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Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective
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Transfusion and Apheresis Science xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
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Review
Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective Dilek Gurlek Gokcebay ∗ , Sibel Akpinar Tekgunduz University of Health Sciences, Ankara Kecioren Training and Research Hospital, Department of Pediatric Hematology and Oncology, Turkey
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Children Febrile neutropenia Granulocyte transfusion Leukapheresis Neutropenia Severe infection
a b s t r a c t Severe neutropenia-associated invasive bacterial or fungal infections are still the major cause of mortality and morbidity in children receiving cancer chemotherapy. Granulocyte transfusion therapy has been used for many years in the management of neutropenic patients with severe infections in whom the clinical condition deteriorated despite appropriate antimicrobial treatment. Transfused granulocytes can increase the recipient’s blood neutrophil count and accumulation of them into the site of infection. There are some data obtained from retrospective or prospective observational studies in pediatric granulocyte transfusion therapy, but results are not conclusive. This review appraises the potential benefits and risks of the use of granulocyte transfusion in children with neutropenic fever. © 2018 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Neutropenic fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Neutrophil mobilization and granulocyte collection from healthy donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Granulocyte transfusion in neutropenic children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Declarations of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction Despite improvement in treatment modalities, neutropenic fever is still the most common cause of mortality and morbidity in pediatric cancer patients. Febrile reactions occur in approximately one-third of neutropenic episodes in children with chemotherapyinduced neutropenia or shortly after hematopoietic stem cell transplantation (HSCT) [1]. When the absolute neutrophil count decreases below 500 cells/L, the risk of severe bacterial or fungal infection increases [2]. Prompt evaluation of the patient and treatment with broad-spectrum antibacterial or antifungal therapy with adequate supportive care are mainstays of therapy [3]. However, these treatment modalities cannot control infections in all patients, and additional therapies are needed for patients in
∗ Corresponding author at: Department of Pediatric Hematology and Oncology,University of Health Sciences, Ankara Kec¸iören Training and Research Hospital, Pinarbasi Mah. Sanatoryum Cad. Ardahan Sok. No:25 06380 Kecioren, Ankara, Turkey. E-mail address: [email protected] (D. Gurlek Gokcebay).
whom the clinical condition deteriorates. In such situations, granulocyte transfusions from healthy donors are used to increase the neutrophil accumulation in the sites of infection [4]. Granulocyte transfusion therapy (GTT) has been used for many years in the management of neutropenic patients with severe infections [5]. The studies conducted in the 1970s and 1980s have contradictory results showing positive or no beneficial effects [6,7]. In studies reporting the negative effects of GTT, transfusing an insufficient granulocyte dose was associated with failure of therapy [8]. Thus, difficulties in the separation of granulocytes from other blood cells, the risk of adverse events, and development of more effective antimicrobial or antifungal drugs contributed to a decrease in the use of GTT. In the 1990s, the improvement of the leukapheresis techniques and the availability of granulocyte colony-stimulating factor (G-CSF) increased the practice of GTT [9]. In children, prospective studies related to GTT are limited in the literature. In this article, we review the use of GTT in children with neutropenic fever.
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Please cite this article in press as: Gurlek Gokcebay D, Akpinar Tekgunduz S. Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. Transfus Apheresis Sci (2018), https://doi.org/10.1016/j.transci.2018.02.009
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2. Neutropenic fever Fever in neutropenic children (absolute neutrophil count (ANC) <500 cells/L or expected to decrease below 500/L in 48 h) is defined as a single oral temperature >38.3 ◦ C or oral temperature >38 ◦ C over at least one hour [10]. Chemotherapy-induced neutropenia is frequently associated with fever in 10%–50% of patients with solid tumors and 80% of those with hematologic malignancies will develop fever after a chemotherapy course. Documented infection rates in children with neutropenic fever range from 10% to 40%, and the most common severe infection is bacteremia in profoundly neutropenic patients (ANC <100 cells/L) in reported studies [11–13]. The International Pediatric Fever and Neutropenia Guideline recommends monotherapy with an antipseudomonal penicillin or a fourth-generation cephalosporin or a carbapenem as empirical therapy in pediatric patients presenting with high-risk neutropenic fever. Risk stratification of patients should be based on primary diagnosis, clinical condition, duration of neutropenia and presence of documented infection. Prolonged neutropenic fever (≥96 h), primary diagnosis of AML, high-risk acute lymphoblastic leukemia (ALL) or relapsed acute leukemia, use of high-dose corticosteroids, and allogeneic HSCT are conditions associated with a high risk of invasive fungal disease. The guideline recommends initiation of caspofungin or liposomal Amfotericin-B as an empirical treatment and continuing until neutropenia is resolved [14]. In neutropenic patients who do not respond to medical treatments, GTT is a potentially effective choice to overcome infections. Reported indications for GTT use in neutropenic children are proven gramnegative or fungal infections in more than 80% of the cases [15].
3. Neutrophil mobilization and granulocyte collection from healthy donors Normally, 5% of the total body’s neutrophils circulate in the peripheral blood, and 60% are in the marginated pool. Thus, pharmacologic agents have been used to increase the number of neutrophils collected from donors by mobilization from the bone marrow into the circulation [16]. The neutrophil count increase begins within 2 h after granulocyte-colony stimulating factor (GCSF) administration (5–10 g/kg), and peaks 12 to 18 h later reaching 7- to 10 fold [17]. The combination of G-CSF and 8 mg dexamethasone results the greatest neutrophil yields, significant reduction of G-CSF dose and decreased side effects like muscle and bone pain, headache, fatigue and nausea [18]. When these two agents are used together, the transfused neutrophils have been shown to function normally and have prolonged survival in the recipient [19]. The side effects are usually mild and occurred in more than 90% of granulocyte donors. They resolve when white the cell count returns to normal limits. However, uncommon severe side effects like splenic rupture, retinal hemorrhage, acute iritis, and thrombosis have been reported in the literature [20]. Headache, flushing, hypertension, hyperglycemia and increased gastric acidity are common side effects which are associated with steroid use. Long term use of systemic steroid therapy has been associated with posterior subcapsular cataracts, but in granulocyte donors, no significant risk of cataracts was reported compared to platelet donors [21]. Theoretically, using G-CSF in donors with a prior history of hematopoietic malignancy or family predisposition may transform normal hematopoietic stem cells to a malignant clone. However, Shaw et al. investigated the long term effects of exposure to more than one dose G-CSF in healthy donors, and reported no increased incidence of hematological malignancies [22]. Consequently, informed consent, family history, medical assessment and microbiological screening are recommended for each granulocyte donor [23]. Because Cytomegalovirus (CMV) transmission can
occur, CMV seronegative patients should be transfused with cells from CMV seronegative donors [16]. Previously, granulocytes were obtained from the buffy coat component preparation of whole blood but a large number of units with a high volume were required [24]. Continuous flow centrifugation leukapheresis is now the standard technique to collect granulocytes based on density differences between the cells. Hydroxyethyl starch (HES) is used to decrease contamination of erythrocytes and platelets in the granulocyte suspension [25]. Because the final hematocrit of granulocyte suspensions may be as high as 2% to 7%, the patient and donor’s ABO and RhD blood group should be compatible, and cross-matching must be performed [16]. The acute effects of leukapheresis are mostly related to the citrate used for anticoagulation of the blood during this procedure. Symptoms of hypocalcemia, nausea, vomiting, hypotension, allergic reactions, and rarely air embolism were reported. Also, using HES may cause transient hypertension with flushing and headache [26]. The use of G-CSF plus dexamethasone 12 h before leukapheresis to collect granulocyte suspension has become a standard procedure. Drewniak et al. reported that the function of neutrophils from granulocyte suspensions were intact at 24 h, but the release of proinflammatory cytokines and a pH decrease following 36–48 h storage were observed [27]. Another study showed that granulocyte suspensions stored at 10 ◦ C preserved respiratory burst, killing and migrating activity in vivo [28]. Ideally, granulocyte suspensions should be transfused as soon as possible after apheresis collection, otherwise, stored at room temperature (20–24 ◦ C) without agitation for infusion in a maximum of 24 h. Granulocyte suspensions should be irradiated to prevent transfusion-associated graft-versus-host disease (TA-GVHD) before administration to the neutropenic patient [29].
4. Granulocyte transfusion in neutropenic children Mortality rate is still high in neutropenic children with severe bacterial or fungal infection despite timely initiation of antimicrobial or antifungal agents. Using pre-stimulation with G-CSF and steroids in donors and recent advances in apheresis techniques resulted in an increase of GTT practices for children. Most of the data in pediatric GTT are obtained from observational studies. A prospective study reported that GTT was effective in 30 neutropenic children, and 2% of bacterial, 56% of aspergillus and 50% of candida infections were resolved on day 100 [30]. Sachs et al. prospectively evaluated 27 patients with severe bacterial and fungal infections, and reported GTT resulted in a high improvement rate (25 of 27). They concluded that the high response rate might be related to early initiation of GTT (a median of 6 days of infection period) compared with other studies [31]. Uppuluri et al. also showed early use of GTT resulted in an improved survival rate from 41 to 54% in 72 children receiving 230 granulocyte infusions [32]. A retrospective study evaluated 111 GTT in 35 neutropenic children or defective granulocyte functions, and they reported infection-related and overall survival rates of 82% and 77%, respectively, on day 30 [33]. Ozturkmen et al. reported 69.2% clinical, and 53.8% hematologic response rate in their study [34]. Another study showed 92% clinical response, and 15% infection-related mortality in 18 children who received GTT. They reported that 46% of children developed respiratory adverse events but all of them improved [35]. Several studies showed that higher granulocyte counts in the apheresis product results in greater control of infection [36,37]. Siedel et al. assessed 778 GTT in 49 children and 10 young adults, and reported that median ANC increment on day 5 was associated with administered number of granulocytes. They suggested that daily transfusions of at least 1.4 × 108 granulocytes/kg proba-
Please cite this article in press as: Gurlek Gokcebay D, Akpinar Tekgunduz S. Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. Transfus Apheresis Sci (2018), https://doi.org/10.1016/j.transci.2018.02.009
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bly resulted in better outcomes. However, survival on day 28 did neither correlate with the administered number of granulocytes nor ANC increment [38]. Whether the ANC increment is necessary for evaluation of GTT efficiency is uncertain. Tissue infiltration of transfused granulocytes precedes the blood granulocyte rise and their half-life in tissue is longer than in blood. Therefore, daily GTT should be necessary to achieve a sustained ANC increment [23]. van de Wetering et al. reviewed pediatric data published between 1976 and 2006 on the use of GTT and evaluated 510 children. They reported that the reason for using GTT was gram-positive bacteremia in 52%, and fungemia in 48% of the neutropenic patients. All of the patients’ clinical conditions were not improved despite adequate medical and supportive care, and the mean duration of neutropenia was 13 days (range, 2–30 days). The mean number of infused granulocyte suspension was 8.7 (range, 1-46), and the mean granulocyte count in the product was 2 × 109 granulocytes/kg/day (range, 0.5–7 × 109 granulocytes/kg/day). Thirty-four per cent of the donors were not pre-stimulated. A significant difference was found in the yield of granulocytes and mortality rate of the patients between the donors who were stimulated with G-CSF and steroids and those that were not. The survival rate of the patients was 70%, and there was no difference in the number of transfused granulocytes between the patients who survived and died [15]. A recent Cochrane review which evaluated 10 trials involving 587 participants between 1975 and 2015 reported that there was no difference in all-cause mortality over 30 days in patients receiving therapeutic GTT and those did not (RR 0.75, 95% CI 0.54 to 1.04). Similarly, there was no difference found between infused granulocyte dose (< 1 × 1010 cells/kg per day versus ≥ 1 × 1010 cells/kg per day). They concluded that there is insufficient evidence to determine whether granulocyte transfusions affect mortality [39]. The suggested indications of GTT in neutropenic children are: - severe neutropenia defined as ANC <500 cells/L due to congenital or acquired (after chemotherapy or HSCT) bone marrow failure syndromes; - expected duration of neutropenia for at least 5 days; and - bacteremia, fungemia, invasive bacterial tissue infiltration, or invasive fungal infection, unresponsive to appropriate antimicrobial therapy [23]. Reported minor transfusion reactions associated with GTT are fever and chills, but more severe reactions can occur in approximately 5% of the patients including respiratory distress. Severe pulmonary reactions might be related to sequestration of transfused cells in the pulmonary vascular bed and are mostly seen in patients with preexisting respiratory dysfunction. Wright et al. reported severe pulmonary reactions were associated with the concomitant use of amphotericin, but it was not confirmed by others [40]. Premedication with acetaminophen, antihistamines or steroids to the recipient and minimum 6 h interval between GTT and amphotericin administration mostly prevents adverse reactions of GTT. Besides this, most of the transfusion reactions have been reported in patients who were alloimmunized to leukocyte antibodies. Adkins et al. showed that the presence of human leukocyte antigen (HLA) antibodies in the patients serum was adversely affected post-transfusion neutrophil increment [41]. Based on the above mentioned facts, it is difficult to standardize the use of GTT in children, because of the heterogeneity of the studies in terms of underlying disease, the type of infection, antimicrobial treatment, duration of neutropenia and the dose of infused granulocytes. A large-scale randomized controlled trial would help to resolve controversy in the use of GTT in neutropenic children. In conclusion, GTT is a supportive therapy that can be administered until recovery of the neutrophil count in neutropenic children
3
whose infection cannot be controlled despite appropriate antimicrobial therapy. Declarations of interest None. References [1] Castagnola E, Fontana V, Caviglia I, Caruso S, Faraci M, Fioredda F, et al. A prospective study on the epidemiology of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after hemopoietic stem cell transplantation. Clin Infect Dis 2007;45:1296–304. [2] Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328–40. [3] Ku BC, Bailey C, Balamuth F. Neutropenia in the febrile child. Pediatr Emerg Care 2016;32:329–34. [4] Hester JP, Dignani MC, Anaissie EJ, Kantarjian HM, O’Brien S, Freireich EJ. Collection and transfusion of granulocyte concentrates from donors primed with granulocyte stimulating factor and response of myelosuppressed patients with established infection. J Clin Apher 1995;10:188–93. [5] Alavi JB, Root RK, Djerassi I, Evans AE, Gluckman SJ, MacGregor RR, et al. A randomized clinical trial of granulocyte transfusions for infection in acute leukemia. N Engl J Med 1977;296:706–11. [6] Herzig RH, Herzig GP, Graw Jr RG, Bull MI, Ray KK. Successful granulocyte transfusion therapy for gram-negative septicemia: a prospectively randomized controlled study. N Eng J Med 1977;296:701–5. [7] Winston DJ, Ho WG, Gale RP. Therapeutic granulocyte transfusions for documented infections: a controlled trial in ninety-five infectious granulocytopenic episodes. Ann Intern Med 1982;97:509–15. [8] Vamvakas EC, Pineda AA. Meta-analysis of clinical studies of the efficacy of granulocyte transfusions in the treatment of bacterial sepsis. J Clin Apher 1996;11:1–9. [9] Dale DC, Liles WC, Summer WR, Nelson S. Review: granulocyte colony-stimulating factor–role and relationships in infectious diseases. J Infect Dis 1995;172:1061–75. [10] Hughes WT, Armstrong D, Bodey GP, Brown AE, Edwards JE, Feld R, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clin Infect Dis 1997;25:551–73. [11] Hakim H, Flynn PM, Knapp KM, Srivastava DK, Gaur AH. Etiology and clinical course of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol 2009;31:623–9. [12] Roguin A, Kasis I, Ben-Arush MW, Sharon R, Berant M. Fever and neutropenia in children with malignant disease. Pediatr Hematol Oncol 1996;13:503–10. [13] Agyeman P, Aebi C, Hirt A, Niggli FK, Nadal D, Simon A, et al. Predicting bacteremia in children with cancer and fever in chemotherapy-induced neutropenia: results of the prospective multicenter SPOG 2003 FN study. Pediatr Infect Dis J 2011;30:e114–9. [14] Lehrnbecher T, Robinson P, Fisher B, Alexander S, Ammann RA, Beauchemin M, et al. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 Update. J Clin Oncol 2017;35:2082–94. [15] van de Wetering MD, Weggelaar N, Offringa M, Caron HN, Kuijpers TW. Granulocyte transfusions in neutropaenic children: a systematic review of the literature. Eur J Cancer 2007;208:2082–92. [16] Marfin AA, Price TH. Granulocyte transfusion therapy. J Intensive Care Med 2015;30:79–88. [17] Liles WC, Huang JE, Llewellyn C, SenGupta D, Price TH, Dale DC. A comparative trial of granulocyte-colony-stimulating factor and dexamethasone, separately and in combination, for the mobilization of neutrophils in the peripheral blood of normal volunteers. Transfusion 1997;37:182–7. [18] Stroncek DF, Yau YY, Oblitas J, Leitman SF. Administration of G-CSF plus dexamethasone produces greater granulocyte concentrate yields while causing no more donor toxicity than G-CSF alone. Transfusion 2001;41:1037–44. [19] Drewniak A, van Raam BJ, Geissler J, Tool AT, Mook OR, van den Berg TK, et al. Changes in gene expression of granulocytes during in vivo granulocyte colony-stimulating factor/dexamethasone mobilization for transfusion purposes. Blood 2009;144:5979–98. [20] Korbling M. Effects of granulocyte colony-stimulating factor in healthy subjects. Curr Opin Hematol 1998;5:209–14. [21] Clayton JA, Vitale S, Kim J, Conry-Cantilena C, Byrne P, Reed GF, et al. Prevalence of posterior subcapsular cataracts in volunteer cytapheresis donors. Transfusion 2011;51:921–8. [22] Shaw BE, Confer DL, Hwang W, Pulsipher MA. A review of the genetic and long-term effects of G-CSF injections in healthy donors: a reassuring lack of evidence for the development of haematological malignancies. Bone Marrow Transpl 2015;50:334–40. [23] Peters C. Granulocyte transfusions in neutropenic patients: beneficial effects proven? Vox Sang 2009;96:275–83.
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Please cite this article in press as: Gurlek Gokcebay D, Akpinar Tekgunduz S. Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. Transfus Apheresis Sci (2018), https://doi.org/10.1016/j.transci.2018.02.009
ARTICLE IN PRESS
TRASCI-2314; No. of Pages 4
Transfusion and Apheresis Science xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Review
Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective Dilek Gurlek Gokcebay ∗ , Sibel Akpinar Tekgunduz University of Health Sciences, Ankara Kecioren Training and Research Hospital, Department of Pediatric Hematology and Oncology, Turkey
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Children Febrile neutropenia Granulocyte transfusion Leukapheresis Neutropenia Severe infection
a b s t r a c t Severe neutropenia-associated invasive bacterial or fungal infections are still the major cause of mortality and morbidity in children receiving cancer chemotherapy. Granulocyte transfusion therapy has been used for many years in the management of neutropenic patients with severe infections in whom the clinical condition deteriorated despite appropriate antimicrobial treatment. Transfused granulocytes can increase the recipient’s blood neutrophil count and accumulation of them into the site of infection. There are some data obtained from retrospective or prospective observational studies in pediatric granulocyte transfusion therapy, but results are not conclusive. This review appraises the potential benefits and risks of the use of granulocyte transfusion in children with neutropenic fever. © 2018 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Neutropenic fever . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Neutrophil mobilization and granulocyte collection from healthy donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Granulocyte transfusion in neutropenic children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Declarations of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction Despite improvement in treatment modalities, neutropenic fever is still the most common cause of mortality and morbidity in pediatric cancer patients. Febrile reactions occur in approximately one-third of neutropenic episodes in children with chemotherapyinduced neutropenia or shortly after hematopoietic stem cell transplantation (HSCT) [1]. When the absolute neutrophil count decreases below 500 cells/L, the risk of severe bacterial or fungal infection increases [2]. Prompt evaluation of the patient and treatment with broad-spectrum antibacterial or antifungal therapy with adequate supportive care are mainstays of therapy [3]. However, these treatment modalities cannot control infections in all patients, and additional therapies are needed for patients in
∗ Corresponding author at: Department of Pediatric Hematology and Oncology,University of Health Sciences, Ankara Kec¸iören Training and Research Hospital, Pinarbasi Mah. Sanatoryum Cad. Ardahan Sok. No:25 06380 Kecioren, Ankara, Turkey. E-mail address: [email protected] (D. Gurlek Gokcebay).
whom the clinical condition deteriorates. In such situations, granulocyte transfusions from healthy donors are used to increase the neutrophil accumulation in the sites of infection [4]. Granulocyte transfusion therapy (GTT) has been used for many years in the management of neutropenic patients with severe infections [5]. The studies conducted in the 1970s and 1980s have contradictory results showing positive or no beneficial effects [6,7]. In studies reporting the negative effects of GTT, transfusing an insufficient granulocyte dose was associated with failure of therapy [8]. Thus, difficulties in the separation of granulocytes from other blood cells, the risk of adverse events, and development of more effective antimicrobial or antifungal drugs contributed to a decrease in the use of GTT. In the 1990s, the improvement of the leukapheresis techniques and the availability of granulocyte colony-stimulating factor (G-CSF) increased the practice of GTT [9]. In children, prospective studies related to GTT are limited in the literature. In this article, we review the use of GTT in children with neutropenic fever.
https://doi.org/10.1016/j.transci.2018.02.009 1473-0502/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Gurlek Gokcebay D, Akpinar Tekgunduz S. Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. Transfus Apheresis Sci (2018), https://doi.org/10.1016/j.transci.2018.02.009
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2. Neutropenic fever Fever in neutropenic children (absolute neutrophil count (ANC) <500 cells/L or expected to decrease below 500/L in 48 h) is defined as a single oral temperature >38.3 ◦ C or oral temperature >38 ◦ C over at least one hour [10]. Chemotherapy-induced neutropenia is frequently associated with fever in 10%–50% of patients with solid tumors and 80% of those with hematologic malignancies will develop fever after a chemotherapy course. Documented infection rates in children with neutropenic fever range from 10% to 40%, and the most common severe infection is bacteremia in profoundly neutropenic patients (ANC <100 cells/L) in reported studies [11–13]. The International Pediatric Fever and Neutropenia Guideline recommends monotherapy with an antipseudomonal penicillin or a fourth-generation cephalosporin or a carbapenem as empirical therapy in pediatric patients presenting with high-risk neutropenic fever. Risk stratification of patients should be based on primary diagnosis, clinical condition, duration of neutropenia and presence of documented infection. Prolonged neutropenic fever (≥96 h), primary diagnosis of AML, high-risk acute lymphoblastic leukemia (ALL) or relapsed acute leukemia, use of high-dose corticosteroids, and allogeneic HSCT are conditions associated with a high risk of invasive fungal disease. The guideline recommends initiation of caspofungin or liposomal Amfotericin-B as an empirical treatment and continuing until neutropenia is resolved [14]. In neutropenic patients who do not respond to medical treatments, GTT is a potentially effective choice to overcome infections. Reported indications for GTT use in neutropenic children are proven gramnegative or fungal infections in more than 80% of the cases [15].
3. Neutrophil mobilization and granulocyte collection from healthy donors Normally, 5% of the total body’s neutrophils circulate in the peripheral blood, and 60% are in the marginated pool. Thus, pharmacologic agents have been used to increase the number of neutrophils collected from donors by mobilization from the bone marrow into the circulation [16]. The neutrophil count increase begins within 2 h after granulocyte-colony stimulating factor (GCSF) administration (5–10 g/kg), and peaks 12 to 18 h later reaching 7- to 10 fold [17]. The combination of G-CSF and 8 mg dexamethasone results the greatest neutrophil yields, significant reduction of G-CSF dose and decreased side effects like muscle and bone pain, headache, fatigue and nausea [18]. When these two agents are used together, the transfused neutrophils have been shown to function normally and have prolonged survival in the recipient [19]. The side effects are usually mild and occurred in more than 90% of granulocyte donors. They resolve when white the cell count returns to normal limits. However, uncommon severe side effects like splenic rupture, retinal hemorrhage, acute iritis, and thrombosis have been reported in the literature [20]. Headache, flushing, hypertension, hyperglycemia and increased gastric acidity are common side effects which are associated with steroid use. Long term use of systemic steroid therapy has been associated with posterior subcapsular cataracts, but in granulocyte donors, no significant risk of cataracts was reported compared to platelet donors [21]. Theoretically, using G-CSF in donors with a prior history of hematopoietic malignancy or family predisposition may transform normal hematopoietic stem cells to a malignant clone. However, Shaw et al. investigated the long term effects of exposure to more than one dose G-CSF in healthy donors, and reported no increased incidence of hematological malignancies [22]. Consequently, informed consent, family history, medical assessment and microbiological screening are recommended for each granulocyte donor [23]. Because Cytomegalovirus (CMV) transmission can
occur, CMV seronegative patients should be transfused with cells from CMV seronegative donors [16]. Previously, granulocytes were obtained from the buffy coat component preparation of whole blood but a large number of units with a high volume were required [24]. Continuous flow centrifugation leukapheresis is now the standard technique to collect granulocytes based on density differences between the cells. Hydroxyethyl starch (HES) is used to decrease contamination of erythrocytes and platelets in the granulocyte suspension [25]. Because the final hematocrit of granulocyte suspensions may be as high as 2% to 7%, the patient and donor’s ABO and RhD blood group should be compatible, and cross-matching must be performed [16]. The acute effects of leukapheresis are mostly related to the citrate used for anticoagulation of the blood during this procedure. Symptoms of hypocalcemia, nausea, vomiting, hypotension, allergic reactions, and rarely air embolism were reported. Also, using HES may cause transient hypertension with flushing and headache [26]. The use of G-CSF plus dexamethasone 12 h before leukapheresis to collect granulocyte suspension has become a standard procedure. Drewniak et al. reported that the function of neutrophils from granulocyte suspensions were intact at 24 h, but the release of proinflammatory cytokines and a pH decrease following 36–48 h storage were observed [27]. Another study showed that granulocyte suspensions stored at 10 ◦ C preserved respiratory burst, killing and migrating activity in vivo [28]. Ideally, granulocyte suspensions should be transfused as soon as possible after apheresis collection, otherwise, stored at room temperature (20–24 ◦ C) without agitation for infusion in a maximum of 24 h. Granulocyte suspensions should be irradiated to prevent transfusion-associated graft-versus-host disease (TA-GVHD) before administration to the neutropenic patient [29].
4. Granulocyte transfusion in neutropenic children Mortality rate is still high in neutropenic children with severe bacterial or fungal infection despite timely initiation of antimicrobial or antifungal agents. Using pre-stimulation with G-CSF and steroids in donors and recent advances in apheresis techniques resulted in an increase of GTT practices for children. Most of the data in pediatric GTT are obtained from observational studies. A prospective study reported that GTT was effective in 30 neutropenic children, and 2% of bacterial, 56% of aspergillus and 50% of candida infections were resolved on day 100 [30]. Sachs et al. prospectively evaluated 27 patients with severe bacterial and fungal infections, and reported GTT resulted in a high improvement rate (25 of 27). They concluded that the high response rate might be related to early initiation of GTT (a median of 6 days of infection period) compared with other studies [31]. Uppuluri et al. also showed early use of GTT resulted in an improved survival rate from 41 to 54% in 72 children receiving 230 granulocyte infusions [32]. A retrospective study evaluated 111 GTT in 35 neutropenic children or defective granulocyte functions, and they reported infection-related and overall survival rates of 82% and 77%, respectively, on day 30 [33]. Ozturkmen et al. reported 69.2% clinical, and 53.8% hematologic response rate in their study [34]. Another study showed 92% clinical response, and 15% infection-related mortality in 18 children who received GTT. They reported that 46% of children developed respiratory adverse events but all of them improved [35]. Several studies showed that higher granulocyte counts in the apheresis product results in greater control of infection [36,37]. Siedel et al. assessed 778 GTT in 49 children and 10 young adults, and reported that median ANC increment on day 5 was associated with administered number of granulocytes. They suggested that daily transfusions of at least 1.4 × 108 granulocytes/kg proba-
Please cite this article in press as: Gurlek Gokcebay D, Akpinar Tekgunduz S. Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. Transfus Apheresis Sci (2018), https://doi.org/10.1016/j.transci.2018.02.009
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bly resulted in better outcomes. However, survival on day 28 did neither correlate with the administered number of granulocytes nor ANC increment [38]. Whether the ANC increment is necessary for evaluation of GTT efficiency is uncertain. Tissue infiltration of transfused granulocytes precedes the blood granulocyte rise and their half-life in tissue is longer than in blood. Therefore, daily GTT should be necessary to achieve a sustained ANC increment [23]. van de Wetering et al. reviewed pediatric data published between 1976 and 2006 on the use of GTT and evaluated 510 children. They reported that the reason for using GTT was gram-positive bacteremia in 52%, and fungemia in 48% of the neutropenic patients. All of the patients’ clinical conditions were not improved despite adequate medical and supportive care, and the mean duration of neutropenia was 13 days (range, 2–30 days). The mean number of infused granulocyte suspension was 8.7 (range, 1-46), and the mean granulocyte count in the product was 2 × 109 granulocytes/kg/day (range, 0.5–7 × 109 granulocytes/kg/day). Thirty-four per cent of the donors were not pre-stimulated. A significant difference was found in the yield of granulocytes and mortality rate of the patients between the donors who were stimulated with G-CSF and steroids and those that were not. The survival rate of the patients was 70%, and there was no difference in the number of transfused granulocytes between the patients who survived and died [15]. A recent Cochrane review which evaluated 10 trials involving 587 participants between 1975 and 2015 reported that there was no difference in all-cause mortality over 30 days in patients receiving therapeutic GTT and those did not (RR 0.75, 95% CI 0.54 to 1.04). Similarly, there was no difference found between infused granulocyte dose (< 1 × 1010 cells/kg per day versus ≥ 1 × 1010 cells/kg per day). They concluded that there is insufficient evidence to determine whether granulocyte transfusions affect mortality [39]. The suggested indications of GTT in neutropenic children are: - severe neutropenia defined as ANC <500 cells/L due to congenital or acquired (after chemotherapy or HSCT) bone marrow failure syndromes; - expected duration of neutropenia for at least 5 days; and - bacteremia, fungemia, invasive bacterial tissue infiltration, or invasive fungal infection, unresponsive to appropriate antimicrobial therapy [23]. Reported minor transfusion reactions associated with GTT are fever and chills, but more severe reactions can occur in approximately 5% of the patients including respiratory distress. Severe pulmonary reactions might be related to sequestration of transfused cells in the pulmonary vascular bed and are mostly seen in patients with preexisting respiratory dysfunction. Wright et al. reported severe pulmonary reactions were associated with the concomitant use of amphotericin, but it was not confirmed by others [40]. Premedication with acetaminophen, antihistamines or steroids to the recipient and minimum 6 h interval between GTT and amphotericin administration mostly prevents adverse reactions of GTT. Besides this, most of the transfusion reactions have been reported in patients who were alloimmunized to leukocyte antibodies. Adkins et al. showed that the presence of human leukocyte antigen (HLA) antibodies in the patients serum was adversely affected post-transfusion neutrophil increment [41]. Based on the above mentioned facts, it is difficult to standardize the use of GTT in children, because of the heterogeneity of the studies in terms of underlying disease, the type of infection, antimicrobial treatment, duration of neutropenia and the dose of infused granulocytes. A large-scale randomized controlled trial would help to resolve controversy in the use of GTT in neutropenic children. In conclusion, GTT is a supportive therapy that can be administered until recovery of the neutrophil count in neutropenic children
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Please cite this article in press as: Gurlek Gokcebay D, Akpinar Tekgunduz S. Granulocyte transfusions in the management of neutropenic fever: A pediatric perspective. Transfus Apheresis Sci (2018), https://doi.org/10.1016/j.transci.2018.02.009