Granulozytentransfusion: Update 2020

Zusammenfassung

Die therapeutische Anwendung von Granulozytenkonzentraten erfolgt im klinischen Alltag im Gegensatz zu der anderer Blutprodukte nur selten und unregelmäßig. Der zurückhaltende Einsatz beruht unter anderem auf dem Fehlen einer breiten Evidenz, logistischen und wirtschaftlichen Problemen und dem Vorhandensein anderer potenter Therapieoptionen neutropener Infektionen. Dennoch gab es in den letzten Jahren neue wissenschaftliche Erkenntnisse nicht nur zu Physiologie und Pathophysiologie der Granulozyten, wie neu charakterisierten zellulären Verteidigungsstrategien oder deren Mitwirkung bei thrombotischen oder malignen Ereignissen, sondern auch zu deren therapeutischem Effekt. Dieser wird von einer Vielzahl an Parametern, wie der Art der Infektion, dem Transfusionszeitpunkt und der Dosis, beeinflusst. Das macht die Indikationsstellung zu einer komplexen Einzelfallentscheidung und es gilt, die heterogene Datenlage systematisch zusammenzufassen. Außerdem wurden die etablierten Indikationen neutropener bzw. neutropathischer Infektionen um experimentelle, mögliche neue Anwendungsgebiete wie die Mukositis oder Leukämiebehandlung erweitert. Die erfolgreiche Anwendung setzt eine geeignete, moderne Herstellungsweise voraus. Neben der Apherese, bei der eine relativ hohe Spenderbelastung unter anderem durch Nebenwirkungen von Mobilisationsregime und Sedimentationsbeschleunigern berücksichtigt werden muss, existieren weitere Verfahren wie die Gewinnung von Granulozyten aus Buffy Coats von Vollblutspenden. Diese versprechen eine Reduktion logistischer Probleme und unerwünschter Wirkungen auf den Spender. Unerwünschte Wirkungen bei Empfängern von Granulozytentransfusionen sollten nach wie vor berücksichtigt und gegen einen erhofften therapeutischen Effekt abgewogen werden.

Abstract

The prescription of granulocyte transfusions as a therapeutic approach in the clinical routine is – in contrast to other blood components – inconsistent and rare. This restrained application practice is due to the lack of broad evidence, logistical and financial problems, and the availability of other potent therapy options of neutropenic infections, amongst others. Nevertheless, in the last few years newsworthy scientific findings regarding this topic arose. Not only the characterization of cellular defense strategies, but also of the pathophysiological role of granulocytes, like a contribution to thrombotic and malignant events, got developed. Moreover, the therapeutic effect of these cells has been further elaborated. This effect depends on a multitude of parameters, e.g. the sort of infection, the timing and the dose of transfusions. This makes the indication a complex decision for each individual case and the heterogenous data needs to be systematically reviewed. Furthermore, the well-established indications of neutropenic and neutropathic infections got complemented by experimental, potential new application areas like mucositis or treatment of leukemia. Successful application requires a suitable, modern manufacturing process. Common apheresis procedures expose donors to relatively high physical stress, for example due to adverse effects of the mobilization regime or sedimentation agents. New protocols, like the extraction of granulocytes from buffy coats or whole blood, promise a reduction of logistical problems and adverse events in donors. Undesirable effects on recipients of granulocyte transfusions should still be taken into consideration and being weighed up against an expected therapeutic effect.

Schlüsselwörter

Granulozyten - Apherese - Sepsis - Transfusion

Key words

granulocytes - apheresis - sepsis - transfusion

Publication History

Article published online:
25 August 2020

• Literatur

• 1 Bundesärztekammer, Vorstand und wiss. Beirat. Hrsg. Querschnitts-Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. 4. überarbeitete und aktualisierte Aufl. 2015. Köln: Deutscher Ärzteverlag; 2015
• 2 Thålin C, Hisada Y, Lundström S. et al. Neutrophil Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer-Associated Thrombosis. Arterioscler Thromb Vasc Biol 2019; 39: 1724-1738 doi:10.1161/ATVBAHA.119.312463
• 3 Birkenmaier C, Dornia C, Lehle K. et al. Analysis of Thrombotic Deposits in Extracorporeal Membrane Oxygenators by High-resolution Microcomputed Tomography: A Feasibility Study. ASAIO J 2019; DOI: 10.1097/MAT.0000000000001089.
• 4 Wu L, Saxena S, Singh RK. Neutrophils in the Tumor Microenvironment. Adv Exp Med Biol 2020; 1224: 1-20 doi:10.1007/978-3-030-35723-8_1
• 5 Németh T, Sperandio M, Mócsai A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov 2020; 19: 253-275 doi:10.1038/s41573-019-0054-z
• 6 Semerad CL, Liu F, Gregory AD. et al. G-CSF is an Essential Regulator of Neutrophil Trafficking from the Bone Marrow to the Blood. Immunity 2002; 17: 413-423 doi:10.1016/s1074-7613(02)00424-7
• 7 Dancey JT, Deubelbeiss KA, Harker LA. et al. Neutrophil kinetics in man. J Clin Invest 1976; 58: 705-715 doi:10.1172/JCI108517
• 8 Tak T, Tesselaar K, Pillay J. et al. Whatʼs your age again? Determination of human neutrophil half-lives revisited. J Leukoc Biol 2013; 94: 595-601 doi:10.1189/jlb.1112571
• 9 Pillay J, den Braber I, Vrisekoop N. et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood 2010; 116: 625-627 doi:10.1182/blood-2010-01-259028
• 10 Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer 2016; 16: 431-446 doi:10.1038/nrc.2016.52
• 11 Selders GS, Fetz AE, Radic MZ. et al. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen Biomater 2017; 4: 55-68 doi:10.1093/rb/rbw041
• 12 Summers C, Rankin SM, Condliffe AM. et al. Neutrophil kinetics in health and disease. Trends Immunol 2010; 31: 318-324 doi:10.1016/j.it.2010.05.006
• 13 Cartwright GE, Athens JW, Wintrobe MM. Analytical Review: The Kinetics of Granulopoiesis in Normal Man. Blood 1964; 24: 780-803 doi:10.1182/blood.V24.6.780.780
• 14 Rosales C. Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?. Front Physiol 2018; 9: 113 doi:10.3389/fphys.2018.00113
• 15 Strauss RG. Therapeutic granulocyte transfusions: neutropenic patients with acute leukemia continue to need them – why are definitive evidence-based practice guidelines elusive?. Transfusion 2019; 59: 6-8 doi:10.1111/trf.15025
• 16 Netelenbos T, Massey E, de Wreede LC. et al. The burden of invasive infections in neutropenic patients: incidence, outcomes, and use of granulocyte transfusions. Transfusion 2019; 59: 160-168 doi:10.1111/trf.14994
• 17 Berglund S, Watz E, Remberger M. et al. Granulocyte transfusions could benefit patients with severe oral mucositis after allogeneic hematopoietic stem cell transplantation. Vox Sang 2019; 114: 769-777 doi:10.1111/vox.12835
• 18 Creasey T, Jones GL, Collin M. Granulocyte infusion: benefit beyond neutrophils?. Transfus Med 2016; 26: 390-392 doi:10.1111/tme.12319
• 19 Morton S, Mijovic A, Marks DI. et al. Use of granulocyte transfusions among haematology units in England and North Wales. Transfus Med 2018; 28: 243-248 doi:10.1111/tme.12452
• 20 Hiemstra IH, van Hamme JL, Janssen MH. et al. Dexamethasone promotes granulocyte mobilization by prolonging the half-life of granulocyte-colony-stimulating factor in healthy donors for granulocyte transfusions. Transfusion 2017; 57: 674-684 doi:10.1111/trf.13941
• 21 Ikemoto J, Yoshihara S, Fujioka T. et al. Impact of the mobilization regimen and the harvesting technique on the granulocyte yield in healthy donors for granulocyte transfusion therapy. Transfusion 2012; 52: 2646-2652 doi:10.1111/j.1537-2995.2012.03661.x
• 22 Yeo B, Redfern AD, Mouchemore KA. et al. The dark side of granulocyte-colony stimulating factor: a supportive therapy with potential to promote tumour progression. Clin Exp Metastasis 2018; 35: 255-267 doi:10.1007/s10585-018-9917-7
• 23 Ambruso DR. Hydroxyethyl starch and granulocyte transfusions: Considerations of utility and toxicity profile for patients and donors. Transfusion 2015; 55: 911-918 doi:10.1111/trf.12892
• 24 Lee JH, Leitman SF, Klein HG. A controlled comparison of the efficacy of hetastarch and pentastarch in granulocyte collections by centrifugal leukapheresis. Blood 1995; 86: 4662-4666
• 25 Dullinger K, Pamler I, Brosig A. et al. Granulocytapheresis with modified fluid gelatin versus high-molecular-weight hydroxyethyl starch: a matched-pair analysis. Transfusion 2017; 57: 397-403 doi:10.1111/trf.13898
• 26 Huestis DW, Loftus TJ, Gilcher R. et al. Modified fluid gelatin. An alternative macromolecular agent for centrifugal leukapheresis. Transfusion 1985; 25: 343-348 doi:10.1046/j.1537-2995.1985.25485273814.x
• 27 Brunkhorst FM, Engel C, Bloos F. et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: 125-139 doi:10.1056/NEJMoa070716
• 28 Perner A, Haase N, Guttormsen AB. et al. Hydroxyethyl starch 130/0.42 versus Ringerʼs acetate in severe sepsis. N Engl J Med 2012; 367: 124-134 doi:10.1056/NEJMoa1204242
• 29 Myburgh JA, Finfer S, Bellomo R. et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012; 367: 1901-1911 doi:10.1056/NEJMoa1209759
• 30 Auwerda JJ, Leebeek FWG, Wilson JHP. et al. Acquired lysosomal storage caused by frequent plasmapheresis procedures with hydroxyethyl starch. Transfusion 2006; 46: 1705-1711 doi:10.1111/j.1537-2995.2006.00962.x
• 31 Arbeitskreis Blut. Stellungnahme 21. Einsatz von Hydroxyethylstärke (HES) als Sedimentationsbeschleuniger bei der Gewinnung von Granulozytenkonzentraten. Bundesgesundheitsbl 2020; 63: 792-795 doi:10.1007/s00103-020-03141-8
• 32 Maguire LC, Strauss RG, Koepke JA. et al. The elimination of hydroxyethyl starch from the blood donors experiencing single of multiple intermittent-flow centrifugation leukapheresis. Transfusion 1981; 21: 347-353 doi:10.1046/j.1537-2995.1981.21381201811.x
• 33 Handrigan MT, Burns AR, Donnachie EM. et al. Hydroxyethyl Starch Inhibits Neutrophil Adhesion and Transendothelial Migration. Shock 2005; 24: 434-439 doi:10.1097/01.shk.0000180625.53800.63
• 34 Hofbauer R, Moser D, Hornykewycz S. et al. Hydroxyethyl starch reduces the chemotaxis of white cells through endothelial cell monolayers. Transfusion 1999; 39: 289-294 doi:10.1046/j.1537-2995.1999.39399219286.x
• 35 Matharu NM, Butler LM, Rainger GE. et al. Mechanisms of the anti-inflammatory effects of hydroxyethyl starch demonstrated in a flow-based model of neutrophil recruitment by endothelial cells. Crit Care Med 2008; 36: 1536-1542 doi:10.1097/CCM.0b013e318169f19a
• 36 Dieterich HJ, Weissmuller T, Rosenberger P. et al. Effect of hydroxyethyl starch on vascular leak syndrome and neutrophil accumulation during hypoxia. Crit Care Med 2006; 34: 1775-1782 doi:10.1097/01.CCM.0000218814.77568.BC
• 37 Feng X, Yan W, Wang Z. et al. Hydroxyethyl starch, but not modified fluid gelatin, affects inflammatory response in a rat model of polymicrobial sepsis with capillary leakage. Anesth Analg 2007; 104: 624-630 doi:10.1213/01.ane.0000250366.48705.96
• 38 Rossaint J, Berger C, Kraft F. et al. Hydroxyethyl starch 130/0.4 decreases inflammation, neutrophil recruitment, and neutrophil extracellular trap formation. Br J Anaesth 2015; 114: 509-519 doi:10.1093/bja/aeu340
• 39 Doblinger N, Bredthauer A, Mohrez M. et al. Impact of hydroxyethyl starch and modified fluid gelatin on granulocyte phenotype and function. Transfusion 2019; 59: 2121-2130 doi:10.1111/trf.15279
• 40 Szymanski J, Troendle J, Leitman S. et al. The effect of repeated stimulated granulocyte donations on hematopoietic indexes in donors: a 24-year donor center experience. Transfusion 2019; 59: 259-266 doi:10.1111/trf.15000
• 41 Leavey PJ, Thurman G, Ambruso DR. Functional characteristics of neutrophils collected and stored after administration of G-CSF. Transfusion 2000; 40: 414-419 doi:10.1046/j.1537-2995.2000.40040414.x
• 42 Hattenkofer M, Gruber M, Metz S. et al. Time course of chemotaxis and chemokinesis of neutrophils following stimulation with IL-8 or FMLP. Eur J Inflamm 2018; 16: 1-8 doi:10.1177/2058739218819171
• 43 van de Geer A, Gazendam RP, Tool ATJ. et al. Characterization of buffy coat-derived granulocytes for clinical use: a comparison with granulocyte colony-stimulating factor/dexamethasone-pretreated donor-derived products. Vox Sang 2017; 112: 173-182 doi:10.1111/vox.12481
• 44 Sahlin A, Blomgran R, Berlin G. Granulocyte concentrates prepared from residual leukocyte units produced by the Reveos automated blood processing system. Transfusion and Apheresis Science 2019; DOI: 10.1016/j.transci.2019.102682.
• 45 Estcourt LJ, Stanworth SJ, Hopewell S. et al. Granulocyte transfusions for treating infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev 2016; (04) CD005339 DOI: 10.1002/14651858.CD005339.pub2.
• 46 Estcourt LJLJ, Stanworth S, Doree C. et al. Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction. Cochrane Database Syst Rev 2015; (06) CD005341 DOI: 10.1002/14651858.CD005341.pub3.
• 47 Yoshihara S, Ikemoto J, Fujimori Y. Update on granulocyte transfusions: accumulation of promising data, but still lack of decisive evidence. Curr Opin Hematol 2016; 23: 55-60 doi:10.1097/MOH.0000000000000203
• 48 Gea-Banacloche J. Granulocyte transfusions: A concise review for practitioners. Cytotherapy 2017; 19: 1256-1269 doi:10.1016/j.jcyt.2017.08.012
• 49 Price TH, Boeckh M, Harrison RW. et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood 2015; 126: 2153-2161 doi:10.1182/blood-2015-05-645986
• 50 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 doi:10.1038/bmt.2008.237
• 51 Teofili L, Valentini CG, Di Blasi R. et al. Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia. PLoS One 2016; 11: e0159569 doi:10.1371/journal.pone.0159569
• 52 Garg A, Gupta A, Mishra A. et al. Role of granulocyte transfusions in combating life-threatening infections in patients with severe neutropenia: Experience from a tertiary care centre in North India. PLoS One 2018; 13: e0209832 doi:10.1371/journal.pone.0209832
• 53 Vrablova L, Blahutova S, Cermakova Z. et al. Granulocyte transfusions collected after steroid priming for severe infections during neutropenia: A single center experience. Transfus Clin Biol 2019; 26: 299-303 doi:10.1016/j.tracli.2018.09.001
• 54 West KA, Gea-Banacloche J, Stroncek D. et al. Granulocyte transfusions in the management of invasive fungal infections. Br J Haematol 2017; 177: 357-374 doi:10.1111/bjh.14597
• 55 Kadri SS, Remy KE, Strich JR. et al. Role of granulocyte transfusions in invasive fusariosis: systematic review and single-center experience. Transfusion 2015; 55: 2076-2085 doi:10.1111/trf.13099
• 56 Safdar A, Hanna HA, Boktour M. et al. Impact of high-dose granulocyte transfusions in patients with cancer with candidemia: retrospective case-control analysis of 491 episodes of Candida species bloodstream infections. Cancer 2004; 101: 2859-2865 doi:10.1002/cncr.20710
• 57 Raad II, Chaftari AM, Al Shuaibi MM. et al. Granulocyte transfusions in hematologic malignancy patients with invasive pulmonary aspergillosis: outcomes and complications. Ann Oncol 2013; 24: 1873-1879 doi:10.1093/annonc/mdt110
• 58 Wright DG, Robichaud KJ, Pizzo PA. et al. Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions. N Engl J Med 1981; 304: 1185-1189 doi:10.1056/NEJM198105143042001
• 59 Dutcher JP, Kendall J, Norris D. et al. Granulocyte transfusion therapy and amphotericin B: adverse reactions?. Am J Hematol 1989; 31: 102-108 doi:10.1002/ajh.2830310206