Therapeutic Efficacy Of Granulocyte Colony-stimulating F

治疗性粒细胞输注的功效受到使用标准单采技术获得的细胞数量相对较少的限制。在先前的研究中，我们证明，由粒细胞集落刺激因子（G-CSF）或G-CSF和地塞米松（dexa）联合刺激供体制备的粒细胞浓缩物所含的粒细胞数量比单独使用地塞米松制备的产品多2.3倍和3.5倍（单独地塞米松的产物含量为2.09 × 10 e10个细胞，而G-CSF和G-CSF加dexa的产物含量分别为4.87和7.31 × 10 e10个细胞）（dexa相对于单独G-CSF或G-CSF加dexa的产物含量p小于0.01）。72%的接受G-CSF加dexa的捐赠者有躁动、失眠、骨痛或头痛。10%的供体由于动员方案的不便和不适而要求停止参与研究。五十六例临床中心患者接受了G-CSF动员的粒细胞。35例为重度再生障碍性贫血，包括15例重度再生障碍性贫血（SAA）患者、12例干细胞移植受者、7例淋巴瘤/白血病患者和1例乳腺癌患者。其余21例患者有CGD。在血小板减少症患者中，21例有系统性丝状真菌感染，11例有细菌感染，2例有念珠菌血症，1例有RSV感染。输注后1小时粒细胞计数的平均增量为2600/uL，高于基线的计数大于500/uL持续12至24小时。在14例粒细胞输注后存活超过2周的血小板减少、免疫抑制患者中，有1例发生HLA同种异体致敏，15例CGD患者中有2例发生HLA同种异体致敏。在没有HLA同种异体致敏的情况下，粒细胞输注与进行性缺氧、肺浸润和ARDS样事件相关，15例SAA患者中有4例，而21例CGD患者中有1例。在伴有组织霉菌的血小板减少症患者中，21例中有10例在粒细胞输注治疗期间稳定或改善，但21例中只有5例存活住院。相比之下，11例细菌性疾病中有5例出院。21例CGD患者中有18例真菌（12例中的9例）或细菌（9例中的9例）感染消退。这些G-CSF动员的粒细胞的初步研究表明，它们可能在精心选择的患有危及生命的感染的血小板减少症患者中提供生存益处，但可能与显著的进行性肺毒性相关。NHLBI的止血/输血医学临床试验网络正在组织一项关于G-CSF动员的粒细胞输注在丝状真菌感染的严重血小板减少患者中的疗效的随机前瞻性多中心研究。

The efficacy of therapeutic granulocyte transfusions is limited by the relatively small number of cells obtained using standard apheresis techniques. In prior studies, we demonstrated that granulocyte concentrates prepared by granulocyte-colony stimulating factor (G-CSF) or the combination of G-CSF and dexamethasone (dexa) stimulation of the donor contained 2.3- and 3.5-fold greater numbers of granulocytes than products prepared using dexamethasone alone (product content 2.09 x 10e10 cells with dexamethasone alone versus 4.87 and 7.31 x 10e10 cells total with G-CSF and G-CSF plus dexa, respectively) (p less than 0.01 for dexa vs G-CSF alone or G-CSF plus dexa). Seventy-two percent of donors getting G-CSF plus dexa had restlessness, insomnia, bone pain, or headache. Ten percent of donors requested discontinuation of participation in the study due to the inconvenience and discomfort of the mobilization regimen. Fifty-six Clinical Center patients have received G-CSF mobilized granulocytes. Thirty-five were profoundly neutropenic, including 15 patients with severe aplastic anemia (SAA), 12 stem cell transplant recipients, 7 patients with lymphoma/leukemia, and 1 with breast cancer. The remaining 21 patients had CGD. In the neutropenic patients, 21 had systemic filamentous fungal infections, 11 had bacterial infections, two had candidemia and one had RSV infection. The mean increment in granulocyte count 1-hour post-transfusion was 2600/uL, and counts greater than 500/uL above baseline were sustained for 12 to 24 hours. One of the 14 neutropenic, immunosuppressed patients who survived longer than 2 weeks after the initiation of granulocyte transfusions developed HLA allosensitization, as did two of the 15 CGD patients. In the absence of HLA allosensitization, granulocyte transfusions were associated with progressive hypoxia, pulmonary infiltrates, and an ARDS-like event in four of 15 SAA patients, versus one of 21 CGD patients. Of the neutropenic patients with tissue molds, 10 of 21 stabilized or improved during granulocyte transfusion therapy, but only 5 of 21 survived hospitalization. In contrast, five of 11 with bacterial processes were discharged from hospital. Eighteen of 21 patients with CGD had resolution of their fungal (9 of 12) or bacterial (9 of 9) infections. These pilot studies of G-CSF mobilized granulocytes suggest that they may confer survival benefit in carefully selected neutropenic patients with life-threatening infections, but may be associated with significant progressive pulmonary toxicity. A randomized prospective multicenter study of the efficacy of G-CSF mobilized granulocyte transfusions in severely neutropenic patients with filamentous fungal infections is being organized by the Hemostasis/Transfusion Medicine Clinical Trials Network of NHLBI.