造血干细胞移植后侵袭性真菌病的临床研究

目的探讨造血干细胞移植(hematopoietic stem cell transplantation,HSCT)后侵袭性真菌病(invasive fungal disease,IFD)的发生率、发病时间、临床表现及治疗效果。方法对军事医学科学院附属医院造血干细胞移植科2000年1月至2006年12月326例行HSCT的病例进行回顾性分析。结果326例行HSCT的患者中39例发生了IFD,发生率为11.9%。确诊9例,临床诊断21例,拟诊9例。39例IFD中,念珠菌病7例,霉菌病32例。HLA相合同胞、无关相合或相关不合及自体HSCT的IFD发生率分别为11.1%(26/234),18.5%(10/54)和7.9%(3/38)。30例出现IFD患者有移植物抗宿主病(graft versus host disease,GVHD)。IFD发生的中位时间78(17~198)d,临床表现主要是发热,广谱抗生素治疗无效,部分患者出现低氧血症。39例中,存活21例,死亡18例,联合抗真菌药物治疗9例患者6例存活。结论IFD是HSCT后的主要死亡原因,无关供者和相关不合的HSCT的IFD发生率明显升高,有GVHD患者发生IFD机会明显增加,联合抗真菌治疗效果有待进一步证实。     

Complications of hematopoietic stem transplantation: Fungal infections

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole.     

造血干细胞移植患者粒细胞缺乏期间血流感染的单中心临床分析

目的 分析造血干细胞移植(HSCT)患者粒细胞缺乏(粒缺)期间血流感染的流行病学特征,为经验性治疗的选择提供依据.方法 回顾性分析我院2008年1月至2010年10月784例HSCT在粒缺期发热的患者,分析其血流感染的发生率、临床表现、病原菌分布及药敏试验结果.结果 784例HSCT患者中441例在粒缺期间出现发热,确定为血流感染者75例,在所有患者中发病率为9.6%(75/784),在粒缺发热患者中发病率为17.0%(75/441).病原菌分布依次为:G-菌株占64.4%,产超广谱β内酰胺酶(ESBL)菌株占80.9%(38/47),除1株鲍曼不动杆菌外均对碳青霉烯类药物敏感;G+菌株占30.1%,耐甲氧西林葡萄球菌比例为50.0%,除1株鹑鸡肠球菌外均对万古霉素敏感;真菌菌株占5.5%,均为念珠菌属.HSCT患者在粒缺期血流感染的病死率为6.7%.结论 我院骨髓移植病房的血流感染病原菌分布依次为G-菌、G+菌和真菌.碳青霉烯类及糖肽类药物分别是前两者治疗的首选.

Abstract：

Objectlve To analyze the epidemiologic features of blood stream infection(BSI)during the period of agranulocytosis after hematopoietic stem cell transplantation(HSCT)in our hospital,and provide the basis for the empirical therapy.Methods The consecutive hematopoietic stem cell transplantation recipients conducted between January 2008 and October 2010 were studied retrospectively,to identify the current incidence,etiology for BSI and associated mortality during the period of agranulocytosis.Results Totally 75 patients were diagnosed as BSI.The incidence of BSI was 9.6%(75/784)in HSCT during the period of agranulocytosis,17.0%(75/441)in febrile patients.The pathogen testing showed that 64.4%were G-bacteria,30.1%were G+ bacterial and 5.5%were fungi.All G-bacteria except one were sensitive to carbapenems;all G+ bacteria except one were sensitive to vancomycin.Among the 75 patients,9(12.0%)experienced septic shock and 5(6.7%)died.Conclusions The pathogens of the BSI in the cohort are G-bacteria,followed by G+ bacteria and fungi.Carbapenems and vancomycin are the first drugs for the experiential therapy.     

异基因造血干细胞移植治疗恶性血液病(附9例报告)

9例恶性血液病患者 ,采用异基因外周血干细胞移植 ( allo- HSCT)治疗 7例 ,外周血与骨髓干细胞混合移植 2例 ;供者均为人白细胞相关抗原 ( HL A)完全相合同胞兄妹。预处理方案用马利兰 ( BU)、环磷酰胺( CY) ,环孢霉素 A ( Cs A)联合短程甲氨蝶呤 ( MTX)预防移植物抗宿主病 ( GVHD)。结果 :患者治疗后均重建造血 ,中性粒细胞≥ 0 .5× 10 9/ L 的中位数为 14天 ,血小板≥ 2 0× 10 9/ L 的中位数为 16天。发生急性 GVHD5例 ,慢性 GVHD2例 ,肝静脉闭塞病 ( VOD) 1例 ,巨细胞病毒血症 9例。2例 ABO血型不合者移植后未发生溶血及纯红再障。1例耐药复发淋巴瘤 ,供、受者均为乙肝病毒携带者 ,移植后达完全缓解。中位随访时间 15个月 ,无病生存 8例。认为 allo- HSCT是治疗恶性血液病 (尤其是耐药复发者 )的有效方法 ,ABO血型不合及乙肝供者不是移植的障碍     

伊曲康唑在异基因造血干细胞移植患者真菌感染中的应用

目的观察伊曲康唑治疗异基因造血干细胞移植患者的真菌感染的疗效。方法2002年10月至2005年10月诊断真菌感染的患者75例,其中确定诊断4例,临床诊断22例,拟诊49例。全部病例均于诊断后给予伊曲康唑注射液治疗,125～200mg／次,第1、2天给予2次／d,以后1次／d,病情稳定后改为口服胶囊或口服液治疗。结果总有效率为76．0％（57／75）;确诊病例3例有效（3／4）、临床诊断病例有效率为81．8％（18／22）、拟诊病例为73．5％（36／49）。临床诊断病例和拟诊病例的疗效之间差异无统计学意义（P=0．446）。结论伊曲康唑治疗异基因造血干细胞移植患者的真菌感染是有效的。     

同基因造血干细胞移植治疗白血病的临床疗效

目的探讨同基因造血干细胞移植（syn—HSCT）治疗白血病的疗效。方法对1例慢性髓性白血病一慢性期及1例急性髓性白血病M2型的患者进行了syn—HSCT的外周血干细胞移植,分别采用改良的马利兰／环磷酰胺及环磷酰胺／全身放疗方案作为预处理,未采用预防移植物抗宿主病（GVHD）措施。结果2例患者移植后造血恢复顺利,中性粒细胞绝对数（ANC）〉0．5×10^9／L时间分别为移植后8天和13天,血小板〉20×10^9／L时间分别为移植后8天和14天。移植后均未发生急性和慢性GVHD。分别随访至移植后12月和60月,慢性髓性白血病患者在骨髓细胞学及染色体水平完全缓解,在低BCL／ABL融合基因水平带病生存,急性髓性白血病M2型患者病情处于持续完全缓解状态,仍在继续随访中。结论Syn—HSCT相关并发症少,移植相关病死率低,复发率并不高,可能存在同基因移植物抗白血病作用,是治疗白血病的有效方法。     

异基因造血干细胞移植治疗白血病20例临床观察

目的探讨不同类型异基因造血干细胞移植(allo-HSCT)治疗白血病的疗效、造血重建及存活情况。方法哈尔滨血液病肿瘤研究所2003年3月至2006年7月进行异基因造血干细胞移植的白血病患者20例,其中同胞间人类白细胞抗原(HLA)相合的异基因外周血造血干细胞移植(allo-PBSCT)12例,无亲缘关系HLA不全相合脐血移植(UCBT)4例,无关供者的异基因外周血干细胞移植(其中1例HLA-CW位点亚型不合)3例,无关供者骨髓移植1例(经过去除红细胞处理)。结果19/20受者获造血重建,UCBT患者造血重建速度较HLA相合的同胞allo-PBSCT慢,异基因造血干细胞移植后20例患者中发生急性移植物抗宿主病(aGVHD)7例,其中4例Ⅰ~Ⅱ度,3例Ⅲ~Ⅳ度。3例患者死于复发,3例死于移植物抗宿主病(GVHD),另15例至今仍无病存活,中位存活时间30(1~41)个月。结论allo-HSCT是目前治愈白血病的有效方法,对于无同胞HLA相合的供者,选择较高细胞数量,HLA1~2个位点不合的UCBT仍然有效、可行。     

造血干细胞移植后肺部感染的诊治进展

自19世纪60年代末期第1例造血干细胞移植成功以来,造血干细胞移植为血液系统疾病、实体肿瘤、遗传和代谢性疾病提供了一种重要的治疗方式。但移植后感染性并发症很常见,尤其肺部感染具有较高的发病率和病死率。本文即对造血干细胞移植后肺部感染的诊治特点作一综述。     

异基因造血干细胞移植治疗高危恶性血液病

目的 分析HLA配型相合同胞供者异基因造血干细胞移植（allo-HSCT）治疗高危恶性血液病的疗效及影响疗效的相关因素。方法 回顾性分析90例有高危因素的恶性血液病患者,其中急性髓细胞白血病（AML）43例,急性淋巴细胞性白血病（ALL）28例,急性混合细胞性白血病（AHL）2例;移植前处于第1次完全缓解期（CR1）11例,均为Ph染色体阳性,第二次及以上CR期23例,未缓解／复发39例;骨髓增生异常综合征（MDS）-难治性贫血伴原始细胞增多或难治性贫血伴原始细胞增多一转化型17例。预处理方案采用全身照射加环磷酰胺（CY／TBI）方案11例,白消安加环磷酰胺方案79例。干细胞来源包括骨髓移植（BMT）27例,外周血造血干细胞移植（PBSCT）30例,BMT＋PBSCT33例;移植物抗宿主病（GVHD）预防采用经典环孢素A加短程甲氨蝶呤（MTX）。平均随访时间为15个月。结果 至随访终点,62．2％（56／90）存活,55．5％（50／90）无病存活,31．1％（28／90）复发。HSCT后预计4年累积总体生存率（OS）为45．5％,无病生存率（DFS）为34．9％。移植前处于CR、未缓解／复发和MDS患者HSCT后4年的累积0s分别为54．0％、28．2％和70．1％（P=0．027）。发生0～Ⅰ和Ⅱ～Ⅳ度GVHD的患者HSCT后的4年OS分别为57．6％和26．7％（P=0．015）,而患者性别、年龄、移植前有无脑膜白血病、预处理方案、干细胞来源均不是OS,DFS及复发的影响因素。多因素分析表明,移植前处于CR期者长期生存率明显提高,而ALL长期生存率明显低于AML／MDS。结论 对有高危因素的血液系统恶性肿瘤患者,选择allo—HSCT可使部分患者延长无病生存乃至根治。移植前处于CR期者长期生存率明显提高,ALL复发率明显高于AML／MDS。对于急性白血病挽救性治疗争取在取得CR后移植;对于MDS患者一经诊断,无需化疗,可尽早移植。     

造血干细胞移植并发肝静脉闭塞症23例

肝静脉闭塞症（HVOD）是造血干细胞移植（HSCT）后一种严重且危险的并发症，一般表现为移植后3周内即出现黄疸、肝肿大、肝区疼痛、腹腔积液及液体潴留和不明原因的体重增加。现将我院240例HSCT患者中并发HVOD23例报道如下。     

造血干细胞移植后人疱疹病毒6的感染

造血干细胞移植(HSCT)是治愈血液系统恶性疾病的有效手段,移植后病毒感染是导致移植失败和患者致死的主要原因之一.人疱疹病毒6型(HHV-6)是最近发现的一种新型疱疹病毒,在人群中的感染率非常高,初次感染后潜伏在人体内,当患者免疫功能受到抑制时,病毒再激活并导致一系列威胁生命的并发症.本文综述了HHV-6的生物学特征、对造血干细胞移植产生的可能影响及其治疗.     

造血干细胞移植的肺部并发症

造血干细胞移植(HSCT)目前已广泛应用于临床,为血液系统肿瘤及实体肿瘤,免疫性及遗传性疾病患者带来了生存的希望.但HSCT术后肺部并发症时常发生.本文就HSCT术后可能发生的肺部并发症的发病因素、诊断及治疗方面作一综述.     

异基因造血干细胞移植治疗恶性血液病

目的：探讨异基因造血干细胞移植(Allo—HSCT)治疗恶性血液病的疗效、造血重建、免疫重建及长期生存的情况。方法：血液系统恶性疾病患者12例，其中同胞HLA相合异基因骨髓移植(Allo-BMT)及外周血干细胞移植(Allo—PBSCT)7例；无亲缘关系HLA不全相合脐血移植(UCBT)5例。结果：11／12例受者获造血重建，UCBT患者造血重建速度较同胞PBSCT或BMT慢，1例UCBT移植后46d造血功能未重建，回输自体骨髓后恢复自体造血。11例Allo—HSCT受者免疫功能重建开始于移植后30d，死亡2例，均为移植后复发病例。结论：Allo—HSCT是目前治愈恶性血液病的最佳方法，对于无同胞HLA相合的供者，选择较高细胞数量、HLA1～2个位点不合的UCBT仍然安全有效。     

异基因造血干细胞移植后肺部侵袭性真菌感染现行诊断标准的应用价值

  目的 分析我国现行血液病/恶性肿瘤患者侵袭性真菌感染诊断标准的可操作性,提高对异基因造血干细胞移植（allo-HSCT）后肺部侵袭性真菌感染特点的认识。方法 回顾性分析连续收治的51例allo-HSCT后肺部侵袭性真菌感染病例的临床特点。结果 肺部侵袭性真菌感染共占同期收治allo-HSCT后肺部感染病例的42.1%（51/121）。确诊1例（2.0%）,临床诊断24例（47.1%）,拟诊26例（51.0%）。使用免疫抑制剂、糖皮质激素和存在移植物抗宿主病为主要宿主因素。2种或2种以上宿主因素同时存在的病例占66.7%(34/51)。94.1%(48/51)病例的肺部高分辨CT表现为结节和（或）斑片影。真菌抗原检测阳性率相对较高［(1,3)-β-D葡聚糖（G）试验阳性率58.6%,半乳甘露聚糖（GM）试验阳性率33.3%］。20例（39.2%）患者伴有动脉血氧分压和氧饱和度下降。结论 使用免疫抑制剂、糖皮质激素和存在移植物抗宿主病为主要宿主因素,肺部高分辨CT表现以结节和（或）斑片影多见,真菌抗原检测是支持临床诊断的主要因素。     

Mesenchymal stem cells for the treatment of refractory pure red cell aplasia after major ABO-incompatible hematopoietic stem cell transplantation

Pure red cell aplasia (PRCA) is a well-known, although infrequent, hematological complication after allogeneic hematopoietic stem cell transplantation (HSCT). PRCA occurs in cases of major ABO mismatch between donor and recipient and is believed to be due to inhibition of donor erythroid progenitors by residual host isohemagglutinins. The purpose of our study was to further evaluate the efficacy of human adipose tissue-derived mesenchymal stem cells (AMSC) as the salvage therapy for refractory PRCA after major ABO-incompatible HSCT. Two patients with refractory pure red cell aplasia received intravenous infusions of AMSC at a dose of 1.5 × 10⁶/kg of the patients’ weight, and rapid recovery from PRCA without any side effects was observed. We conclude that AMSC seems to be a promising therapeutic option in patients with PRCA after ABO-mismatched HSCT, in whom conventional treatment fails.     

Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation

Despite the refinements in molecular methods for the detection of cytomegalovirus (CMV) and the advent of highly effective preemptive strategies, CMV remains a leading cause of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. CMV can cause tissue-invasive disease including pneumonia, hepatitis, colitis, retinitis, and encephalitis. Mortality in HCT recipients with CMV disease can be as high as 60%. CMV infection has been associated with increased risk of secondary bacterial and fungal infections, increased risk of graft-versus-host disease, and high rates of non-relapse mortality following HCT. The risk of CMV is highly dependent on the donor (D) and the recipient (R) serostatus (D⁻/R⁺ > D⁺/R⁺ > D⁺/R⁻ > D⁻/R⁻). Among allogeneic HCT recipients, high-dose corticosteroids, T-cell depletion, graft-versus-host disease, and mismatched or unrelated donors constitute the main predisposing factors. However, not all seropositive individuals with these risk factors develop CMV, which strongly suggests that host factors, such as those regulating CMV-specific T-cell responses, play a major role in predisposition to CMV in HCT recipients. Here, we discuss emerging concepts in CMV infection in HCT with emphasis on immunological factors that govern CMV reactivation and the applicability of immune monitoring to understand correlates of pathogenesis and its potential to guide clinical decision making.     

异基因造血干细胞移植后严重环孢素A相关神经毒性的临床分析

目的分析严重环孢素A（CsA）相关神经毒性（SNCT）在异基因造血干细胞移植（allo-HSCT）后患者中的发病率、临床表现、影像学特征及其影响因素。方法统计我院2003年1月至2006年6月164例接受allo-HSCT的恶性血液病患者,调查内容包括：SNCT的前驱症状、临床特征,SNCT与CsA血浓度、年龄、移植方式、HIJA配型、预处理方案、抗人胸腺细胞球蛋白（ATG）的应用及治疗急性移植物抗宿主病（GVHD）时静脉用糖皮质激素的关系。结果7．93％（13／164）患者出现SNCT,其中癫痫8例,瘫痪6例,昏迷2例,小脑共济失调3例,类线粒体脑肌病1例。13例患者在出现SNCT前均有前驱症状,其中8例表现为头痛,4例烦躁,6例血压升高。行头颅MRI检查的患者中91,67％（11／12）发现皮层或皮层下白质异常信号;6例行CT检查均未发现异常。经CsA减量或停药后,10例获得完全恢复,2例部分恢复,1例死亡。单因素logistic回归分析显示：CsA血浓度、HLA配型、移植方式、应用ATG和治疗急性GVHD时静脉用糖皮质激素与SNCT的关系有统计学意义;多因素分析显示,CsA血浓度和ATG与SNCT的关系差异有统计学意义,危险度分别为（1．007,OR=1．007．P=0．006）和（6．727,OR=6．727,P=0．030）。结论allo—HSCT后91．67％SNCT患者存在头颅MRI异常,高CsA血浓度和防治GVHD时ATG使用能增加SNCT发生的危险度。     

Trends in hematopoietic stem cell transplant activity in Lebanon

Hematopoietic stem cell transplantation (HSCT) has been accessible to the population residing in Lebanon and surrounding countries since 1997. HSCT programs were developed in two major hospitals in Beirut: American University of Beirut Medical Center (AUBMC) and Makassed General Hospital. Mount Lebanon Hospital initiated an autologous HSCT activity later. Between 2012 and 2016, the HSCT activity in Lebanon reached a total of 897 transplants, among which 303 (33.8%) were allogeneic HSCT and 594 (66.2%) were autologous HSCT. Overall, autologous HSCT activity has remained stable over the past 5 years, whereas allogeneic HSCT activity has seen a steep increase between 2012 and 2013 followed by a modest increase later. Haploidentical transplantation has mushroomed and represented almost half of allogeneic HSCT activity in 2016. AUBMC and Makassed General Hospital are members of the European Blood and Marrow Transplantation (EBMT) and East Mediterranean Blood and Marrow Transplantation groups, and AUBMC has been accredited by JACIE (Joint Accreditation Committee – ISCT & EBMT) since 2016. The past 5 years have seen an increase in HSCT-related research and publications, mainly from AUBMC. These research activities were predominantly focused on personalized conditioning for allogeneic HSCT and post-transplant maintenance therapy.     

Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between 1991 and 2000

To examine shifts in the etiology, incidence, evolution, susceptibility, and patient mortality of bacterial and fungal bloodstream isolates (BSIs) from hematopoietic stem cell transplantation (HSCT) recipients, we reviewed the BSIs of 796 patients who underwent an HSCT in our institution during a 10-year period. Four hundred eighty-nine episodes of bacterial and fungal BSI were detected in 330 patients (41%). Three hundred ten isolates (63%) were gram-positive bacteria, 142 (29%) were gram-negative, and 18 and 19 isolates were different species of anaerobic organism and Candida spp. (both 4%). Coagulase-negative staphylococci (CoNS), with 210 isolates, were the organism most frequently isolated in each year of study and during the three phases of immune recovery after HSCT. The ratio of gram-positive to gram-negative has declined from 3.3 (1991–1992) to 1.8 (1999–2000). Crude mortality occurred in 47 cases of 489 BSI episodes (10%). Mortality according to groups was gram-negative, 7%; gram-positive, 9%; and anaerobic bacteria, 11%. Candida spp. was the group that accounted for the highest crude mortality, with 42%. Gram-positive microorganisms were isolated more often than gram-negative organisms, but the trend is reversing. CoNS were the leading pathogen during the 10 years of study and during the three phases of immune recovery after HSCT. Crude mortality of HSCT patients with BSI was low except for infections caused by Candida spp.Disclosures. Conflict of interest: none. Redundant publications: no substantial overlapping with previous papers. This study was presented at the 43rd ICAAC (K-1370).