异基因造血干细胞移植后侵袭性真菌感染危险因素分析及预防策略
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摘要
目的：IFI是HSCT后常见的严重并发症,其发病率有逐渐增高的趋势,已成为移植后最重要的死亡原因之一。近年来随着移植方式和预防策略的改变,HSCT后IFI的流行病学有了很大的变化,天然免疫基因多态性对IFI易感性所起的作用开始引起人们的关注,既往有IFI感染的患者极易在HSCT术后出现感染复发,针对此类患者的抗真菌二次预防能有效降低IFI复发风险,但对于最佳的预防用药以及用药持续时间,尚无统一的标准。
本研究对HSCT术后IFI进行回顾性分析,总结IFI流行病学的特点,分析导致IFI发生的危险因素,从基因水平寻找可能预测IFI的相关因素,并开展抗真菌治疗二次预防的临床研究,观察治疗的安全性和有效性,期望最终降低HSCT术后IFI发病率,提高HSCT患者的移植疗效。
第1章异基因造血干细胞移植术后侵袭性真菌感染的流行病学研究与危险因素分析
方法：我们对1998年11月至2009年12月在浙江大学医学院附属第一医院骨髓移植中心接受异基因造血干细胞移植(HSCT)的408例患者,进行观察分析,总结HSCT后IFI发病情况,病原菌分布,采用多因素分析判断危险因素。
结果：408例患者,男性251例,女性157例,中位年龄28岁(8-52岁),中位随访时间为28月(1-145月)。92例(22.5%)经病原学、临床症状及辅助检查等诊断或临床诊断为IFI(确诊4例,临床诊断88例)。移植后100天,6个月和1年的IFI累积发病率分别为6.83%,12.79%,20.48%。按HSCT移植后时间进行分类,早期IFI27例(30.4%),晚期IFI65例(69.6%),其中有43例发生在移植后+180天以后(45.7%)。念珠菌属仍是HSCT后早期IFI主要的致病菌,霉菌尤其是曲霉菌是极晚期IFI的主要病原菌。IFI与生存明显相关(P<0.001)。多因素分析显示：HLA配型不合、重度的aGVHD、持续粒缺>2周为早期IFI的危险因素；cGVHD,中大剂量糖皮质激素长期使用,CMV疾病为晚期IFI的危险因素,而移植前IFI病史阳性是发生移植后早期和晚期IFI的共同危险因素。
结论：本研究显示IFI与HSCT预后明显相关,HSCT后不同时期IFI病原菌分布及危险因素存在差异。临床应根据IFI病原学特点及HSCT后时间分布特点,采取不同的策略,更有针对性地用药及开始治疗,从而改善预后。
第2章供/受者天然免疫反应通路的基因多态性与异基因造血干细胞移植后侵袭性真菌感染的关系研究
方法：我们对2001年1月至2009年3月在浙江大学医学院附属第一医院骨髓移植中心接受allo-HSCT、在本中心标本库中储存有标本的患者及其干细胞供者,共240对,进行开展天然免疫基因TLRs的基因多态性与移植后IFI发生风险和移植疗效的关系研究,以期发现导致移植后IFI的个体差异性和高风险基因型。结果：99例(41.2%)患者经病原学、临床症状及辅助检查等确诊、临床诊断或拟诊发生移植后IFI。原发疾病为血液系统恶性肿瘤、移植后发生Ⅱ度以上急性GVHD(acute GVHD, aGVHD)或广泛性慢性GVHD (Chronic GVHD, cGVHD)是移植后IFI的危险因素。通过TLRs基因多态性与allo-HSCT后IFI发生风险的单因素分析,我们发现在5个TLRs基因的10个SNP位点中,TLR8基因的两个多态性位点(+1A/G,rs3764880；+354C/T,rs2159377)影响移植后IFI的发生率。供/患者的其他TLRs基因(TLR1, TLR2, TLR3, TLR9)的基因多态性对移植后IFI的发生风险均无明显影响。
结论：通过围绕天然免疫重要分子TLRs基因多态性与移植后侵袭性真菌感染发生风险的的关系研究,首次报道干细胞供者TLR8的基因型显著影响移植后侵袭性真菌感染发生风险,为建立基于干细胞供者和患者基因背景的移植前风险分层、真菌感染预警指标体系,并为无关供者中最佳供者选择、制定个体化的真菌感染预防和治疗方案提供依据。
第三部分抗真菌药物二次预防性应用对异基因造血干细胞移植后IFI预后影响的临床研究
方法：选取2008年至2009年在浙江大学医学院附属第一医院骨髓移植中心接受allo-HSCT的125例患者,对其中既往有IFI病史的患者在HSCT粒缺状态时予以伊曲康唑二次预防,以评估其疗效及安全性。
结果：125例患者,男性72例,女性53例,中位年龄25岁(9-48岁),中位随访时间为19.2月(1-39.5月)。29例(23.2%)经病原学、临床症状及辅助检查等确诊或临床诊断为IFI(确诊1例,临床诊断28例)。其中念珠菌16例,霉菌13例。IFI按HSCT移植后时间进行分类,早期IFI6例,晚期IFI23例,其中16例IFI发生于HSCT后180天。移植后100天,6个月,1年的IFI累积发病率为分别4.96%,11.08%,21.40%。感染相关死亡率及早期IFI发生率明显低于历史对照(P<0.05)。
结论：本研究显示对既往有真菌感染的患者在HSCT化疗后粒细胞缺乏期予以抗真菌感染的二次预防,能明显减低细胞期IFI的发生率。但对于晚期IFI的发生率无明显影响。
Objective:Invasive fungal infections are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). During the past2decades, changes in transplantation practices and strategies to diagnose and treat IFI have likely impacted the epidemiology of IFI. Polymorphism of genes, which take part in the allogeneic immune response after allo-HSCT, lead to allograft immunoreactivity differences between individuals. It also may affect IFI after transplantation.The risk of recurrence of fungal infection following allo-HSCT in patients with a previous history of IFI is high, effective secondary prophylaxis of IFI for patients undergoing allo-HSCT might significantly improve outcomes, including reduced transplant-related mortality. Nevertheless, lack of data from well designed prospective studies leaves questions such as the optimal treatment or duration of treatment unsettled.
We retrospectively analyzed the incidence of IFI after allo-HSCT to summarize the characteristics of the epidemiology of IFI, analysis of risk factor for IFI, look for related factors may predict IFI from gene level, and observe the safety and efficacy of secondary prophylaxis of IFI for patients undergoing allo-HSCT. The aim of the study is to reduce the incidence rate of IFI after allo-HSCT transplantation and improve the outcome of patients with allo-HSCT.
Part1Risk Factors and Epidemiology of Invasive Fungal Infection in allogeneic hematopoietic stem cell transplantation
Methods:We analyzed allo-HSCT recipients with a proven or probable IFI at our hospital during the period November1998through December2009. We summarized the incidence of IFI after HSCT, pathogen distribution, Univariate and multivariable analyses were used to evaluate the risk factors.
Results:A total of408allo-HSCT recipients were included in this study. The patients included251males and157females with a median age of28years (age range,8-52years), the median follow-up time was28months (1-145months).92(22.5%) patients with a proven or probable IFI after allo-HSCT(4patients were proven,88patients were probable). The cumulative incidence rate of IFI for100days,6months and1year was6.83%,12.79%,20.48%respectively. According to the time after allo-HSCT,27patients with early IFI (29.35%),65patients with late IFI (70.65%), of which43cases occurred in the+180days after allo-HSCT(66.15%). Candida is the most common pathogen of early IFI. Mould is the most common pathogen of late IFI. IFI was significantly associated with survival (P＜0.001).Multivariable analyses showed that previous history of IFI, HLA mismatched, neutrophil＜0.5×109/L more than2weeks, serious aGVHD as risk factors of early IFI after allo-HSCT, and previous history of IFI, treated with corticosteroids, CMV disease and cGVHD as risk factors of late IFI after allo-HSCT.
Conclusion:The results indicate that IFI after allo-HSCT was was significantly associated with survival. The distribution of pathogens and risk factors in different period after allo-HSCT is differences. According to characteristic of IFI after allo-HSCT, the importance of the optimal treatment strategies should be emphasized.
Part2Relationship between Gene Polymorphism of Recipient/Donor Immune Pathway and Invasive Fungal Infection after Allogeneic Hematopoietic Stem Cell Transplantation
Methods:We analyzed allo-HSCT recipients at our center during the period January2001through March2009. We analysis gene polymorphism of innate immune gene TLRs among240pairs of specimens of recipients and donors, in order to find out IFI individual difference and high risk genotype of IFI after transplantation.
Results:There were99patients (41.2%) occured IFI after allo-HSCT. Hematological malignant diseases, serious acute GVHD, and extensive chronic GVHD were risk factor for IFI after allo-HSCT. Univariate analysis of the relationship between risk factors of IFI after allO-HSCT and the TLRs gene polymorphism, we found that in the10SNP loci in5TLRs, two polymorphisms of TLR8gene,(+1A/G, rs3764880;+354C/T, rs2159377) effect the incidence of IFI after allo-HSCT. Other gene polymorphism of TLRs(TLR1,TLR2,TLR3, TLR9) had no significant effects on the risk of IFI after allo-HSCT.
Conclusion:The study of the relationship between the gene polymorphism of natural immune molecule TLRs and the risk factors after allo-HSCT showed that TLR8genotype of donor stem cell significantly influenced the incidence of IFI after allo-HSCT at the first time. It provide the evidence to establishment a fungal infection index system, which based on risk stratification of genetic background before transplantation of donors and recipients stem cell, and provide basis for selection of unrelated donor and prevention and treatment of IFI
Part3Secondary Prophylaxis of Invasive Fungal Infection in Allogeneic Hematopoietic Stem Cell Transplantation recipients
Methods:We analyzed allo-HSCT recipients at our center from2008to2009. The patients with previous proven or probable IFI treated with Itraconazole as secondary antifungal prophylaxis in allo-HSCT during agranulocytosis phase, and to evaluate its efficacy and safety.
Results:A total of125allo-HSCT recipients were included in this study. The patients included72males and53females with a median age of25years (age range,9-48years), the median follow-up time was19.2months (1-39.5months).29patients (23.2%) with a proven or probable IFI after allo-HSCT(1cases were proven,28cases were probable). According to the time after allo-HSCT, there were6patients of early IFI and23patiemts of late IFI, including16cases of IFI occurred in180days after HSCT. The cumulative incidence rate of IFI for100days,6months andl year was4.96%,11.08%,21.40%respectively.The incidence of early IFI and mortality were significantly lower than historical controls (P＜0.05).
Conclusion:This study shows that secondary prophylaxis for patients with previous proven or probable IFI can obviously reduce the incidence of IFI during agranulocytosis phase after allo-HSCT. The prevention strategies of late IFI should plan new attempt.
本研究对HSCT术后IFI进行回顾性分析,总结IFI流行病学的特点,分析导致IFI发生的危险因素,从基因水平寻找可能预测IFI的相关因素,并开展抗真菌治疗二次预防的临床研究,观察治疗的安全性和有效性,期望最终降低HSCT术后IFI发病率,提高HSCT患者的移植疗效。
第1章异基因造血干细胞移植术后侵袭性真菌感染的流行病学研究与危险因素分析
方法：我们对1998年11月至2009年12月在浙江大学医学院附属第一医院骨髓移植中心接受异基因造血干细胞移植(HSCT)的408例患者,进行观察分析,总结HSCT后IFI发病情况,病原菌分布,采用多因素分析判断危险因素。
结果：408例患者,男性251例,女性157例,中位年龄28岁(8-52岁),中位随访时间为28月(1-145月)。92例(22.5%)经病原学、临床症状及辅助检查等诊断或临床诊断为IFI(确诊4例,临床诊断88例)。移植后100天,6个月和1年的IFI累积发病率分别为6.83%,12.79%,20.48%。按HSCT移植后时间进行分类,早期IFI27例(30.4%),晚期IFI65例(69.6%),其中有43例发生在移植后+180天以后(45.7%)。念珠菌属仍是HSCT后早期IFI主要的致病菌,霉菌尤其是曲霉菌是极晚期IFI的主要病原菌。IFI与生存明显相关(P<0.001)。多因素分析显示：HLA配型不合、重度的aGVHD、持续粒缺>2周为早期IFI的危险因素；cGVHD,中大剂量糖皮质激素长期使用,CMV疾病为晚期IFI的危险因素,而移植前IFI病史阳性是发生移植后早期和晚期IFI的共同危险因素。
结论：本研究显示IFI与HSCT预后明显相关,HSCT后不同时期IFI病原菌分布及危险因素存在差异。临床应根据IFI病原学特点及HSCT后时间分布特点,采取不同的策略,更有针对性地用药及开始治疗,从而改善预后。
第2章供/受者天然免疫反应通路的基因多态性与异基因造血干细胞移植后侵袭性真菌感染的关系研究
方法：我们对2001年1月至2009年3月在浙江大学医学院附属第一医院骨髓移植中心接受allo-HSCT、在本中心标本库中储存有标本的患者及其干细胞供者,共240对,进行开展天然免疫基因TLRs的基因多态性与移植后IFI发生风险和移植疗效的关系研究,以期发现导致移植后IFI的个体差异性和高风险基因型。结果：99例(41.2%)患者经病原学、临床症状及辅助检查等确诊、临床诊断或拟诊发生移植后IFI。原发疾病为血液系统恶性肿瘤、移植后发生Ⅱ度以上急性GVHD(acute GVHD, aGVHD)或广泛性慢性GVHD (Chronic GVHD, cGVHD)是移植后IFI的危险因素。通过TLRs基因多态性与allo-HSCT后IFI发生风险的单因素分析,我们发现在5个TLRs基因的10个SNP位点中,TLR8基因的两个多态性位点(+1A/G,rs3764880；+354C/T,rs2159377)影响移植后IFI的发生率。供/患者的其他TLRs基因(TLR1, TLR2, TLR3, TLR9)的基因多态性对移植后IFI的发生风险均无明显影响。
结论：通过围绕天然免疫重要分子TLRs基因多态性与移植后侵袭性真菌感染发生风险的的关系研究,首次报道干细胞供者TLR8的基因型显著影响移植后侵袭性真菌感染发生风险,为建立基于干细胞供者和患者基因背景的移植前风险分层、真菌感染预警指标体系,并为无关供者中最佳供者选择、制定个体化的真菌感染预防和治疗方案提供依据。
第三部分抗真菌药物二次预防性应用对异基因造血干细胞移植后IFI预后影响的临床研究
方法：选取2008年至2009年在浙江大学医学院附属第一医院骨髓移植中心接受allo-HSCT的125例患者,对其中既往有IFI病史的患者在HSCT粒缺状态时予以伊曲康唑二次预防,以评估其疗效及安全性。
结果：125例患者,男性72例,女性53例,中位年龄25岁(9-48岁),中位随访时间为19.2月(1-39.5月)。29例(23.2%)经病原学、临床症状及辅助检查等确诊或临床诊断为IFI(确诊1例,临床诊断28例)。其中念珠菌16例,霉菌13例。IFI按HSCT移植后时间进行分类,早期IFI6例,晚期IFI23例,其中16例IFI发生于HSCT后180天。移植后100天,6个月,1年的IFI累积发病率为分别4.96%,11.08%,21.40%。感染相关死亡率及早期IFI发生率明显低于历史对照(P<0.05)。
结论：本研究显示对既往有真菌感染的患者在HSCT化疗后粒细胞缺乏期予以抗真菌感染的二次预防,能明显减低细胞期IFI的发生率。但对于晚期IFI的发生率无明显影响。
Objective:Invasive fungal infections are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). During the past2decades, changes in transplantation practices and strategies to diagnose and treat IFI have likely impacted the epidemiology of IFI. Polymorphism of genes, which take part in the allogeneic immune response after allo-HSCT, lead to allograft immunoreactivity differences between individuals. It also may affect IFI after transplantation.The risk of recurrence of fungal infection following allo-HSCT in patients with a previous history of IFI is high, effective secondary prophylaxis of IFI for patients undergoing allo-HSCT might significantly improve outcomes, including reduced transplant-related mortality. Nevertheless, lack of data from well designed prospective studies leaves questions such as the optimal treatment or duration of treatment unsettled.
We retrospectively analyzed the incidence of IFI after allo-HSCT to summarize the characteristics of the epidemiology of IFI, analysis of risk factor for IFI, look for related factors may predict IFI from gene level, and observe the safety and efficacy of secondary prophylaxis of IFI for patients undergoing allo-HSCT. The aim of the study is to reduce the incidence rate of IFI after allo-HSCT transplantation and improve the outcome of patients with allo-HSCT.
Part1Risk Factors and Epidemiology of Invasive Fungal Infection in allogeneic hematopoietic stem cell transplantation
Methods:We analyzed allo-HSCT recipients with a proven or probable IFI at our hospital during the period November1998through December2009. We summarized the incidence of IFI after HSCT, pathogen distribution, Univariate and multivariable analyses were used to evaluate the risk factors.
Results:A total of408allo-HSCT recipients were included in this study. The patients included251males and157females with a median age of28years (age range,8-52years), the median follow-up time was28months (1-145months).92(22.5%) patients with a proven or probable IFI after allo-HSCT(4patients were proven,88patients were probable). The cumulative incidence rate of IFI for100days,6months and1year was6.83%,12.79%,20.48%respectively. According to the time after allo-HSCT,27patients with early IFI (29.35%),65patients with late IFI (70.65%), of which43cases occurred in the+180days after allo-HSCT(66.15%). Candida is the most common pathogen of early IFI. Mould is the most common pathogen of late IFI. IFI was significantly associated with survival (P＜0.001).Multivariable analyses showed that previous history of IFI, HLA mismatched, neutrophil＜0.5×109/L more than2weeks, serious aGVHD as risk factors of early IFI after allo-HSCT, and previous history of IFI, treated with corticosteroids, CMV disease and cGVHD as risk factors of late IFI after allo-HSCT.
Conclusion:The results indicate that IFI after allo-HSCT was was significantly associated with survival. The distribution of pathogens and risk factors in different period after allo-HSCT is differences. According to characteristic of IFI after allo-HSCT, the importance of the optimal treatment strategies should be emphasized.
Part2Relationship between Gene Polymorphism of Recipient/Donor Immune Pathway and Invasive Fungal Infection after Allogeneic Hematopoietic Stem Cell Transplantation
Methods:We analyzed allo-HSCT recipients at our center during the period January2001through March2009. We analysis gene polymorphism of innate immune gene TLRs among240pairs of specimens of recipients and donors, in order to find out IFI individual difference and high risk genotype of IFI after transplantation.
Results:There were99patients (41.2%) occured IFI after allo-HSCT. Hematological malignant diseases, serious acute GVHD, and extensive chronic GVHD were risk factor for IFI after allo-HSCT. Univariate analysis of the relationship between risk factors of IFI after allO-HSCT and the TLRs gene polymorphism, we found that in the10SNP loci in5TLRs, two polymorphisms of TLR8gene,(+1A/G, rs3764880;+354C/T, rs2159377) effect the incidence of IFI after allo-HSCT. Other gene polymorphism of TLRs(TLR1,TLR2,TLR3, TLR9) had no significant effects on the risk of IFI after allo-HSCT.
Conclusion:The study of the relationship between the gene polymorphism of natural immune molecule TLRs and the risk factors after allo-HSCT showed that TLR8genotype of donor stem cell significantly influenced the incidence of IFI after allo-HSCT at the first time. It provide the evidence to establishment a fungal infection index system, which based on risk stratification of genetic background before transplantation of donors and recipients stem cell, and provide basis for selection of unrelated donor and prevention and treatment of IFI
Part3Secondary Prophylaxis of Invasive Fungal Infection in Allogeneic Hematopoietic Stem Cell Transplantation recipients
Methods:We analyzed allo-HSCT recipients at our center from2008to2009. The patients with previous proven or probable IFI treated with Itraconazole as secondary antifungal prophylaxis in allo-HSCT during agranulocytosis phase, and to evaluate its efficacy and safety.
Results:A total of125allo-HSCT recipients were included in this study. The patients included72males and53females with a median age of25years (age range,9-48years), the median follow-up time was19.2months (1-39.5months).29patients (23.2%) with a proven or probable IFI after allo-HSCT(1cases were proven,28cases were probable). According to the time after allo-HSCT, there were6patients of early IFI and23patiemts of late IFI, including16cases of IFI occurred in180days after HSCT. The cumulative incidence rate of IFI for100days,6months andl year was4.96%,11.08%,21.40%respectively.The incidence of early IFI and mortality were significantly lower than historical controls (P＜0.05).
Conclusion:This study shows that secondary prophylaxis for patients with previous proven or probable IFI can obviously reduce the incidence of IFI during agranulocytosis phase after allo-HSCT. The prevention strategies of late IFI should plan new attempt.
引文
[1]Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients,2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis 2010; 50:1091-1100.
[2]Upton A, Kirby KA, Carpenter P, et al. Invasive aspergillosis following hematopoietic cell transplantation:outcomes and prognostic factors associated with mortality. Clin Infect Dis 2007; 44(4):531—540.
[3]Neofytos D, Horn D, Anaissie E, et al. Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients:analysis of Multicenter Prospective Antifungal Therapy(PATH) Allianee registry. Clin Infect Dis 2009; 48:265-273.
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