Granulocyte transfusion therapy in children.

A prospective study of 45 granulocyte transfusions in children using continuous flow centrifugation is reported. During 13 episodes of proven or presumed infection, only two children failed to show a favorable response to granulocyte transfusion. The neutropenic child shows a significantly increased absolute granulocyte count one hour after transfusion. The granulocyte counts at one hour after transfusion are inversely proportional to the child's size. A child with chronic granulomatous disease who had documented Nocardia asteroides sepsis and pneumonia exhibited complete recovery following granulocyte transfusion. Dramatic responses to the nonrandom use of granulocyte transfusion have been observed in children with major gram-negative bacterial infections. Endorsement of granulocyte transfusion for instances of presumed, but unproven, infection in the neutropenic child will require randomization to control the variables of antibiotic therapy and bone marrow remission.     

中性粒细胞输注治疗血液病严重粒细胞缺乏症的感染

目的 评价中性粒细胞输注治疗血液病严重粒细胞缺乏症的感染的临床疗效.方法 回顾分析9例严重粒细胞缺乏症合并感染者接受粒细胞输注的病例资料.结果 8例感染得到控制,1例治疗失败而死亡,无1例出现粒细胞输注的严重不良事件.结论 中性粒细胞输注治疗用于粒细胞缺乏的血液病患者,具有一定疗效,且供受者均耐受良好,其临床价值值得进一步探索.     

Use of G-CSF for granulocyte transfusion therapy

Patients with neutropenia, especially neutropenia following aggressive myeloablative therapy, are at high risk for developing infectious complications caused by bacteria and opportunistic fungi. Infections remain one of the leading causes of treatment failure in patients with cancer. Thus, new and innovative therapeutic strategies are needed for management of neutropenic patients with infection. Because neutrophils represent the first line of host defense, granulocyte transfusion therapy should be a logical therapeutic approach. Although such therapy has been employed sporadically for several decades, clinical benefit has been compromised by technical problems and low granulocyte yields resulting from inadequate donor stimulation. The discovery of granulocyte colony-stimulating factor (G-CSF) as a means to elevate blood neutrophil counts when administered to normal donors has rekindled interest in granulocyte transfusion therapy. Extensive experience has been gained worldwide with G-CSF in clinical practice, and adverse events have been minimal when G-CSF has been administered to patients or healthy persons in human trials. This review focuses on the use of G-CSF in granulocyte transfusion therapy, including technical considerations of granulocyte leukapheresis and storage, donor selection and stimulation, as well as treatment results and associated risks.     

Secondary prophylaxis of invasive fungal infections with combination antifungal therapy and G-CSF-mobilized granulocyte transfusions in three children with hematological malignancies

Fungal infections represent a life-threatening complication for patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation. Historically, antifungal monotherapy is associated with a poor outcome. We treated three children with hematological malignancies and proven fungal infections (one cerebral mold infection, one disseminated Candida infection, one naso-pharyngeal mucor infection) with combination antifungal therapy plus granulocyte-colony-stimulation-factor-mobilized granulocyte transfusions as secondary prophylaxis during subsequent neutropenic episodes. With this approach, the fungal infection was effectively treated, and the anticancer therapy was completed without major delay. All children survived the fungal infection and the underlying malignancy. These experiences illustrate the feasibility of this approach using more than one antifungal agent together with immune-therapy in high-risk patients.     

G-CSF mobilised granulocyte transfusions in 32 paediatric patients with neutropenic sepsis

Introduction In this retrospective, uncontrolled, observational study, the effect of granulocyte colony-stimulating factor (G-CSF)-stimulated granulocyte transfusions (GTX) in neutropenic paediatric patients with sepsis was evaluated.Patients and methods Granulocytes were collected from unrelated, ABO group-matched and cytomegalic-antibody compatible donors. For neutrophil mobilization, donors received a single subcutaneous dose of glycosylated G-CSF (Lenograstim, Chugai Pharma, Japan) plus oral dexamethasone (8 mg). In total, 168 (range 1–19 per patient) GTX were transfused in 32 children with a median age of 7.4 (0.25 to 16) years.Results The underlying diseases comprised predominantly haematooncological malignancies (31 children). In 15 of 32 patients, neutropenia was related to allogeneic stem cell transplantation. All children suffered from sepsis based on international criteria (fever, tachycardia, respiratory rate >2 SD above normal in the context of a suspected or proven infection). In ten children bacteria were isolated, in six children a fungal infection was diagnosed and four sepsis episodes were caused by viral infections. GTX contained a median neutrophil number of 6.3 (range 1.9–13.9)×10¹⁰ per transfusion and obtained a sustained haematological response after GTX. Nineteen out of 32 children survived the neutropenic sepsis, particularly nine out of 11 patients with bacterial sepsis.Discussion In contrast to the non-survivors, we observed a significant decrease in the C-reactive protein levels shortly after initiation of the GTX treatment in the surviving patients. A clear-cut benefit of GTX for children with neutropenic sepsis cannot be concluded from these data, but in children with (severe) bacterial sepsis refractory to antibiotic treatment, GTX were feasible, safe and could reduce mortality rates in this subgroup of patients.     

Clinical perspectives of granulocyte transfusions: Efficacy to date

The literature pertaining to the use of granulocyte transfusions as treatment for progressive bacterial, yeast, and fungal infections in severely neutropenic patients is reviewed. Efficacy in treating bacterial infections that are unresponsive to antimicrobial therapy is well established—especially if bone marrow failure does not recover rapidly and neutropenia is persistent. The role of therapeutic granulocyte transfusions for yeast and fungal infections has potential merit, but current data are incomplete and findings are inconsistent. The possibility of greater success has been raised by use of recombinant granulocyte colony stimulating factor to greatly increase the yield of neutrophils collected from normal donors.     

Granulocyte transfusion therapy in chronic granulomatous disease. Report of a patient and review of the literature

A l6-year-old boy with chronic granulomatous disease (CGD) and multiple Staphylococcus aureus hepatic abscesses failed to respond to intense antimicrobial therapy and surgical drainage procedures. He was started on a l3-day course of daily granulocyte transfusions obtained by intermittent-flow leukapheresis (haemonetics Model 30 [Braintree, Massachusetts]) utilizing hydroxyethyl starch. Each transfusion contained an average of 9 × l0(9) granulocytes. He defervesced on the seventh transfusion day, and the sedimentation rate returned to normal on the thirteenth transfusion day. Radionuclide scan showed decrease in size of the liver abscesses. No other new therapeutic modalities were attempted during the period of granulocyte transfusion. Although the use of granulocyte transfusion has been suggested to treat infections in CGD, we report the first successful use of granulocyte transfusion therapy in S. aureus abscess disease in CGD. Granulocyte transfusions may be helpful in treating infections refractory to standard medical- surgical management in patients with CGD and other disorders of neutrophil function.     

Granulocyte collection.

Techniques for collecting granulocytes for transfusion either to neutropenic patients or to neonates are described. Currently, the best granulocyte concentrates are prepared using continuous-flow centrifugation leukapheresis of steroid-stimulated donors in the presence of pentastarch. Donor reactions are mild and are similar to those expected with automated plateletpheresis.     

An analysis of quantitative relationships of granulocyte transfusion therapy in canines

Granulocyte transfusions were administered to dogs rendered neutropenic by prior cyclophosphamide treatment. Linear regression analysis established significant direct relationships between numbers of granulocytes infused per kg body weight and blood increment achieved. Migration of granulocytes to cerebrospinal fluid during induced Candida albicans meningitis related to concurrent increments in blood following transfusion. Levels of C. albicans systemic infection were inversely related to numbers of granulocytes administered during a four-day course of therapy. These studies demonstrate the quantitative relationships of granulocyte transfusion therapy to potential therapeutic effects at the tissue level.     

Safety and efficacy of therapeutic early onset granulocyte transfusions in pediatric patients with neutropenia and severe infections

BACKGROUND: Bacterial and fungal infections in profound neutropenia after chemotherapy are associated with high mortality despite appropriate antibacterial and antifungal treatment. Granulocyte transfusions are used as a therapeutic addendum, but concern regarding pulmonary reactions often results in delayed use in clinical practice. Accordingly, many patients are already at advanced stages of their infectious disease once granulocytes are transfused. Thus, a prospective Phase II trial was conducted to test the safety and efficacy of therapeutic early-onset granulocyte transfusions in immunocompromised children with neutropenia and severe infections. STUDY DESIGN AND METHODS: Twenty-seven children with hematologic disorder or malignancy and severe neutropenia with clinically and/or microbiologically documented severe infection unresponsive to standard treatment were included. They received granulocyte colony-stimulating factor (G-CSF)-elicited, crossmatched granulocyte concentrates every other day until complete recovery from infection was documented. RESULTS: A median of two granulocyte transfusions with a median of 8 x 10(8) granulocytes per kilogram of body weight were administered. All transfusions were well tolerated, and no pulmonary symptoms were observed. A total of 92.6 percent of our patients were able to clear their initial infection, and 81.5 percent were alive and without signs or symptoms of their infection 1 month later. All six children with aspergillosis cleared their infection. CONCLUSIONS: G-CSF-elicited, crossmatched granulocyte concentrates are a safe and efficient therapeutic addendum in immunocompromised children with prolonged neutropenia and severe infections. Early transfusion of granulocyte concentrates can lead to an overall response rate of 92.6 percent without adverse events. Randomized clinical trials with an early-onset design are required to determine appropriate clinical applications.     

Granulocyte transfusion therapy for infections in candidates and recipients of HPC transplantation: a comparative analysis of feasibility and outcome for community donors versus related donors

BACKGROUND: Feasibility, response to granulocyte transfusion therapy, and clinical outcome were compared among HPC transplant recipients enrolled in a prospective study of a community blood bank-based unrelated donors program, a prospective granulocyte study using family donors, and matched control patients without granulocyte transfusion therapy. STUDY DESIGN AND METHODS: Overall, 40 patients (327 collections) received granulocyte concentrates from unrelated donors, 34 patients (219 collections) received granulocyte concentrates from related donors, and 74 patients served as controls. Study entry criteria for patients included an absolute neutrophil count (ANC) of less than 200 per microL and documented invasive fungal or bacterial infections. RESULTS: There was a median delay of 3 days (range, 0-14) in patients receiving transfusions from unrelated donors between day of diagnosis of infection and start of granulocyte transfusion therapy as compared with a median delay of 5 days (range, 0-25) in patients receiving transfusions from related donors (p = 0.01). The ANC increment after the first, second, and seventh transfusions in patients who had community donors was significantly higher or comparable to patients who had family donors. Overall, clinical outcome was comparable between the three patient groups. Kaplan-Meier analysis revealed no difference between all cohorts in overall 6-month survival (p = 0.28, log-rank) or event-free survival (p = 0.17, log-rank). CONCLUSION: These results suggest that future efficacy trials should consider inclusion of unrelated community donors for timely institution of granulocyte transfusion therapy.     

Use of granulocyte transfusion in early period in life-threatening infections of pediatric hematology and oncology patients: A single-center experience

Despite all the developments in medicine, infections continue to be one of the most important causes of mortality in pediatric hematology and oncology patients. The more severe the degree of neutropenia develops after intensive chemotherapy in cancer patients, and the longer the neutropenia duration, the higher the risk of infection. Granulocyte transfusion (GT) is used as supportive therapy in cases where the bone marrow needs time to recover in invasive bacterial or fungal infections along with severe neutropenia. The patients who had granulocyte transfusions in our clinic between June 2019 and June 2020 were reviewed retrospectively. A total of 15 units of granulocyte concentrate were used in 11 febrile neutropenia attacks of 9 patients. The demographic characteristics of the patients and features belonging to the period of GT were recorded. In our study, the clinical response rate after GT was 90.9 %, while the hematological response rate was 40 %. Most of the patients were treated succesfully, the mortality rate was 9%. We think that the most critical factor for success with GTs is determining the neutropenic patient in particular with a combination of high-risk malignancy and acute life-threatening infection for using GT. Also, early use of GT in those patients who do not recover despite appropriate antimicrobial and supportive treatment may contribute to improvement of the clinical conditon in a shorter period of time and reduction of repeated GTs.     

Impact of colony-stimulating factor therapy on clinical outcome and frequency rate of nosocomial infections in intensive care unit neutropenic patients

OBJECTIVES: To determine whether the use of recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) reduces the mortality rate and the frequency rate of nosocomial infections in neutropenic patients requiring intensive care unit (ICU) admission. DESIGN: Retrospective consecutive case series analysis. SETTING: Medical ICU of a teaching hospital. PATIENTS: We compared two groups of patients, according to whether or not they received G-CSF. In the ICU, 28 leukopenic patients received filgrastim (5 microg of body weight per day intravenously). In all these patients, G-CSF was continued until recovery from leukopenia, defined as a leukocyte count >1,000/mm3. A total of 33 ICU leukopenic patients did not receive G-CSF. End points included leukocyte count, bone marrow recovery, frequency of ICU nosocomial infections (pneumonia, urinary tract, and catheter-related infections), and mortality rate. MEASUREMENTS AND MAIN RESULTS: There were no differences in number of patients who recovered from leukopenia or in whom blood leukocyte count increased. Nosocomial infections occurred in the same percentage in both groups. The percentage of patients who died was identical in both groups. The percentage of patients with and without filgrastim therapy who recovered from leukopenia but died, was 86% and 78%, respectively. CONCLUSION: In the ICU, clinical outcome of neutropenic patients was not changed by G-CSF therapy. It is possible that G-CSF therapy may not be helpful in improving the ICU clinical outcome of neutropenic patients. Additional controlled studies designed to address this question are warranted.     

Leukapheresis and granulocyte transfusion.

Granulocyte transfusion is becoming widely used in the treatment of infections in granulocytopenic patients. Several techniques are available for granulocyte collection. Some involve centrifugation of the whole blood and one removes granulocytes from whole blood by reversible adhesion to nylon fibers. The risks to the donor from leukapheresis do not appear to be greater than from whole blood donation. Granulocytes collected by centrifuge techniques function normally in vitro and have normal intravascular recovery and disappearance following transfusion. Granulocytes collected by filtration leukapheresis function almost normally in vitro but have a reduced intravascular recovery and abnormal kinetics as they leave the circulation. The role of leukocyte typing and compatibility testing for granulocyte transfusion is controversial. When the recipient has circulating antibody against donor leukocytes, transfused leukocytes do not circulate or migrate to sites of infection but are sequestered in the liver and spleen. Clinical studies have not defined whether patients benefit equally well clinically from transfusion of compatible or incompatible granulocytes. Initial reports of clinical trials of granulocyte transfusion were promising. However, similar patients who did not receive granulocytes were not studied. Most subsequent controlled trials showed a clear benefit from granulocyte transfusion while others did not. Differences in antibiotic therapy, chemotherapy, use of laminar flow rooms, and grouping of patients make it difficult to compare these clinical trials. Some, but not all, infected granulocytopenic patients benefit from transfusion. Granulocyte transfusions improve survival of granulocytopenic patients with gram negative sepsis and prolonged bone marrow aplasia. Studies are now attempting to identify other patients who should receive granulocytes, the optimum dose and schedule of transfusions, the optimum time to begin transfusion, and the value, if any, of prophylactic transfusions.     

Altered expression of adhesion molecules (L-selectin and Mac-1) on granulocytes during storage

BACKGROUND: The success of granulocyte transfusion therapy for neutropenic patients with sepsis is dependent on the number and quality of the granulocytes transfused. There is a progressive impairment in granulocyte function during storage. STUDY DESIGN AND METHODS: The effect of 1 to 2, 4, 24, and 48 hours' storage on receptor expression associated with granulocyte function has been analyzed. RESULTS: After 24 hours' storage, significant changes were found in the expression of receptors associated with adhesion to the endothelium: a decrease in L- selectin expression (p < 0.01) and an increase in Mac-1 expression (p < 0.01). Receptors (CR1 and FcRIII), associated with adhesion to target, were either increased (CR1) or unaltered (FcRIII). The capacity to produce a reactive oxygen metabolite (hydrogen peroxide) remained essentially unchanged after 48 hours' storage. The ability of N-formyl- methionyl-leucyl-phenyl alanine to mobilize Mac-1 and CR1 was reduced after 48 hours' storage. CONCLUSION: Since the regulation of adhesion molecules is important for the recruitment of granulocytes into an inflammatory site, the observed in vitro changes in L-selectin and Mac- 1 expression during storage may be of importance for the quality of granulocyte concentrates.     

Systemic Candida infections in patients with leukemia: an overview of drug therapy

Systemic fungal infections are becoming increasingly common in patients with hematologic malignancies receiving antineoplastic therapy. The presence of acute myeloid or acute lymphoid leukemia, plus the use of chemotherapy to totally ablate malignant bone marrow cells, puts patients in a protracted neutropenic state. During this profound and prolonged neutropenic phase, patients receive antibiotic therapy for suspected or identified bacterial infections. However, when fever or other signs of infection continue despite antibiotic therapy, patients frequently need to be treated for suspected or identified systemic fungal infections. These infections may occur in patients receiving either standard antileukemia therapy or research protocol therapy involving new drugs, new drug combinations, higher doses, or newer schedules of established drugs. After antifungal therapy is initiated, it may be continued postdischarge in outpatient or homecare settings. Therefore, becoming knowledgeable about antifungal therapy is important for all oncology nurses regardless of practice setting.     

Granulocyte Transfusion Therapy of Experimental Pseudomonas Pneumonia

Pseudomonas pneumonia was produced in dogs with radiation-induced leukopenia. Treatment of this infection with either gentamicin alone or gentamicin plus daily granulocyte transfusion was compared in a randomized controlled trail. The dogs receiving granulocytes plus gentamicin survived significantly longer than those treated with gentamicin alone (P < 0.05). The Pseudomonas immunotype which was inoculated into the dogs were recovered at autopsy from none of the granulocyte-transfused dogs, whereas seven or eight of the dogs treated with gentamicin alone had the inoculated Pseudomonas immunotype in the area of induced pneumonia at autopsy. As measured by the limulus test, the granulocyte-transfused dogs also did not have endotoxemia as frequently as the dogs given only gentamicin (P < 0.05). This controlled study establishes that transfused granulocytes can favorably alter the course of experimental Pseudomonas pneumonia and suggests that granulocyte transfusion may be a useful therapy in serious bacterial infections of leukopenic subjects.     

Functional characteristics of neutrophils collected and stored after administration of G-CSF

BACKGROUND: Granulocyte transfusion may be used in neutropenic patients with severe bacterial or fungal infections that are unresponsive to antibiotic therapy. However, the inability to store granulocyte concentrates limits their clinical usefulness. STUDY DESIGN AND METHODS: Neutrophil chemotaxis and NADPH oxidase activity and the integrity of the neutrophil NADPH oxidase system were examined after apheresis collection and during storage to 48 hours. Neutrophils were mobilized in vivo by G-CSF, collected by apheresis techniques, and stored in apheresis bags in the presence and absence of additional G-CSF. For all experiments, cells were further purified by standard techniques of dextran sedimentation and hypotonic RBC lysis. RESULTS: Neutrophil chemotaxis was preserved to 24 hours of storage but was not affected by the G-CSF added to storage units. The NADPH oxidase system was also preserved as a functioning complex, and both cytosolic proteins and membrane-associated proteins were normal to 48 hours. However, there were divergent responses by intact cells to activating stimuli and reduced oxidase activity in the cell-free system. G-CSF did not appear to significantly affect NADPH oxidase activity or NADPH oxidase system integrity during storage. CONCLUSION: Neutrophils collected after the administration of G-CSF retained functional and biochemical characteristics for at least 24 hours of storage, which suggests additional effects of G-CSF mobilization beyond enhancing PMN yields and the possibility of storage of these components after collection.     

Survival among children and adults treated with granulocyte transfusions: Twenty years’ experience at a Brazilian blood center

BackgroundIt remains controversial whether granulocyte transfusions as a supportive treatment improve survival in patients with febrile neutropenia or granulocyte dysfunctions. We describe survival rates subsequent to granulocyte transfusions in pediatric and adults patients treated at a major blood center in Brazil.Material and methodsWe retrospectively reviewed the clinical charts of pediatric and adult patients treated with granulocyte transfusions at our institution from January 2000 to October 2019. We assessed demographic characteristics, clinical features, indications for transfusion, units transfused, dose of granulocytes administered and survival rates 30 and 100 days after the initial transfusion.ResultsWe identified 64 pediatric and 67 adult patients treated with 262 granulocyte transfusions. An optimal dose (> 0.6 × 10⁹ granulocytes per kilogram per transfused unit) was available for transfusion in 80.4 % of pediatric patients but in only 19.6 % of adults (p = 0.017). Thirty days after their first granulocyte transfusion, 38 (59.4 %) pediatric and 61 (91 %) adult patients had died. Patients receiving the optimal dose of granulocytes had better survival outcomes, but even among this sub-group, adults were more likely to die than were children either at 30 days (OR = 8.67, 95 %CI 2.69–34.9) or 100 days (OR = 6.27, 95 %CI 1.86–25.9) after their initial granulocyte transfusion.ConclusionSurvival rates following granulocyte transfusion varied by the dose transfused and were higher in children than in adults.     

Gram-negative sepsis treated with neutrophils collected exclusively by intermittent flow centrifugation leukapheresis

The effectiveness of neutrophils prepared for transfusion by intermittent flow centrifugation leukapheresis (IFCL) as treatment for serious bacterial infections in neutropenic patients has not been documented in the literature. Their value, in fact, has been questioned. We report that IFCL neutrophils are similar to cells prepared by other techniques in the ability to support neutropenic patients with culture-proven, gram-negative sepsis unresponsive to antibiotics.