sepsis. Methods We identified 20 patients with severe neutropenia who received a granulocyte transfusion at Norris Comprehensive Cancer Center or Keck Hospital of USC in Los Angeles, California between 2014-2022. 19 of these patients received a total of 166 transfusions for treatment of suspected or confirmed sepsis. One patient received a prophylactic dose of granulocytes and was excluded from this study. Granulocyte donors were mobilized with 480 mcg G-CSF and a minimum yield of 4 x 10 10 granulocytes was obtained. The primary outcome was attainment of “clinical improvement” defined as either safe discharge from the hospital or resolution of symptoms. Descriptive statistics were presented as counts and percentages for categorical variables and as means with standard deviations for continuous variables. Categorical variables were accessed by Chi-square test or Fischer's exact test when appropriate. For continuous variables, Kruskal-Wallis test was used. P-values of ±0.05 were regarded as significant and all tests were two-tailed and analyzed with SAS (9.4). Results In our cohort, 47.4% were male, ages ranged from 20-70, and 57.9% identified as Hispanic. The most common diagnosis was acute myeloid leukemia (AML) (n=13), followed by aplastic anemia (n=3), myelodysplastic syndrome (MDS) (n=2), and acute lymphoblastic leukemia (ALL) (n=1). The most common infections were fungal or presumed fungal (n=9) and mixed fungal and bacterial (n=7). Prior to the start of granulocyte transfusions, 63.2% of patients were neutropenic (ANC <500) for at least 30 days and 84.2% had an absolute neutrophil count (ANC) <100. In surviving patients, the average number of days from the first transfusion to clinical improvement was 17.5 days. 47.4% of patients had a reported reaction to the granulocytes, with the most common being fever and tachycardia. Of the 19 patients treated, seven (37%) died from infection. Of those who died, two (29%) died from E. coli bacteremia and five (71%) from mixed bacterial and fungal sepsis. All nine patients with acute fungal infections without concomitant bacterial infections survived. Conclusion In this cohort, granulocyte transfusions appear to have had a positive effect with 63% of critically ill patients attaining clinical improvement from infection. All patients who had a purely fungal infection achieved clinical improvement and all patients who died had bacterial or mixed infection. Time to transfusion from initial infection, number of transfusions, and demographic variables did not appear to impact overall survival. Granulocyte transfusion could be an effective therapeutic modality in the treatment of infection in patients with prolonged severe neutropenia, especially those with fungal infections. Adequately powered randomized controlled trials are the next step in determining the effectiveness of this treatment.

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.

In high-risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T-cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T-cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post-transplant relapsed acute leukaemia who received T-replete, HLA-mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre-transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T-cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7-13 (median 1.73 × 109 /L vs. 0.1 × 109 /L; p < 0.0001). Expanded T-cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon-gamma production. All patients developed grade 1-3 cytokine release syndrome (CRS) with elevated serum IL-6 and interferon-gamma.

Mucormycosis in Children With Hematologic Malignancies: A Case Series and Review of the Literature.

Mucormycosis is classified as the third leading cause of invasive fungal disease in immunocompromised patients and is characterized by high morbidity and mortality (33%-56%). The aim of this study is to describe presentation, treatment and outcome of Dutch pediatric hemato-oncology patients recently diagnosed with mucormycosis and to review the literature to gain more insight specifically into contemporary outcome data. Ten cases were diagnosed in the Princess Máxima Center for Pediatric Oncology from 2018 to 2021 and were retrospectively reviewed. In addition, 9 case series (n = 148) were included from literature. In our case series, 5 patients of 10 children (age 2-17 years) had disseminated invasive fungal disease. Four patients had localized pulmonary disease and 1 had a localized renal infection. One diagnosis was made postmortem. The underlying diseases were acute lymphoblastic leukemia (n = 6), acute myeloid leukemia (n = 2) and lymphoma (n=2). Seven patients received combination therapy comprising of a lipid amphotericin B formulation and a triazole, surgery was performed in 67%. All neutropenic patients received granulocyte transfusions and/or granulocyte colony-stimulating factor. Mucormycosis-related mortality was 20%. In the literature review, mucormycosis-related mortality was 36% for all patients and 66% for patients with disseminated disease. Survival rates were similar over the past 2 decades. The most common underlying disorder was acute lymphoblastic leukemia. Liposomal amphotericin B was the mainstay of treatment. Seventy percent of patients underwent surgery. Although survival of mucormycosis improved significantly overtime, it plateaued in the past decades. This series shows that with screening, early diagnostics and early antifungal and if possible surgical treatment, mortality is low and even disseminated disease is salvageable if approached aggressively with a combination of surgery and antifungal treatment. Further research focused on diagnostics, combination antifungal and adjunctive therapy is necessary to enhance the survival of mucormycosis in children.

Granulocyte Transfusions in Patients with Chronic Granulomatous Disease Undergoing Hematopoietic Cell Transplantation or Gene Therapy.

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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10875-022-01261-1.

The Safety and Efficacy of Granulocyte Transfusions in Pediatric Recipients with Severe Neutropenia

Background:Pediatric oncology and stem cell transplant patients are at high risk for severe bacterial and fungal infections due to the myelosuppressive effects of chemotherapy and conditioning, respectively. Febrile neutropenia is one of the most concerning complications of chemotherapy. Even with the rapid initiation of empiric antibiotics, morbidity and mortality in this patient population occur frequently. Prognosis is worse in patients with proven bacteremia, with mortality rates of 18% and 5% reported in patients with gram‐negative and gram‐positive bacteremia, respectively (de Naurois et al. Annals of Oncology, 2010). Although gram positive organisms are known to be the most common cause of bacteremia in neutropenic patients (Kibbler et al. Curr Opin in Infect Dis, 1999), recent studies within the last 5 years have reported gram-negative organisms as the most common cause of bacteremia in this patient population (Mert et al. J Infect Dev Ctries, 2019, Islas-Muñoz et al. Int J Infect Dis, 2018, Sierra et al. Medicina, 2020, Cattaneo et al. Ann Hematol, 2018, Parodi et al. PloS one, 2019).Granulocytes harvested from healthy donors can temporarily raise the functional neutrophil counts in transfusion recipients. Data in the adult population show that while these transfusions are safe, they may be of limited efficacy, with patients receiving more than 6 x10 8 having better outcomes (Price et al. Blood, 2015). However, there is a paucity of data in the pediatric population (Atallah et al. Curr Opin in Hematol, 2006, Price et al. Semin Hematol, 2007, Estcourt et al. Cochrane Database Syst Rev, 2015).Objective:To determine the safety of granulocyte transfusions in pediatric recipients with severe neutropenia.Methods:Following IRB approval, we completed a retrospective cohort study of neutropenic pediatric recipients with various infections who received granulocyte transfusions. We reviewed the records of 74 pediatric recipients at the Maria Fareri Children's Hospital at Westchester Medical Center who received granulocyte transfusions from 2011-2019. The medical record was reviewed for patient age, underlying medical condition, indication for granulocyte transfusion, duration of fever, time to resolution of infection, mortality, and adverse reactions to the granulocyte transfusion. Mobilized granulocytes (dexamethasone) were collected from healthy donors at the New York Blood Center, as we have previously reported (Sulis/Cairo et al, Blood 2002, Price et al, Blood 2015).Results:The average age was 11 years (<1-20) with 38 male patients and 36 female patients. The majority of patients were either stem cell transplant recipients, patients with hematologic malignancies, or both. The most common indication for granulocyte transfusion was a documented bacterial infection (56.7%). Fifty-two percent had gram negative infection and 45.2% had gram positive infection. Nine percent were staph infections. Patients received granulocytes for a median of 7.5 days. 54% of the patients cleared their infection with antibiotics prior to receiving the granulocytes. In the remaining patients, infection resolved in 32.4% while receiving granulocyte transfusions in addition to antimicrobial therapy. In this subset of patients, 63.6% had bacterial infection with 71.4% having gram positive infection, all of which were staph infections. The infection cleared after a median of 4 days of granulocyte transfusions. Patients in this subset were on antibiotics for a median of 5 days prior to starting granulocytes. Adverse events related to the granulocyte infusion occurred in 6 patients, with 3 patients having a fever during the transfusion (CTCAE 1), 1 with hypothermia (CTCAE 2), and 1 with joint pain (CTCAE 1). 3 patients died during the period when they were receiving granulocytes. 2 due to infection complication and one due to seizure. 30 day survival was 86.5% and 100 day survival was 85.1%.Conclusions:Granulocyte transfusions can be safely administered to pediatric patients with severe neutropenia. 32.4% cleared the infection with granulocyte transfusion. 100 day survival is 85.1%. Adverse events had CTCAE scores of 1-2. A majority of patients had gram negative infections, but the majority of patients that had resolution of infection with granulocytes had staph infections. It is possible that granulocytes may have greater efficacy against staph infections than other types of infection. [Display omitted] DisclosuresLiu: Incyte: Honoraria; Pharmacyclics: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Pfizer: Research Funding; Beigene: Honoraria, Speakers Bureau; Celgene: Research Funding. Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees.

Successful Treatment of Refractory Acute Lymphoblastic Leukemia with Tisagenlecleucel in the Setting of Life-Threatening Infection

Tisagenlecleucel is a CD19 directed immunotherapy approved for the treatment of young patients with relapsed or refractory precursor B-cell acute lymphoblastic leukemia (ALL). The most important toxicity related to tisagenlecleucel therapy is cytokine release syndrome (CRS). CRS is an exaggerated systemic inflammatory response that occurs frequently along with T-cell expansion following the administration of tisagenlecleucel. Tisagenlecleucel guidelines recommend delaying treatment when an active infection is present due to the concern that the pre-existing inflammatory response associated with infection may predispose patients to severe CRS. We describe two cases where tisagenlecleucel was successfully administered to patients in the setting of life-threatening infection. Patient 1 is a 23-year-old Caucasian male with refractory Philadelphia chromosome negative B-cell ALL who had received prior treatment with chemotherapy, blinatumomab, inotuzumab ozogamicin and a haploidentical stem cell transplant (SCT) followed by multiple Zalmoxis infusions. Five months following SCT he relapsed. At relapse, he underwent leukapheresis followed by bridging chemotherapy with ifosfamide and etoposide. He developed severe neutropenia and respiratory failure associated with a right lower lung consolidation. A biopsy demonstrated a mucormycosis infection and he required surgical debridement including resection of portions of the lung, diaphragm and liver. At this time, he had 92% blasts in the bone marrow. Eleven days after his surgery he received tisagenlecleucel despite being persistently febrile. Prior to the infusion, he received a modified lymphodepleting chemotherapy regimen including two days of fludarabine and cytarabine. Due to severe neutropenia, he was receiving granulocyte transfusions. These were discontinued prior to the infusion and resumed after 12 days. CRP and ferritin the day prior to infusion were 26.2 mg/dL and 18,419 ng/mL. He remained persistently febrile for 13 days post-infusion. He received a single dose of tociluzimab 7 days following his infusion due to high fevers. He did not require any treatment with corticosteroids for CRS. The absolute neutrophil count recovered to &gt;500x103/µL at 31 days post infusion. A bone marrow aspirate done 26 days post-infusion did not show any evidence of leukemia by multicolor flow cytometry (MFC). He remains alive without evidence of disease 11 months after treatment with tisagenlecleucel. Patient 2 is a 4-year-old Hispanic female with refractory B-cell ALL found to have a TP53 deletion and t(1;19). She had received prior treatment with chemotherapy, blinatumomab and local radiation therapy to the site of extramedullary disease found in the left maxillary sinus at relapse. She underwent leukapheresis and received bridging chemotherapy with mercaptopurine and methotrexate. After 3 days of lymphodepleting chemotherapy she developed septic shock and E. Coli bacteremia. She became severely ill requiring continuous renal replacement therapy for 5 days and extracorporeal membrane oxygenation (ECMO) for 6 days. Shortly after ECMO decannulation she developed fever and was found to have multiple pulmonary opacities concerning for fungal infection. Blasts were noted in the peripheral blood. Sixteen days after presenting with septic shock and 11 days from ECMO she received tisagenlecleucel. CRP at the time of infusion was 22.9 mg/dL. She developed persistent fevers post-infusion for 17 days. She received two doses of tociluzimab 20- and 21-days post-infusion due to recurrence of high fever and reactive lymphadenopathy with third spacing and concern for renovascular compromise. She did not require any treatment with corticosteroids for CRS. Bone marrow aspirate done 32 days post-infusion did not show any evidence of leukemia by MFC. The absolute neutrophil count recovered to &gt;500x103/µL at 59 days post infusion. The patient remained without evidence of disease for 7 months following treatment but died due to infectious complications with persistent pancytopenia. Tisagenlecleucel is a potentially life-saving treatment for relapsed and refractory B-cell acute lymphoblastic leukemia in children and young adults 24 years of age or younger. Tisagenlecleucel is an option for the treatment of patients with active infection and/or inflammation with progressive leukemia when no other therapeutic alternative exists. Disclosures August: Novartis Pharmaceuticals: Speakers Bureau. Myers:Novartis Pharmaceuticals: Consultancy, Speakers Bureau.

Central Nervous System Fungal Infections in Children with Leukemia, Risk Factors and Outcome: A Multicentric Study

Introduction:Invasive fungal infections, including central nervous system fungal infections (CNSFI), cause significant morbidity and mortality in children with leukemia,necessitating early diagnosis and treatment.Material and Method: In this retrospective study, the demographic features, diagnostic approach, treatment and outcome of CNSFI in 32 children with leukemia treated in 12 centers in Turkey were evaluated.Results:Of the 32 patients,12 were female,20 were male.The diagnosis was ALL in 23, recurrent ALL in 5, CML in 1, AML in 1; two others had underwent allogeneic bone marrow transplantation. Most (22/32-68,7%) CNSFI episodes occurred during the remission induction phase of the treatment. All recieved broad-spectrum antibiotics for prolonged neutropenic fever. Twenty two had seizures. Six patient had headache, two patient had double vision and headache, one patient had loss of vision and one patient had fascial paralysis. Radiologic imaging was performed for neurologic symptoms and/or prolonged fever in patients with febrile neutropenia after a median of seven days (1-22). Twenty three had multiple and 9 single brain lesions in magnetic resonance imaging. In 15/23 patients, invasive pulmonary fungal infection; in two patients, hepatosplenic fungal infection were detected concurrently. On blood cultures, one patient had geotrichum capitatum fungemia and one had candida albicans fungemia.Galactomannan was positive in 15 (46%) patients. Fourteen patients underwent surgery, in ten microbiological evidence of fungi was confirmed; four aspergillus flavus, one aspergillus niger, one candida, one mucormycosis and one trichoderma longibrachiatum. Hemophagocytosis was observed in three patients. Nine received granulocyte transfusions. Fifteen were transferred to the ICU. Extracorporeal Membrane Oxygenation (ECMO) was used in one patient. Eleven patients (34%) died due to CNSFI at a median of 30 (15-42) days from the beginning of the episode. Out of 21 survivors, seven have permanent neurological sequela. Eighteen patients were recieving antifungal prophylaxis (Fluconazole (16), voriconazole(1) and itraconazole(1), before the CNSFI diagnosis. Thirteen patients received a single antifungal agent, 19 were treated with a combination of antifungals. Median duration of antifungal treatment was 186 (20-730)days. Liposomal amphoterisin-B and voriconazole were the two mostly used agents. Six of the 12 centers participating in the study had a construction going on near their ward at the time of diagnosis.Conclusion: CNSFI is a major cause of mortality and morbidity in children with leukemia and prolonged neutropenic fever. The evaluation of children with leukemia and prolonged neutropenic fever for invasive fungal infections and the addition of empirical antifungal treatment to antimicrobial treatment is important. Cranial imaging in children with leukemia and prolonged neutropenic fever, even in the absence of local sign and symptoms may lead to earlier diagnosis of CNSFI. DisclosuresNo relevant conflicts of interest to declare.

Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction

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.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.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.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.We used standard methodological procedures expected by the Cochrane Collaboration.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 10(10) per day versus ≥ 1 x 10(10) 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 is a difference in pulmonary serious adverse events (1 study; 24 participants; RR 0.85, 95% CI 0.38 to 1.88; very low-quality evidence).None of the studies reported number of days on therapeutic antibiotics, number of adverse events requiring discontinuation of treatment, or quality of life.Six studies reported their funding sources and all were funded by governments or charities.In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is insufficient evidence to determine whether granulocyte transfusions affect all-cause mortality. To be able to detect a decrease in all-cause mortality from 35% to 30% would require a study containing at least 2748 participants (80% power, 5% significance). There is low-grade evidence that therapeutic granulocyte transfusions may not increase the number of participants with clinical resolution of an infection.

Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction.

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 10(10) 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 10(10) to 4.0 x 10(10) 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 10 x 10(10) 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.

Donor Granulocyte Transfusions in Febrile Neutropenic Pediatric Oncology Patients

To describe the clinical course of febrile neutropenic pediatric oncology patients undergoing granulocyte transfusions (GTF), we performed a retrospective chart review of all pediatric oncology patients with febrile neutropenia receiving granulocyte transfusions between September 2009 and September 2011 in a University Hospital setting. Thirty-seven patients received a total of 51 courses of GTFs. In 35 febrile episodes patients had leukemia and in 16 episodes patients had solid tumors. Three patients received allogeneic hematopoietic stem cell transplantation from their HLA identical sibling. Mean duration of fever and neutropenia was 18.5±17.5 days. Infections were classified as fever of unknown origin (21%, n= 11), microbiologically documented infection (44%, n= 23), clinically suspected infection (35%, n= 18). The mean granulocyte yield, WBC count and granulocyte count of the products were 3.1±1.2x1010/unit, 158.6±66.4x103/mm3 and 134.5±62x 103/mm3, respectively. The median donor WBC count at leukapheresis was 32.91x109/L. GTFs were well tolerated except one patient who had fever during transfusion. Thirty-nine (76.5%) of the episodes resolved from infection and discharged from the hospital. Of the 12 patients (23.5%) who died, seven of them were refractory to treatment, three patients had relapsed disease and two patients had newly diagnosed disease. This case series documents the course of 37 septic neutropenic pediatric oncology patients who underwent a total of 51 GTF courses. GTFs were generally well tolerated and improve short-term outcome in neutropenic pediatric oncology patients.

Granulocyte Transfusion Combined with Granulocyte Colony Stimulating Factor in Severe Infection Patients with Severe Aplastic Anemia: A Single Center Experience from China

ObjectiveTo investigate the efficacy and safety of granulocyte transfusion combined with granulocyte colony stimulating factor (G-CSF) in severe infection patients with severe aplastic anemia (SAA).MethodsFifty-six patients in severe infections with SAA who had received granulocyte transfusions combined with G-CSF from 2006 to 2012 in our department were analyzed. A retrospective analysis was undertaken to investigate the survival rates (at 30 days, 90 days and 180 days), the responses to treatment (at 7 days and 30 days, including microbiological, radiographic and clinical responses), the neutrophil count and adverse events after transfusion.ResultsAll SAA patients with severe infections were treated with granulocyte transfusions combined with G-CSF. Forty-seven patients had received antithymocyte globulin/antilymphocyte globulin and cyclosporine A as immunosuppressive therapy. The median number of granulocyte components transfused was 18 (range, 3–75). The survival at 30 days, 90 days and 180 days were 50(89%), 39(70%) and 37(66%) respectively. Among 31 patients who had invasive fungal infections, the survival at 30 days, 90 days and 180 days were 27(87%), 18(58%) and 16(52%) respectively. Among the 25 patients who had refractory severe bacterial infections, the survival at 30 days, 90 days and 180 days were 23(92%), 21(84%) and 21(84%) respectively. Survival rate was correlated with hematopoietic recovery. Responses of patients at 7 and 30 days were correlated with survival rate. Common adverse effects of granulocyte transfusion included mild to moderate fever, chills, allergy and dyspnea.ConclusionGranulocyte transfusions combined with G-CSF could be an adjunctive therapy for treating severe infections of patients with SAA.

Granulocyte transfusions in fulminant invasive fungal sinusitis

PurposeFulminant invasive fungal sinusitis (IFS) is an aggressive disease seen in patients who are severely neutropenic. The use of granulocyte transfusions to address neutropenia-associated IFS has been described for almost 2 decades. The objectives are to provide our experience using granulocyte transfusions in patients with IFS and to provide a current review of the literature. Materials and methodsA retrospective chart review was performed at the Medical College of Wisconsin to identify patients who received granulocyte transfusions for IFS. Data collected included age, original diagnosis, IFS pathogen, dates, transfusion number, reason for discontinuation, additional therapies, last known follow-up, and status at last known follow-up. A Medline search and manual review of citations within bibliographies was also performed. ResultsA total of 20 patients received granulocyte transfusions at the Medical College of Wisconsin between October 2003 and June 2009; 3 of these patients received granulocyte transfusions for fulminant IFS. A total of 22 reported cases of IFS treated with granulocyte transfusions exist in the current literature. ConclusionsAlthough limitations to the use of granulocyte transfusions exist, they still represent a viable treatment option in individuals who fail to respond to more conventional therapies.

Granulocyte transfusions in severe aplastic anemia: an eleven-year experience

Infections, particularly those caused by invasive fungi, are a major cause of death in patients with severe aplastic anemia. The purpose of this study was to analyze our experience with granulocyte transfusions in such patients. A retrospective analysis was performed on all patients with severe aplastic anemia who had received granulocyte transfusions between 1997 and 2007 in our institute. Survival to hospital discharge was the primary outcome. Secondary outcomes included microbiological, radiographic and clinical responses of the infection at 7 and 30 days after initiating granulocyte therapy, and post-transfusion absolute neutrophil count, stratified by HLA alloimmunization status. Thirty-two patients with severe aplastic anemia underwent granulocyte transfusions; the majority had received horse antithymocyte globulin and cyclosporine A. One quarter of patients had demonstrable HLA alloimmunization prior to the initiation of granulocyte therapy. Infections were evenly divided between invasive bacterial and fungal infections unresponsive to maximal antibiotic and/or antifungal therapy. The median number of granulocyte components transfused was nine (range, 2-43). The overall survival to hospital discharge was 58%. Survival was strongly correlated with hematopoietic recovery. Among the 18 patients who had invasive fungal infections, 44% survived to hospital discharge. Response at 7 and 30 days correlated with survival. The mean post-transfusion absolute neutrophil count did not differ significantly between response groups (i.e. patients grouped according to whether they had complete or partial resolution of infection, stable disease or progressive infection). There was also no difference in mean post-transfusion absolute neutrophil count between the patients divided according to HLA alloimmunization status. Granulocyte transfusions may have an adjunctive role in severe infections in patients with severe aplastic anemia. HLA alloimmunization is not an absolute contraindication to granulocyte therapy.

Correction of chronic granulomatous disease after second unrelated‐donor umbilical cord blood transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for chronic granulomatous disease (CGD), but many patients lack a suitably matched related donor. We report successful outcomes after mismatched, unrelated-donor umbilical cord blood transplantation (uUCBT) in two boys with X-linked CGD. Both patients experienced autologous recovery after first transplants, required second transplants to achieve durable donor engraftment, and are alive 27 and 15 months post-transplant. Both had invasive fungal disease and received granulocyte transfusions. In conclusion, uUCBT is effective in children with CGD, but immunosuppression in the conditioning regimen may need to be increased to decrease the risk of graft rejection.

Cytomegalovirus pneumonia in adults with leukemia: an emerging problem.

Cytomegalovirus (CMV) pneumonia is reportedly unusual among adults with leukemia who have not undergone transplantation. To assess the frequency of CMV pneumonia and its outcome during the present time, we reviewed the experience of 2136 hospitalized adults with leukemia. Sixty-one patients (2.9%) had CMV pneumonia diagnosed. The frequency doubled from 1.4% in 1992--1994 to 2.8% in 1995--1997 (P<.05). Fifty-four patients (89%) had received treatment with an immunosuppressive chemotherapeutic regimen that contained fludarabine (n=37), high-dose cytoxan (n=17), or both (n=10), and 15 patients (25%) had received granulocyte transfusions that were stimulated with hematopoietic growth factors from unscreened donors. The overall CMV pneumonia--associated mortality rate was 57%. Among autopsied patients who had leukemia, the frequency of CMV pneumonia increased from 0%, 2.3%, and 0% in 1992, 1993, and 1994, respectively, to 4.6%, 6.5%, and 16% in 1995, 1996, and 1997, respectively (P<.05). CMV has emerged as an important cause of life-threatening pneumonia in adults with leukemia who have received potent immunosuppressive therapies and stimulated granulocyte transfusions from unscreened donors.

Randomized trial of granulocyte transfusions versus intravenous immune globulin therapy for neonatal neutropenia and sepsis

We prospectively studied newborn infants with sepsis and neutropenia who were randomly selected to receive standard supportive care and either adjuvant granulocyte transfusions or intravenous immune globulin (IVIG) infusions; 21 infants received granulocyte transfusions and 14 received IVIG infusions. Half of the patients were premature (gestational age less than or equal to 32 weeks); the average postnatal age was 5 days (range 3 to 8 days). All infants had neutropenia by the criteria of Manroe et al., and the mean average bone marrow neutrophil storage pool ranged between 35% and 37%. There were no significant differences with respect to serum IgG, IgA, IgM, and total hemolytic complement values between treatment groups or between survivors and nonsurvivors. Clinical severity as defined by hypoxia, acidosis, and hypotension was similar between treatment groups. Group B streptococcus was the most common organism identified and accounted for almost 33% of all bacterial isolates. There was a significantly different survival rate in the group receiving polymorphonuclear leukocyte transfusions (100%, 21/21) compared with the group receiving IVIG infusions (64%, 9/14; p = less than 0.03). There were no significant complications in either treatment group with respect to fluid overload, secondary infection, blood group sensitization, pulmonary complications, or graft-versus-host disease. This pilot study suggests a possible benefit of granulocyte transfusions compared with 'IVIG therapy in the adjuvant treatment of neonatal neutropenia and overwhelming bacterial sepsis.

Granulocyte transfusion kinetics measured by chemiluminescence, nitroblue tetrazolium reduction, and recovery of indium-111-labeled granulocytes.

A 20-year-old man with chronic granulomatous disease (CGD) and who was receiving granulocyte transfusions for a refractory liver abscess was studied to compare the kinetics of 111In-labeled granulocytes with those of two functional granulocyte assays, nitroblue tetrazolium reduction and chemiluminescence. Transfused granulocytes were eliminated in both rapid and slow phases. Peak recovery was noted in the first sample, which was obtained 10 minutes after transfusion for each assay. The elimination kinetics were similar over 24 hours. These results confirm the value of using 111In-labeled granulocytes as a marker of transfused granulocytes. These data also confirm that the oxidative metabolic function of granulocytes prepared by continuous-flow leukapheresis remains intact while in the recipient's circulation. The response of the patient adds support for the use of granulocyte transfusions in certain patients with CGD.

Are Granulocyte Transfusions of Value in Septic Neonates Without Neutrophil Storage Pool Depletion?

To the Editor.— A recent report by Cairo et al1 suggests the possible value of granulocyte transfusions in septic neonates who do not have bone marrow neutrophil pool (NSP) depletion. In this study, three of seven neonates who had documented sepsis and who did not receive granulocyte transfusions did not survive, and only one of seven of these neonates had neutrophil storage pool depletion at the time of entry into the study. Because approximately one half of the neonates who had documented sepsis and did not receive granulocyte transfusions survived, one must conclude that a significant number of neonates in the study of Cairo et al probably received granulocyte transfusions unnecessarily.

The significance of pulmonary infiltrates developing in patients receiving granulocyte transfusions

Summary. We reviewed a series of 109 patients given granulocyte transfusions between 1974 and 1978, to determine if pulmonary infiltrates developing during granulocyte transfusion therapy carried any specific prognostic significance. Eighteen patients developed new infiltrates while receiving granulocytes. Six of these patients died during the acute episode, an overall mortality rate no different from patients not developing new infiltrates. However, the subgroup with pulmonary infiltrates who died had some special features including: infiltrates that developed between 7 and 21 d after transfusions were begun; infiltrates that progressed or persisted during the period of transfusion; and infiltrates that were local rather than diffuse. Autopsies on five of the six patients who died revealed disseminated fungal infection in three, pulmonary haemorrhage in one, and alveolar hyaline membranes in association with Pseudomonas sepsis in one. Besides this high‐risk group specific aetiologies could rarely be assigned for other more diffuse or earlier/later developing infiltrates, despite usual diagnostic studies.We conclude that local infiltrates developing more than 1 week after transfusions are begun are life threatening; they are often caused by resistant infectious organisms and would seem to represent a failure of granulocyte therapy. Aggressive diagnostic and therapeutic interventions are warranted in patients developing this kind of infiltrate while receiving granulocytes. Conversely, pulmonary infiltrates occurring early or longer than 3 weeks after granulocyte tranfusions are begun are not clinically ominous and may be a manifestation of the beneficial effect of granulocyte therapy.