Pediatric Hematology and Oncology, 31:425–434, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2013.868562
ORIGINAL ARTICLE Supportive Care
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Granulocyte Transfusions for Children with Infection and Neutropenia or Granulocyte Dysfunction Rosa D´ıaz, MD,1 Esther Soundar, MD, MPH,2 S. Kate Hartman, MD,2 ZoAnn Dreyer, MD,1 Jun Teruya, MD, DSc,2,3 and Shiu-Ki Rocky Hui, MD2 1
Department of Pediatrics, Texas Children’s Hospital, Houston, TX, USA; 2 Department of Pathology, Baylor College of Medicine, Houston, TX, USA; 3 Department of Pediatrics and Medicine, Baylor College of Medicine, Houston, TX, USA
Transfusions of granulocytes can be used as an adjunct therapy to antimicrobials in patients with infection and neutropenia or granulocyte dysfunction. However, there is a lack of strong clinical evidence to support the use of this treatment strategy, particularly in children. We retrospectively reviewed the medical records of children who received granulocytes at our institution from April 2009 to October 2012, with emphasis on primary indication for the transfusion and clinical outcome in terms of infection. The patients had granulocyte dysfunction or severe neutropenia, defined as absolute neutrophil count (ANC) < 500 cells/mm3 due to chemotherapy or hematopoietic stem cell transplant (HSCT), and reasonable hope for bone marrow recovery or engraftment. Eighteen children received granulocytes during 20 distinct episodes: 62% (n = 13) for acute infection, 29% (n = 5) for unresolved chronic infection during the time of HSCT, and 9% (n = 2) for other clinical conditions such as typhilitis and appendectomy. Overall, 92% (n = 12) of the episodes of acute infection had complete or partial resolution, as determined by review of vital signs, physical exam findings and discontinuation of antimicrobials. A substantial number (46%) of children who received granulocytes for acute infection developed respiratory adverse events, but all of these recovered. We conclude that granulocyte transfusions continue to be primarily used in neutropenic patients with acute infections, and that its use in this group of patients is reasonable. However, a prospective randomized clinical trial is needed to evaluate safety and whether the use of granulocytes is superior to antimicrobial-only therapy. Keywords bone marrow transplant, infections, neutropenia, supportive care, transfusion medicine
INTRODUCTION Despite the widespread use of broad spectrum antimicrobials, infections represent a major cause of morbidity and mortality in patients with granulocyte dysfunction or neutropenia secondary to chemotherapy or HSCT. Various studies have reported that the strongest predictor of recovery from infection is an adequate number of blood and tissue neutrophils, and recovery of neutrophil production by the patient’s bone marrow [1]. Therefore, any method that provides functional neutrophils to patients with infection during the neutropenic period should aid in infection clearance and reduce the number of infection-related deaths. This finding led to the use of granulocyte Received 31 October 2013; accepted 19 November 2013. Address correspondence to Rosa D´ıaz, MD, Department of Pediatrics, Pediatric Hematology Oncology Instructor, 1102 Bates Ave, Suite 1025, Houston, TX 77030, USA. Email: [email protected]
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transfusions collected from healthy donors as a way to bridge the gap between neutropenia and marrow recovery in patients undergoing chemotherapy and/or HSCT. Despite being used over the past 40 years, the clinical indications for granulocyte transfusion, its effectiveness, and safety profile remain largely unknown, particularly in children. This therapeutic modality has been discussed in a few case reports and cohort studies that suggest potential benefits with no clear estimation of a positive benefit to risk ratio in various clinical scenarios, including acute bacterial or fungal infection, and prophylaxis in neutropenic patients undergoing HSCT [2–4]. In pediatric patients, the only prospective study to date included 59 children and young adults that received 778 doses of granulocyte transfusion. That study used survival for 28 days after the initiation of granulocyte transfusion treatment as a surrogate marker for effective therapy and showed a survival probability of 0.72 for the cohort [3]. However, we believe that the conventional use of survival to define efficacy may present a disadvantage by: (1) assuming therapeutic failure of granulocytes when patients don’t survive; and (2) not focusing on the intent of granulocyte transfusion to help fight infection. In the present study, we describe our experience with usage of granulocyte transfusions at a tertiary center. We identified 18 children with neutropenia or granulocyte dysfunction who received 20 distinct courses of granulocytes. Here, we report the primary indications for granulocyte transfusion, the clinical response and outcomes in term of infection, and the safety profile of this intervention. To our knowledge, this is the largest study to systematically assess infection outcomes as a way to determine the potential benefits that can be attained with granulocyte transfusions. METHODS Study Design and Patient Selection This is a retrospective review of all children with neutropenia or granulocyte dysfunction who received granulocyte transfusions at Texas Children’s Hospital (TCH) from April 2009 to October 2012. The decision and timing of granulocyte transfusions was determined by the patient’s physician in conjunction with the transfusion medicine and blood bank service and availability of eligible directed volunteer donors. All patients had: (1) granulocyte dysfunction or severe neutropenia, defined as an ANC < 500 cells/mm3 , secondary to chemotherapy or HSCT; and (2) reasonable hope for bone marrow recovery or engraftment. The study was approved by our institutional review board, and consent was waived for all patients due to the retrospective design of the study. Data were collected from medical records, the blood bank database and the granulocyte supplier in order to assess patient demographics, indication for transfusion and granulocyte content of the product, laboratory data, clinical course, and outcome. Granulocyte Collection and Transfusions Granulocyte units were collected, processed, and tested by the Blood Bank at The University of Texas M.D. Anderson Cancer Center. Because there is no local altruistic granulocyte donor program, the patient’s family was responsible for recruiting directed volunteer donors, typically family members and friends from their local social network. The donors presented to the donor center for screening, which included a complete blood count (CBC), a pregnancy test for every woman less than 56 years without hysterectomy, and West Nile virus testing, among others. Approved donors were stimulated 12 hours prior to the collection with 8 mg of oral dexamethasone and 600 mcg of subcutaneous granulocyte-colony stimulating factor (G-CSF). Granulocytes were collected via apheresis over a period of 2.5 to 3.5 hours. A granulocyte count was done on the final product to insure that an adequate dose of at ≥ 1 × 1010 granulocytes was collected. Testing for cytomegalovirus (CMV) was not performed routinely Pediatric Hematology and Oncology
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due to the high regional CMV seropositivity and thus difficulty finding seronegative donors. Granulocyte units incompatible with patient ABO and Rh-D status underwent red blood cell reduction by the donor center with a final red blood cell content typically less than 2 mL. All products were irradiated (25 Gy) prior to transport to TCH. The product was transfused to the patient within 24 hours after collection, with efforts to transfuse as soon as possible after receipt. All patients received acetaminophen, diphenhydramine, and hydrocortisone 30 minutes prior to transfusion per our institutional policy. Granulocytes were transfused over a period of 2 to 4 hours. Vital signs were recorded every 15 minutes after initiation of transfusion, and hourly thereafter. The nurses evaluated patients throughout and after the transfusions for adverse reactions, and reported any adverse events to the physician and to the blood bank, per institutional policy. Granulocyte transfusions were given once daily if available but were occasionally divided into two transfusions within the same day if there was concern for volume overload. Each treating physician decided when to stop granulocyte therapy based on clinical improvement, suspected bone marrow recovery and/or adverse events. Frequency of transfusions was dictated by donor availability, with the goal of daily transfusions. Definitions and Outcomes The first outcome measured in this retrospective review was primary indication for the use of granulocyte transfusion. We also aimed to evaluate the clinical response and infection outcome in patients who received granulocytes for a primary indication of acute infection. Clinical response to acute infection was categorized as (1) complete if the patient had resolution of fever and physical exam findings in the 48-hour period after completion of granulocyte transfusions plus discontinuation of antimicrobials at any time post-granulocyte therapy, (2) partial if there was overall improvement in patient’s clinical status but did not meet criteria for complete clinical response, and (3) progression if there was worsening of the patient’s clinical status or death while on granulocyte therapy. In case of death, it was defined as infection-related death only if infection was recorded as the cause of death in the patient’s death summary. The second outcome measured was overall incidence of adverse reactions, which is defined by the National Healthcare Safety Network (NHSN) [5] as “an undesirable response or effect in a patient temporally associated with the administration of blood or blood component.” We based our definitions of adverse reactions including allergic reactions, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), on the NHSN Biovigilance component and hemovigilance module surveillance protocol (summarized in Table 1) [5].
TABLE 1 Definitions of Adverse Events Adverse reaction
Signs/symptoms
Allergic reaction
Edema, generalized flushing, hypotension, maculopapular rash, itching, respiratory distress, and/or urticaria, within 4 hours of transfusion. Hypoxemia, bilateral infiltrates on XR AND no evidence of circulatory overload. Acute respiratory distress, elevated BNP or CVP, evidence of left heart failure or positive fluid balance, and/or pulmonary edema on XR, within 6 hours of transfusion. Respiratory distress occurring within 24 hours of transfusion AND does not meet definition for allergic reaction, TRALI or TACO.
TRALI TACO
TAD
BNP, brain natriuretic peptide; CVP, central venous pressure; TACO, Transfusion-associated circulatory overload; TAD, Transfusion-associated dyspnea; TRALI, Transfusion-related acute lung injury; XR, X-ray. C Informa Healthcare USA, Inc. Copyright
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TABLE 2 Patient Characteristics Median (range) Age Weight Gender Ethnicity Duration of neutropenia prior to granulocytes Number of granulocyte transfusions Duration of granulocyte therapy Number of WBC per unit
9.5 years (1 to 20) 37.9 kg (11.7 to 79) 6 females/ 12 males 13 Hispanic, 4 Caucasian, 1 African American 16 days (9 to 76) 8.5 (2 to 39) 8 days (2 to 62) 6.7 × 1010
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Kg, kilograms; WBC, white blood cells.
Statistical Analysis Nonparametric tests were employed to analyze the data. Statistical analyses of all continuous variables were carried out using the Mann–Whitney test and all categorical variables were analyzed using Chi-square (χ 2 ) or Fisher’s exact tests. Analyses of variables associated with continuous outcomes were accomplished via Spearman’s correlation test. A P value < .05 was considered to be statistically significant in all the analyses. RESULTS From April 2009 to October 2012, a total of 18 pediatric patients received granulocyte transfusions during 20 separate episodes. Patient characteristics and underlying diagnoses are summarized in Tables 2 and 3, respectively. A total of 176 granulocyte units were transfused over the 40-month study period but unit splitting for concerns of fluid overload increased the total recorded number of transfusions to 265. The median time between split products was 9.2 hours (range 1.3 to 12.6 hours). Patients received an average of 1.8 × 109 WBC per kg of body mass, which resulted in a median ANC increment of 1265 cells/mm3 after receiving the first granulocyte transfusion (range 130 to 8720 cells/mm3 ). Age (P = .007) and weight (P = .005) were negatively associated with ANC increment after the first dose of granulocytes—older and larger children had less ANC increment after the first dose when compared to their counterparts (Table 4). However, other variables such as WBC dose/kg, duration of infection, or neutropenia prior to initiation of granulocyte therapy were not associated with ANC increment after the dose of granulocytes (Table 4). The median follow-up period was 257 days (range 7 to 1230 days). The overall mortality was 55% (n = 10). TABLE 3 Patient Diagnoses Patient Diagnosis Leukemia ALL AML Biphenotypic Granulocyte dysfunction HLH Lymphoma Total
Number of patients N (%) 11 (61) 4 (22) 6 (33) 1 (5) 3 (17) 3 (17) 1 (5) 18
N, total number of children who received granulocyte transfusions. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; HLH-hemophagocytic lymphohistiocytosis. Pediatric Hematology and Oncology
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TABLE 4 Patient Variables Associated with ANC Increment After First Dose of Granulocytes Variable Age (y) Weight(kg) WBC/kg Duration of infection (d) Duration of neutropenia (d)
ANC ≤ 1000 Median (range)
ANC>1000 Median (range)
15 (12–18) 64.4 (42.05–70.35) 1,213 (932–1,815) 13 (11–15.5) 15 (10–30)
4 (2–8) 17.5 (12–33.3) 3,023 (1,616–5,457) 8 (7–14) 19 (10–36)
P value .007 .005 .05 .29 .96
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ANC, absolute neutrophil count; D, days; Kg, kilograms; Y, years.
The first outcome measured in this retrospective review was primary indication for granulocyte transfusion. In our study, population indications for granulocyte therapy were comprised of acute life-threatening infection in 62% (n = 13) of patients, prophylaxis during HSCT in 29% (n = 5) of patients with history of chronic infections but no clinical signs or symptoms of infection, and other clinical conditions, namely typhilitis and appendectomy in the setting of prolonged neutropenia, in 9% (n = 2) of the patients. Then, we evaluated the clinical response and infection outcome in those patients who received granulocyte for a primary indication of acute infection (Table 5). Of the 13 patients who received granulocytes for acute infection, 12 patients (92%) had complete or partial clinical response, while only one patient (8%) had clinical progression of infection (disseminated Fusarium) with an ultimate infection-related death. However, this patient died 187 days after initiation of granulocyte therapy and required three separate HSCT prior to final successful engraftment. There was no association of ANC increment after the first dose of granulocyte with response in terms of infection or ultimate clinical outcome. However, patients who had an ANC increment >1000 cells/mm3 after first dose of granulocyte required fewer granulocyte transfusions than those with ANC increment ≤1000 cells/mm3 (5 vs. 15 granulocyte units, P = .01) in order to have partial or complete resolution of infection. The five patients who received granulocyte transfusions for primary indication of prophylaxis during the time of HSCT had index chronic infections that included: (1) lung infection with atypical Mycobacteria, Aspergillus, and Basidiomycetes species; (2) sinusitis with Fusarium and Aspergillus; and (3) disseminated Mycobacterium and Histoplasma species. Only one patient (20%) had progression of chronic infection with Histoplasma and developed multiorgan failure. This patient had been neutropenic for over 30 days prior to HSCT and developed concurrent infections with Enterococcus, Klebsiella, and Streptococcus species during the course of granulocyte therapy. Finally, of the two patients who received granulocytes for other clinical conditions not clearly infectious in etiology, one patient recovered fully after appendectomy but the patient with typhilitis died of respiratory failure due to concurrent infection with parainfluenza type 3. The second outcome we measured was overall incidence of adverse events. In the group of 13 patients with underlying acute infection, six patients (46%) developed respiratory symptoms including hypoxemia and tachypnea that were likely secondary to granulocyte transfusions (Table 6). Patients did not have testing to detect anti-HLA antibodies against the donor. Granulocyte transfusions were discontinued in only two of these patients due to risks outweighing potential benefits: one patient experienced a relapse of leukemia and thus changed to hospice care; and one patient had a lung biopsy that proved fungal infection was sensitive to voriconazole. Other adverse reactions in the group of 13 patients with acute infection included nonhemolytic febrile reaction in five and itching in one patient. None of the patients in this study developed TRALI or died due to an adverse reaction to granulocyte transfusions. Patients who C Informa Healthcare USA, Inc. Copyright
5/F 9/M 3/M 8/M 12/M 10/F 3/M 2/M 15/M 15/M 3/M 6/F 20/M
Age (y)
AML AML AML CGD ALL ALL Relapsed AML Relapsed AML Relapsed AML Relapsed Hodgkin Relapsed ALL Relapsed ALL AML
Diagnosis B B B F F F B F F B B B B
Type No No Yes Yes No Yes Yes Yes No No No Yes Yes
Localized?
Characteristics of Acute Infections and Clinical Response
Perirectal abscess Bacteremia Brain abscess Bacteremia Perirectal abscess Lung Disseminated Sinus Perirectal abscess Lung Disseminated Osteomyelitis Bacteremia Fasciitis Bacteremia Perirectal abscess Perirectal abscess
Location
Aspergillus Fusarium E. coli P. aeruginosa E. cloacae
Aspergillus Candida, Aspergillus, Alternaria Aspergillus
E. faecalis, P. aeruginosa B. cereus
Organism
AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; B, bacterial; CGD, chronic granulomatous disease; F, fungal; Y, years.
1 2 3 4 5 6 7 8 9 10 11 12 13
TABLE 5
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Complete Complete Complete Partial Complete Complete Complete Complete Progression Complete Complete Complete Complete
Response
15/M
6/F
5/F 20/M
3
4
5 6
TAD TACO
TAD
TACO
Allergic reaction TACO
Adverse event
Hypoxemia, tachypnea Hypoxemia, dyspnea
Hypoxemia, tachypnea
Hypoxemia, dyspnea
Wheezing, cough Hypoxemia, dyspnea, positive fluid balance
Signs/Symptoms
Normal Pulmonary edema
Normal
Diffuse interstitial lung disease
No change∗ Normal
Chest XR
Supportive Supportive
Supportive∗∗ Transferred to PICU for aggressive diuresis and supplemental oxygen via mask. Transferred to PICU for aggressive diuresis and supplemental oxygen via mask. Supportive
Treatment
Yes, in the setting of relapsed leukemia and change to hospice care. No No
Yes∗∗∗ No. Held for 4 days and resumed without further problems. No
Transfusions discontinued?
PICU, Pediatric intensive care unit; TACO, Transfusion-associated circulatory overload; TAD, Transfusion-associated dyspnea; TRALI, Transfusion-related acute lung injury; XR, X-ray. ∗ Patient with underlying pulmonary fungal infection and baseline abnormal chest XR showing confluent air space disease at the left lung base. ∗∗ Supportive care included antipyretics if patient febrile, supplemental oxygen via nasal cannula or mask, inhaled β-2 agonist, and/or diuretic as needed. ∗∗∗ Transfusions stopped as biopsy showed fungus sensitive to antifungals.
10/F 9/M
1 2
Age/Gender
TABLE 6 Adverse Respiratory Events due to Granulocyte Transfusions
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received granulocytes for prophylaxis or other clinical conditions did not experience any adverse events.
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DISCUSSION The precise role of granulocyte transfusions in the modern era awaits definition by well-designed randomized clinical trials as previous attempts have yielded inconclusive results and been plagued with difficulty with recruiting patients. Traditionally, granulocytes have been administered to children with acute infections, such as bacterial sepsis and/or invasive fungal disease, failing to improve despite antimicrobials. More recently, few studies have suggested a potential role in preventing infections or the progression of infections in patients expected to have prolonged neutropenia due to HSCT or chemotherapy. We sought to retrospectively review our experience with the use of granulocyte transfusion and evaluate outcomes. As one of the largest pediatric hospitals in the United States, we take care of a substantial number of children with neutropenia or granulocyte dysfunction and report here the largest study to evaluate systematically the infection outcomes in terms of clinical response of children who received granulocyte transfusions. In our center, granulocytes were most commonly transfused in the setting of acute infection (n = 13, 62%). We observed clinical benefit in 92% of children who received granulocytes for acute infection. Among these 13 patients, the infection-related mortality was 15% (n = 2) and overall survival was 42% (n = 5). Our results support accumulating evidence that granulocyte transfusions help combat acute infections in neutropenic children refractory to adequate antimicrobials. In four previous retrospective studies of pediatric patients treated with granulocyte transfusions, there was reported resolution of the index infection in 60% to 92% of the treated patients [6–10]. Taken together, these results suggest the clear potential benefit of using granulocyte transfusions to treat children with infection and neutropenia or granulocyte dysfunction. Due to the retrospective design of our study, we cannot yet make any conclusions regarding whether the use of granulocyte transfusions is superior to the use of antimicrobials alone as we do not have a comparison group to hold against our study population. At the present time, it remains speculative whether the lack of progression and eventual clearance of infection observed in our group of patients is sufficient evidence to support clinical practice of routinely adding granulocyte transfusions as a supportive measure in this very ill group of patients. It has been suggested that the efficacy of granulocyte therapy is proportional to transfused granulocyte dose [10]. In our study, granulocyte dose was not associated with clinical response or infection outcome. This may be in part due to the small number of patients in the study, overall very good infection outcomes and very large doses of granulocyte transfused. We did find that older children and those with higher weight experienced less change in their neutrophil count following treatment when compared to younger children and those with lower weight. This did not seem to be associated with clinical response or infection outcome in our patients. In addition, we found that patients with ANC changes >1000 cells/mm3 after the first dose of granulocytes required fewer granulocyte transfusions (5 vs. 15 granulocyte units, P = .01) in order to have partial or complete resolution of infection. This is an important clinically relevant finding for physicians planning granulocyte therapy for a patient as it would allow them to plan length of therapy and recruitment of donors. Using a recently defined parameter of ANC > 700 cells/mm3 after at least 50% of received granulocyte transfusions as a marker of a sustained hematologic response [11], we found that all 13 patients in our study with acute infection had a sustained Pediatric Hematology and Oncology
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Granulocyte Transfusions in Children
hematological response. This may explain the very good clinical response and infection outcome documented by our study. It is difficult to reliably determine whether sustained hematologic response reflects a “favorable” subgroup of patients whose granulocyte consumption is slow as they have less severe infection, or really corroborates the clinical efficacy of granulocyte transfusions. Given the severe nature of the underlying infection and diagnoses of our patients, and worsening clinical status despite appropriate antimicrobials, we believe that this finding attests to the beneficial role of transfusing large doses of granulocytes capable of producing sustained hematologic response. Previous studies of granulocyte recipients have documented acute pulmonary transfusion reaction and shortness of breath, dyspnea, hypoxemia, and lung edema [12–15]. Thus, concern for serious pulmonary complications is a major limiting factor in the routine use of granulocyte transfusions. A substantial portion (46%) of the 13 patients who received granulocytes in the setting of acute infection developed respiratory symptoms. Although there is a real risk of respiratory symptoms developing during granulocyte therapy, all the patients in our study recovered with full resolution of respiratory symptoms. The retrospective nature of this study made cause and effect very challenging with respect to adverse events. In a very ill patient whose main medical problem at the time of granulocyte transfusions was overwhelming infection, was the “adverse event” caused by granulocyte transfusion or was it part of the ongoing infection? Whether transfusion of granulocytes is safe remains to be answered. However, our study suggests that respiratory adverse events can be managed successfully with diuresis and oxygen supplementation, and that the high incidence of adverse events may be at least in part due to underlying acute infection as none of the patients who received granulocytes as prophylaxis during HSCT or for other clinical scenarios experience respiratory symptoms. In summary, we found that administration of granulocyte transfusion in conjunction with antimicrobials was associated with partial or complete eradication of lifethreatening infections. However, we were not able to draw conclusions about the safety of this intervention. Both these observations have considerable clinical implications, since life-threatening infections in the setting of prolonged neutropenia or granulocyte dysfunction are commonplace despite the advent of newer antimicrobials. Despite the risks and high cost of granulocyte treatment, the use of granulocyte transfusions is reasonable in the present practice. A prospective randomized trial, such as the phase III prospective, randomized clinical trial, “High Dose Granulocyte Transfusions for the Treatment of Infection in Neutropenia: The RING Study (Resolving Infection in Neutropenia with Granulocytes)” (NCT00627393) will likely provide a better estimation of the positive benefit to risk ratio associated with the transfusion of large doses of granulocytes and help address concerns regarding the safety of this intervention. Nevertheless, such studies are challenging as it may not be possible to withhold a possibly life-saving measure to a child in a life-threatening situation. Until this information is available, we must rely on the present data available which collectively, at least in pediatric patients, seems to support beneficial infectious outcomes with tolerable safety profile. Our recommendation is that the use of granulocyte transfusions as adjunct to antimicrobials should be carefully considered in the setting of neutropenia and infection until we obtain results from what may be the definitive trial currently under way. Declaration of Interest Dr. Jun Teruya declared the following potential conflicts of interest: ECMO Advisory Board, GTC Biotherapeutics, received honorarium from Japan, Boehringer, Ingelheim C Informa Healthcare USA, Inc. Copyright
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GmbH, and Haemonetics. Dr. Diaz, Dr. Soundar, Dr. Hartman, Dr. Dreyer, and Dr. Hui declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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REFERENCES [1] Gerson SL, Talbot GH, Hurwitz S, et al. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med. 1984;100:345–351. [2] Massey E, Paulus U, Doree C, Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2009:CD005341. DOI:10.1002/14651858.CD005341.pub2. [3] Seidel MG, Minkov M, Witt V, et al. Granulocyte transfusions in children and young adults: does the dose matter? J Pediatr Hematol Oncol. 2009;31:166–172. [4] Seidel MG, Peters C, Wacker A, et al. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant. 2008;42:679–684. [5] Centers for Disease Control and Prevention. National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol. 2013. http://www.cdc.gov/nhsn/PDFs/ Biovigilance/BV-HV-protocol-current.pdf. Accessed October 2013. [6] Ozturkmen S, Altuntas F, Olcay L. Granulocyte transfusion therapy in paediatric patients with severe neutropenic infection. Transfus Apher Sci. 2013;48:381–385. [7] Graham AS, Price TH, Brogan TV. Revisiting the use of granulocyte transfusions in pediatric oncology patients. J Pediatr Hematol Oncol. 2009; 31:161–165. [8] Pham HP, Rogoza K, Stotler B, et al. Granulocyte transfusion therapy in pediatric patients after hematopoietic stem cell transplantation: a 5-year single tertiary care center experience. J Pediatr Hematol Oncol. 2010;34:e332–e336. [9] Atay D, Ozturk G, Akcay A, et al. Effect and safety of granulocyte transfusions in pediatric patients with febrile neutropenia or defective granulocyte functions. J Pediatr Hematol Oncol. 2011;33:e220–e225. [10] Stanworth SJ, Massey E, Hyde C, et al. Granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2005:CD005339. DOI:10.1002/14651858.CD005339. [11] Ofran Y, Avivi I, Oliven A, et al. Granulocyte transfusions for neutropenic patients with lifethreatening infections: a single centre experience in 47 patients, who received 348 granulocyte transfusions. Vox Sang. 2007;93:363–369. [12] Strauss RG. Role of granulocyte/neutrophil transfusions for haematology/oncology patients in the modern era. Br J Haematol. 2012;158(3):299–306. [13] Cesaro S, Chinello P, De Silvestro G, et al. Granulocyte transfusions from G-CSF-stimulated donors for the treatment of severe infections in neutropenic pediatric patients with onco-hematological diseases. Support Care Cancer. 2003;11:101–106. [14] Lee JJ, Chung IJ, Park MR, et al. Clinical efficacy of granulocyte transfusion therapy in patients with neutropenia-related infections. Leukemia. 2001;15:203–207. [15] Peters C, Minkov M, Matthes-Martin S, et al. Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol. 1999;106:689–696.
Pediatric Hematology and Oncology
ORIGINAL ARTICLE Supportive Care
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Granulocyte Transfusions for Children with Infection and Neutropenia or Granulocyte Dysfunction Rosa D´ıaz, MD,1 Esther Soundar, MD, MPH,2 S. Kate Hartman, MD,2 ZoAnn Dreyer, MD,1 Jun Teruya, MD, DSc,2,3 and Shiu-Ki Rocky Hui, MD2 1
Department of Pediatrics, Texas Children’s Hospital, Houston, TX, USA; 2 Department of Pathology, Baylor College of Medicine, Houston, TX, USA; 3 Department of Pediatrics and Medicine, Baylor College of Medicine, Houston, TX, USA
Transfusions of granulocytes can be used as an adjunct therapy to antimicrobials in patients with infection and neutropenia or granulocyte dysfunction. However, there is a lack of strong clinical evidence to support the use of this treatment strategy, particularly in children. We retrospectively reviewed the medical records of children who received granulocytes at our institution from April 2009 to October 2012, with emphasis on primary indication for the transfusion and clinical outcome in terms of infection. The patients had granulocyte dysfunction or severe neutropenia, defined as absolute neutrophil count (ANC) < 500 cells/mm3 due to chemotherapy or hematopoietic stem cell transplant (HSCT), and reasonable hope for bone marrow recovery or engraftment. Eighteen children received granulocytes during 20 distinct episodes: 62% (n = 13) for acute infection, 29% (n = 5) for unresolved chronic infection during the time of HSCT, and 9% (n = 2) for other clinical conditions such as typhilitis and appendectomy. Overall, 92% (n = 12) of the episodes of acute infection had complete or partial resolution, as determined by review of vital signs, physical exam findings and discontinuation of antimicrobials. A substantial number (46%) of children who received granulocytes for acute infection developed respiratory adverse events, but all of these recovered. We conclude that granulocyte transfusions continue to be primarily used in neutropenic patients with acute infections, and that its use in this group of patients is reasonable. However, a prospective randomized clinical trial is needed to evaluate safety and whether the use of granulocytes is superior to antimicrobial-only therapy. Keywords bone marrow transplant, infections, neutropenia, supportive care, transfusion medicine
INTRODUCTION Despite the widespread use of broad spectrum antimicrobials, infections represent a major cause of morbidity and mortality in patients with granulocyte dysfunction or neutropenia secondary to chemotherapy or HSCT. Various studies have reported that the strongest predictor of recovery from infection is an adequate number of blood and tissue neutrophils, and recovery of neutrophil production by the patient’s bone marrow [1]. Therefore, any method that provides functional neutrophils to patients with infection during the neutropenic period should aid in infection clearance and reduce the number of infection-related deaths. This finding led to the use of granulocyte Received 31 October 2013; accepted 19 November 2013. Address correspondence to Rosa D´ıaz, MD, Department of Pediatrics, Pediatric Hematology Oncology Instructor, 1102 Bates Ave, Suite 1025, Houston, TX 77030, USA. Email: [email protected]
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transfusions collected from healthy donors as a way to bridge the gap between neutropenia and marrow recovery in patients undergoing chemotherapy and/or HSCT. Despite being used over the past 40 years, the clinical indications for granulocyte transfusion, its effectiveness, and safety profile remain largely unknown, particularly in children. This therapeutic modality has been discussed in a few case reports and cohort studies that suggest potential benefits with no clear estimation of a positive benefit to risk ratio in various clinical scenarios, including acute bacterial or fungal infection, and prophylaxis in neutropenic patients undergoing HSCT [2–4]. In pediatric patients, the only prospective study to date included 59 children and young adults that received 778 doses of granulocyte transfusion. That study used survival for 28 days after the initiation of granulocyte transfusion treatment as a surrogate marker for effective therapy and showed a survival probability of 0.72 for the cohort [3]. However, we believe that the conventional use of survival to define efficacy may present a disadvantage by: (1) assuming therapeutic failure of granulocytes when patients don’t survive; and (2) not focusing on the intent of granulocyte transfusion to help fight infection. In the present study, we describe our experience with usage of granulocyte transfusions at a tertiary center. We identified 18 children with neutropenia or granulocyte dysfunction who received 20 distinct courses of granulocytes. Here, we report the primary indications for granulocyte transfusion, the clinical response and outcomes in term of infection, and the safety profile of this intervention. To our knowledge, this is the largest study to systematically assess infection outcomes as a way to determine the potential benefits that can be attained with granulocyte transfusions. METHODS Study Design and Patient Selection This is a retrospective review of all children with neutropenia or granulocyte dysfunction who received granulocyte transfusions at Texas Children’s Hospital (TCH) from April 2009 to October 2012. The decision and timing of granulocyte transfusions was determined by the patient’s physician in conjunction with the transfusion medicine and blood bank service and availability of eligible directed volunteer donors. All patients had: (1) granulocyte dysfunction or severe neutropenia, defined as an ANC < 500 cells/mm3 , secondary to chemotherapy or HSCT; and (2) reasonable hope for bone marrow recovery or engraftment. The study was approved by our institutional review board, and consent was waived for all patients due to the retrospective design of the study. Data were collected from medical records, the blood bank database and the granulocyte supplier in order to assess patient demographics, indication for transfusion and granulocyte content of the product, laboratory data, clinical course, and outcome. Granulocyte Collection and Transfusions Granulocyte units were collected, processed, and tested by the Blood Bank at The University of Texas M.D. Anderson Cancer Center. Because there is no local altruistic granulocyte donor program, the patient’s family was responsible for recruiting directed volunteer donors, typically family members and friends from their local social network. The donors presented to the donor center for screening, which included a complete blood count (CBC), a pregnancy test for every woman less than 56 years without hysterectomy, and West Nile virus testing, among others. Approved donors were stimulated 12 hours prior to the collection with 8 mg of oral dexamethasone and 600 mcg of subcutaneous granulocyte-colony stimulating factor (G-CSF). Granulocytes were collected via apheresis over a period of 2.5 to 3.5 hours. A granulocyte count was done on the final product to insure that an adequate dose of at ≥ 1 × 1010 granulocytes was collected. Testing for cytomegalovirus (CMV) was not performed routinely Pediatric Hematology and Oncology
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due to the high regional CMV seropositivity and thus difficulty finding seronegative donors. Granulocyte units incompatible with patient ABO and Rh-D status underwent red blood cell reduction by the donor center with a final red blood cell content typically less than 2 mL. All products were irradiated (25 Gy) prior to transport to TCH. The product was transfused to the patient within 24 hours after collection, with efforts to transfuse as soon as possible after receipt. All patients received acetaminophen, diphenhydramine, and hydrocortisone 30 minutes prior to transfusion per our institutional policy. Granulocytes were transfused over a period of 2 to 4 hours. Vital signs were recorded every 15 minutes after initiation of transfusion, and hourly thereafter. The nurses evaluated patients throughout and after the transfusions for adverse reactions, and reported any adverse events to the physician and to the blood bank, per institutional policy. Granulocyte transfusions were given once daily if available but were occasionally divided into two transfusions within the same day if there was concern for volume overload. Each treating physician decided when to stop granulocyte therapy based on clinical improvement, suspected bone marrow recovery and/or adverse events. Frequency of transfusions was dictated by donor availability, with the goal of daily transfusions. Definitions and Outcomes The first outcome measured in this retrospective review was primary indication for the use of granulocyte transfusion. We also aimed to evaluate the clinical response and infection outcome in patients who received granulocytes for a primary indication of acute infection. Clinical response to acute infection was categorized as (1) complete if the patient had resolution of fever and physical exam findings in the 48-hour period after completion of granulocyte transfusions plus discontinuation of antimicrobials at any time post-granulocyte therapy, (2) partial if there was overall improvement in patient’s clinical status but did not meet criteria for complete clinical response, and (3) progression if there was worsening of the patient’s clinical status or death while on granulocyte therapy. In case of death, it was defined as infection-related death only if infection was recorded as the cause of death in the patient’s death summary. The second outcome measured was overall incidence of adverse reactions, which is defined by the National Healthcare Safety Network (NHSN) [5] as “an undesirable response or effect in a patient temporally associated with the administration of blood or blood component.” We based our definitions of adverse reactions including allergic reactions, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), on the NHSN Biovigilance component and hemovigilance module surveillance protocol (summarized in Table 1) [5].
TABLE 1 Definitions of Adverse Events Adverse reaction
Signs/symptoms
Allergic reaction
Edema, generalized flushing, hypotension, maculopapular rash, itching, respiratory distress, and/or urticaria, within 4 hours of transfusion. Hypoxemia, bilateral infiltrates on XR AND no evidence of circulatory overload. Acute respiratory distress, elevated BNP or CVP, evidence of left heart failure or positive fluid balance, and/or pulmonary edema on XR, within 6 hours of transfusion. Respiratory distress occurring within 24 hours of transfusion AND does not meet definition for allergic reaction, TRALI or TACO.
TRALI TACO
TAD
BNP, brain natriuretic peptide; CVP, central venous pressure; TACO, Transfusion-associated circulatory overload; TAD, Transfusion-associated dyspnea; TRALI, Transfusion-related acute lung injury; XR, X-ray. C Informa Healthcare USA, Inc. Copyright
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TABLE 2 Patient Characteristics Median (range) Age Weight Gender Ethnicity Duration of neutropenia prior to granulocytes Number of granulocyte transfusions Duration of granulocyte therapy Number of WBC per unit
9.5 years (1 to 20) 37.9 kg (11.7 to 79) 6 females/ 12 males 13 Hispanic, 4 Caucasian, 1 African American 16 days (9 to 76) 8.5 (2 to 39) 8 days (2 to 62) 6.7 × 1010
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Kg, kilograms; WBC, white blood cells.
Statistical Analysis Nonparametric tests were employed to analyze the data. Statistical analyses of all continuous variables were carried out using the Mann–Whitney test and all categorical variables were analyzed using Chi-square (χ 2 ) or Fisher’s exact tests. Analyses of variables associated with continuous outcomes were accomplished via Spearman’s correlation test. A P value < .05 was considered to be statistically significant in all the analyses. RESULTS From April 2009 to October 2012, a total of 18 pediatric patients received granulocyte transfusions during 20 separate episodes. Patient characteristics and underlying diagnoses are summarized in Tables 2 and 3, respectively. A total of 176 granulocyte units were transfused over the 40-month study period but unit splitting for concerns of fluid overload increased the total recorded number of transfusions to 265. The median time between split products was 9.2 hours (range 1.3 to 12.6 hours). Patients received an average of 1.8 × 109 WBC per kg of body mass, which resulted in a median ANC increment of 1265 cells/mm3 after receiving the first granulocyte transfusion (range 130 to 8720 cells/mm3 ). Age (P = .007) and weight (P = .005) were negatively associated with ANC increment after the first dose of granulocytes—older and larger children had less ANC increment after the first dose when compared to their counterparts (Table 4). However, other variables such as WBC dose/kg, duration of infection, or neutropenia prior to initiation of granulocyte therapy were not associated with ANC increment after the dose of granulocytes (Table 4). The median follow-up period was 257 days (range 7 to 1230 days). The overall mortality was 55% (n = 10). TABLE 3 Patient Diagnoses Patient Diagnosis Leukemia ALL AML Biphenotypic Granulocyte dysfunction HLH Lymphoma Total
Number of patients N (%) 11 (61) 4 (22) 6 (33) 1 (5) 3 (17) 3 (17) 1 (5) 18
N, total number of children who received granulocyte transfusions. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; HLH-hemophagocytic lymphohistiocytosis. Pediatric Hematology and Oncology
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TABLE 4 Patient Variables Associated with ANC Increment After First Dose of Granulocytes Variable Age (y) Weight(kg) WBC/kg Duration of infection (d) Duration of neutropenia (d)
ANC ≤ 1000 Median (range)
ANC>1000 Median (range)
15 (12–18) 64.4 (42.05–70.35) 1,213 (932–1,815) 13 (11–15.5) 15 (10–30)
4 (2–8) 17.5 (12–33.3) 3,023 (1,616–5,457) 8 (7–14) 19 (10–36)
P value .007 .005 .05 .29 .96
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ANC, absolute neutrophil count; D, days; Kg, kilograms; Y, years.
The first outcome measured in this retrospective review was primary indication for granulocyte transfusion. In our study, population indications for granulocyte therapy were comprised of acute life-threatening infection in 62% (n = 13) of patients, prophylaxis during HSCT in 29% (n = 5) of patients with history of chronic infections but no clinical signs or symptoms of infection, and other clinical conditions, namely typhilitis and appendectomy in the setting of prolonged neutropenia, in 9% (n = 2) of the patients. Then, we evaluated the clinical response and infection outcome in those patients who received granulocyte for a primary indication of acute infection (Table 5). Of the 13 patients who received granulocytes for acute infection, 12 patients (92%) had complete or partial clinical response, while only one patient (8%) had clinical progression of infection (disseminated Fusarium) with an ultimate infection-related death. However, this patient died 187 days after initiation of granulocyte therapy and required three separate HSCT prior to final successful engraftment. There was no association of ANC increment after the first dose of granulocyte with response in terms of infection or ultimate clinical outcome. However, patients who had an ANC increment >1000 cells/mm3 after first dose of granulocyte required fewer granulocyte transfusions than those with ANC increment ≤1000 cells/mm3 (5 vs. 15 granulocyte units, P = .01) in order to have partial or complete resolution of infection. The five patients who received granulocyte transfusions for primary indication of prophylaxis during the time of HSCT had index chronic infections that included: (1) lung infection with atypical Mycobacteria, Aspergillus, and Basidiomycetes species; (2) sinusitis with Fusarium and Aspergillus; and (3) disseminated Mycobacterium and Histoplasma species. Only one patient (20%) had progression of chronic infection with Histoplasma and developed multiorgan failure. This patient had been neutropenic for over 30 days prior to HSCT and developed concurrent infections with Enterococcus, Klebsiella, and Streptococcus species during the course of granulocyte therapy. Finally, of the two patients who received granulocytes for other clinical conditions not clearly infectious in etiology, one patient recovered fully after appendectomy but the patient with typhilitis died of respiratory failure due to concurrent infection with parainfluenza type 3. The second outcome we measured was overall incidence of adverse events. In the group of 13 patients with underlying acute infection, six patients (46%) developed respiratory symptoms including hypoxemia and tachypnea that were likely secondary to granulocyte transfusions (Table 6). Patients did not have testing to detect anti-HLA antibodies against the donor. Granulocyte transfusions were discontinued in only two of these patients due to risks outweighing potential benefits: one patient experienced a relapse of leukemia and thus changed to hospice care; and one patient had a lung biopsy that proved fungal infection was sensitive to voriconazole. Other adverse reactions in the group of 13 patients with acute infection included nonhemolytic febrile reaction in five and itching in one patient. None of the patients in this study developed TRALI or died due to an adverse reaction to granulocyte transfusions. Patients who C Informa Healthcare USA, Inc. Copyright
5/F 9/M 3/M 8/M 12/M 10/F 3/M 2/M 15/M 15/M 3/M 6/F 20/M
Age (y)
AML AML AML CGD ALL ALL Relapsed AML Relapsed AML Relapsed AML Relapsed Hodgkin Relapsed ALL Relapsed ALL AML
Diagnosis B B B F F F B F F B B B B
Type No No Yes Yes No Yes Yes Yes No No No Yes Yes
Localized?
Characteristics of Acute Infections and Clinical Response
Perirectal abscess Bacteremia Brain abscess Bacteremia Perirectal abscess Lung Disseminated Sinus Perirectal abscess Lung Disseminated Osteomyelitis Bacteremia Fasciitis Bacteremia Perirectal abscess Perirectal abscess
Location
Aspergillus Fusarium E. coli P. aeruginosa E. cloacae
Aspergillus Candida, Aspergillus, Alternaria Aspergillus
E. faecalis, P. aeruginosa B. cereus
Organism
AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; B, bacterial; CGD, chronic granulomatous disease; F, fungal; Y, years.
1 2 3 4 5 6 7 8 9 10 11 12 13
TABLE 5
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Complete Complete Complete Partial Complete Complete Complete Complete Progression Complete Complete Complete Complete
Response
15/M
6/F
5/F 20/M
3
4
5 6
TAD TACO
TAD
TACO
Allergic reaction TACO
Adverse event
Hypoxemia, tachypnea Hypoxemia, dyspnea
Hypoxemia, tachypnea
Hypoxemia, dyspnea
Wheezing, cough Hypoxemia, dyspnea, positive fluid balance
Signs/Symptoms
Normal Pulmonary edema
Normal
Diffuse interstitial lung disease
No change∗ Normal
Chest XR
Supportive Supportive
Supportive∗∗ Transferred to PICU for aggressive diuresis and supplemental oxygen via mask. Transferred to PICU for aggressive diuresis and supplemental oxygen via mask. Supportive
Treatment
Yes, in the setting of relapsed leukemia and change to hospice care. No No
Yes∗∗∗ No. Held for 4 days and resumed without further problems. No
Transfusions discontinued?
PICU, Pediatric intensive care unit; TACO, Transfusion-associated circulatory overload; TAD, Transfusion-associated dyspnea; TRALI, Transfusion-related acute lung injury; XR, X-ray. ∗ Patient with underlying pulmonary fungal infection and baseline abnormal chest XR showing confluent air space disease at the left lung base. ∗∗ Supportive care included antipyretics if patient febrile, supplemental oxygen via nasal cannula or mask, inhaled β-2 agonist, and/or diuretic as needed. ∗∗∗ Transfusions stopped as biopsy showed fungus sensitive to antifungals.
10/F 9/M
1 2
Age/Gender
TABLE 6 Adverse Respiratory Events due to Granulocyte Transfusions
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received granulocytes for prophylaxis or other clinical conditions did not experience any adverse events.
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DISCUSSION The precise role of granulocyte transfusions in the modern era awaits definition by well-designed randomized clinical trials as previous attempts have yielded inconclusive results and been plagued with difficulty with recruiting patients. Traditionally, granulocytes have been administered to children with acute infections, such as bacterial sepsis and/or invasive fungal disease, failing to improve despite antimicrobials. More recently, few studies have suggested a potential role in preventing infections or the progression of infections in patients expected to have prolonged neutropenia due to HSCT or chemotherapy. We sought to retrospectively review our experience with the use of granulocyte transfusion and evaluate outcomes. As one of the largest pediatric hospitals in the United States, we take care of a substantial number of children with neutropenia or granulocyte dysfunction and report here the largest study to evaluate systematically the infection outcomes in terms of clinical response of children who received granulocyte transfusions. In our center, granulocytes were most commonly transfused in the setting of acute infection (n = 13, 62%). We observed clinical benefit in 92% of children who received granulocytes for acute infection. Among these 13 patients, the infection-related mortality was 15% (n = 2) and overall survival was 42% (n = 5). Our results support accumulating evidence that granulocyte transfusions help combat acute infections in neutropenic children refractory to adequate antimicrobials. In four previous retrospective studies of pediatric patients treated with granulocyte transfusions, there was reported resolution of the index infection in 60% to 92% of the treated patients [6–10]. Taken together, these results suggest the clear potential benefit of using granulocyte transfusions to treat children with infection and neutropenia or granulocyte dysfunction. Due to the retrospective design of our study, we cannot yet make any conclusions regarding whether the use of granulocyte transfusions is superior to the use of antimicrobials alone as we do not have a comparison group to hold against our study population. At the present time, it remains speculative whether the lack of progression and eventual clearance of infection observed in our group of patients is sufficient evidence to support clinical practice of routinely adding granulocyte transfusions as a supportive measure in this very ill group of patients. It has been suggested that the efficacy of granulocyte therapy is proportional to transfused granulocyte dose [10]. In our study, granulocyte dose was not associated with clinical response or infection outcome. This may be in part due to the small number of patients in the study, overall very good infection outcomes and very large doses of granulocyte transfused. We did find that older children and those with higher weight experienced less change in their neutrophil count following treatment when compared to younger children and those with lower weight. This did not seem to be associated with clinical response or infection outcome in our patients. In addition, we found that patients with ANC changes >1000 cells/mm3 after the first dose of granulocytes required fewer granulocyte transfusions (5 vs. 15 granulocyte units, P = .01) in order to have partial or complete resolution of infection. This is an important clinically relevant finding for physicians planning granulocyte therapy for a patient as it would allow them to plan length of therapy and recruitment of donors. Using a recently defined parameter of ANC > 700 cells/mm3 after at least 50% of received granulocyte transfusions as a marker of a sustained hematologic response [11], we found that all 13 patients in our study with acute infection had a sustained Pediatric Hematology and Oncology
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hematological response. This may explain the very good clinical response and infection outcome documented by our study. It is difficult to reliably determine whether sustained hematologic response reflects a “favorable” subgroup of patients whose granulocyte consumption is slow as they have less severe infection, or really corroborates the clinical efficacy of granulocyte transfusions. Given the severe nature of the underlying infection and diagnoses of our patients, and worsening clinical status despite appropriate antimicrobials, we believe that this finding attests to the beneficial role of transfusing large doses of granulocytes capable of producing sustained hematologic response. Previous studies of granulocyte recipients have documented acute pulmonary transfusion reaction and shortness of breath, dyspnea, hypoxemia, and lung edema [12–15]. Thus, concern for serious pulmonary complications is a major limiting factor in the routine use of granulocyte transfusions. A substantial portion (46%) of the 13 patients who received granulocytes in the setting of acute infection developed respiratory symptoms. Although there is a real risk of respiratory symptoms developing during granulocyte therapy, all the patients in our study recovered with full resolution of respiratory symptoms. The retrospective nature of this study made cause and effect very challenging with respect to adverse events. In a very ill patient whose main medical problem at the time of granulocyte transfusions was overwhelming infection, was the “adverse event” caused by granulocyte transfusion or was it part of the ongoing infection? Whether transfusion of granulocytes is safe remains to be answered. However, our study suggests that respiratory adverse events can be managed successfully with diuresis and oxygen supplementation, and that the high incidence of adverse events may be at least in part due to underlying acute infection as none of the patients who received granulocytes as prophylaxis during HSCT or for other clinical scenarios experience respiratory symptoms. In summary, we found that administration of granulocyte transfusion in conjunction with antimicrobials was associated with partial or complete eradication of lifethreatening infections. However, we were not able to draw conclusions about the safety of this intervention. Both these observations have considerable clinical implications, since life-threatening infections in the setting of prolonged neutropenia or granulocyte dysfunction are commonplace despite the advent of newer antimicrobials. Despite the risks and high cost of granulocyte treatment, the use of granulocyte transfusions is reasonable in the present practice. A prospective randomized trial, such as the phase III prospective, randomized clinical trial, “High Dose Granulocyte Transfusions for the Treatment of Infection in Neutropenia: The RING Study (Resolving Infection in Neutropenia with Granulocytes)” (NCT00627393) will likely provide a better estimation of the positive benefit to risk ratio associated with the transfusion of large doses of granulocytes and help address concerns regarding the safety of this intervention. Nevertheless, such studies are challenging as it may not be possible to withhold a possibly life-saving measure to a child in a life-threatening situation. Until this information is available, we must rely on the present data available which collectively, at least in pediatric patients, seems to support beneficial infectious outcomes with tolerable safety profile. Our recommendation is that the use of granulocyte transfusions as adjunct to antimicrobials should be carefully considered in the setting of neutropenia and infection until we obtain results from what may be the definitive trial currently under way. Declaration of Interest Dr. Jun Teruya declared the following potential conflicts of interest: ECMO Advisory Board, GTC Biotherapeutics, received honorarium from Japan, Boehringer, Ingelheim C Informa Healthcare USA, Inc. Copyright
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GmbH, and Haemonetics. Dr. Diaz, Dr. Soundar, Dr. Hartman, Dr. Dreyer, and Dr. Hui declare no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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REFERENCES [1] Gerson SL, Talbot GH, Hurwitz S, et al. Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med. 1984;100:345–351. [2] Massey E, Paulus U, Doree C, Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2009:CD005341. DOI:10.1002/14651858.CD005341.pub2. [3] Seidel MG, Minkov M, Witt V, et al. Granulocyte transfusions in children and young adults: does the dose matter? J Pediatr Hematol Oncol. 2009;31:166–172. [4] Seidel MG, Peters C, Wacker A, et al. Randomized phase III study of granulocyte transfusions in neutropenic patients. Bone Marrow Transplant. 2008;42:679–684. [5] Centers for Disease Control and Prevention. National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol. 2013. http://www.cdc.gov/nhsn/PDFs/ Biovigilance/BV-HV-protocol-current.pdf. Accessed October 2013. [6] Ozturkmen S, Altuntas F, Olcay L. Granulocyte transfusion therapy in paediatric patients with severe neutropenic infection. Transfus Apher Sci. 2013;48:381–385. [7] Graham AS, Price TH, Brogan TV. Revisiting the use of granulocyte transfusions in pediatric oncology patients. J Pediatr Hematol Oncol. 2009; 31:161–165. [8] Pham HP, Rogoza K, Stotler B, et al. Granulocyte transfusion therapy in pediatric patients after hematopoietic stem cell transplantation: a 5-year single tertiary care center experience. J Pediatr Hematol Oncol. 2010;34:e332–e336. [9] Atay D, Ozturk G, Akcay A, et al. Effect and safety of granulocyte transfusions in pediatric patients with febrile neutropenia or defective granulocyte functions. J Pediatr Hematol Oncol. 2011;33:e220–e225. [10] Stanworth SJ, Massey E, Hyde C, et al. Granulocyte transfusions for treating infections in patients with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev. 2005:CD005339. DOI:10.1002/14651858.CD005339. [11] Ofran Y, Avivi I, Oliven A, et al. Granulocyte transfusions for neutropenic patients with lifethreatening infections: a single centre experience in 47 patients, who received 348 granulocyte transfusions. Vox Sang. 2007;93:363–369. [12] Strauss RG. Role of granulocyte/neutrophil transfusions for haematology/oncology patients in the modern era. Br J Haematol. 2012;158(3):299–306. [13] Cesaro S, Chinello P, De Silvestro G, et al. Granulocyte transfusions from G-CSF-stimulated donors for the treatment of severe infections in neutropenic pediatric patients with onco-hematological diseases. Support Care Cancer. 2003;11:101–106. [14] Lee JJ, Chung IJ, Park MR, et al. Clinical efficacy of granulocyte transfusion therapy in patients with neutropenia-related infections. Leukemia. 2001;15:203–207. [15] Peters C, Minkov M, Matthes-Martin S, et al. Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol. 1999;106:689–696.
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