The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long-term outcomes

Nishikawa T, Inagaki J, Nagatoshi Y, Fukano R, Nakashima K, Ito N, Sawa D, Kawano Y, Okamura J. The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long‐term outcomes. Abstract: The impact of a second all‐SCT on the long‐term outcomes of children who relapse after allo‐SCT has been unclear. We retrospectively analyzed the long‐term outcomes of different salvage treatments for such children. Sixty‐six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo‐SCT received either a second allo‐SCT (n = 16) or CTx and/or DLI (n = 50). The median follow‐up for all children was 9.1 yr. The five‐yr OS after relapse was significantly better in patients who underwent a second allo‐SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight‐yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo‐SCT, two died more than five yr after the second allo‐SCT. A second allo‐SCT can therefore lead to a prolonged OS in patients who relapse after allo‐SCT. However, a second allo‐SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo‐SCT.     

Chemoprophylaxis of neonatal fungal infections in very low birthweight infants: efficacy and safety of fluconazole and nystatin

Aim: To review the use of antifungal chemoprophylaxis to prevent neonatal invasive fungal infections (IFI) in very low birthweight infants (VLBW <1500 g). Method: Systematic review of randomised controlled trials. Results: Nine trials were identified (2029 infants), with six comparing fluconazole with placebo/no treatment (840 infants), three comparing nystatin with placebo/no treatment (1200 infants) and two comparing fluconazole and nystatin (257 infants). Prophylactic fluconazole reduced the incidence of IFI in VLBW infants <1500 g to 5.1% compared with 16.0% in infants receiving placebo, relative risk (RR) = 0.36 (95% confidence interval 0.15–0.89). The mortality was 10.9% and 16.7%, respectively (RR 0.76, 0.54–1.08). Oral nystatin reduced the incidence of IFI in VLBW infants to 5.3% compared with 28.0% in infants receiving placebo (RR 0.16, 0.11–0.23). Mortality was 7.5% with nystatin and 10.9% with placebo (RR 0.86, 0.59–1.26). The incidence of IFI in studies comparing fluconazole and nystatin was 3.6% and 8.0%, respectively (RR 0.54, 0.19–1.56), and mortality was not significantly different: 4.6% versus 9.8% (RR 0.43, 0–4.31) Conclusions: Prophylactic fluconazole and oral nystatin are both highly effective in preventing IFI in VLBW infants. Both agents are safe without significant toxicities. Antifungal prophylaxis should therefore be used in all VLBW infants. Given the paucity of data comparing fluconazole with nystatin, the choice of antifungal agent should be influenced by the incidence of IFI, local epidemiology and relative cost.     

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目的探讨血液病患儿侵袭性真菌感染联合药物治疗组合及疗效。方法 2006年1月至2011年4月在中山大学孙逸仙纪念医院就诊的血液病合并侵袭性真菌感染并予以联合治疗患儿39例,对患儿的临床资料及治疗效果进行回顾性分析。结果联合抗真菌药物治疗者共48例次,其中拟诊11例次,临床诊断32例次,确诊5例次。两性霉素B联合卡泊芬净18次,无效3次;两性霉素B联合伊曲康唑静脉13次,口服4次,均有效;两性霉素B联合伏立康唑9次,无效1次;卡泊芬净联合伊曲康唑6次,无效1次;卡泊芬净联合伏立康唑5次,均有效;伊曲康唑联合制霉菌素1次,有效。完全缓解27例,部分缓解7例,放弃1例,恶化死亡4例。三唑类联合两性霉素B或卡泊芬净与两性霉素B联合卡泊芬净相比,效果差异无统计学意义(P>0.05)。结论 免疫功能明显抑制、既往侵袭性真菌感染且再次接受强化疗或造血干细胞移植、严重或突破性真菌感染、单药治疗失败或毒副反应大、合并移植物抗宿主病患儿的联合治疗疗效较满意。三唑类联合两性霉素B或卡泊芬净与两性霉素B联合卡泊芬净均可作为联合用药选择。     

Prophylaxis and therapy using liposomal amphotericin B (AmBisome) for invasive fungal infections in children undergoing organ or allogeneic bone-marrow transplantation

Sixty-one children with a median age of 6 years (range 1-16) were given prophylaxis/therapy for 78 courses of treatment with liposomal amphotericin (AmBisome) and were reviewed retrospectively. Thirty-six received allogeneic bone marrow, 22 a liver transplant, 2 kidneys and 1 a liver and kidney. AmBisome was given as prophylaxis in 30 episodes, as treatment for suspected invasive fungal infections (IFI) in 33 and for a verified IFI in 15. AmBisome prophylaxis was given for a median of 14 days in a dose of 1 mg/kg/day. The median dose of AmBisome was 2.1 mg/kg/day (range 0.9-5.0). The median duration of therapy was 10 days in children with suspected IFI and 20 days in children with verified IFI. The total dose ranged from 0.025 g up to a maximum of 3.95 g. Proven and probable side effects of AmBisome were a decrease in the level of serum potassium (30/78 cases), renal toxicity (22), an increase in the alkaline phosphatases (24), back pain (2), fever and abdominal pain (2), anaphylactic reaction (1), an increase in the bilirubin level (1), nausea (1), chest pain (1) and fever (1). Of 31 children with suspected IFI, fever disappeared in 21 (68%). In 14 verified or suspected IFI cases treated for 5 days or more, the clinical cure rate was 12 (86%). Eradication of fungi from a deep site was verified in 8/10 and the survival rate from 1 1/2 years to more than 7 years was 7/12 (58%). We conclude that AmBisome was well tolerated as prophylaxis and therapy in transplanted children, few acute toxic side effects were seen and the cure rate in verified IFI was high.     

儿童重症监护病房侵袭性真菌感染38例临床分析

目的：探讨儿童重症监护病房（PICU）侵袭性真菌感染（IFI）的临床特征,为其有效防治提供依据。方法：回顾性分析38例IFI患儿的临床特征及治疗转归情况。结果：38例患儿中,以呼吸道感染最多见（89%）;感染前均有较严重的基础疾病,且使用过多种抗生素,其中碳青霉烯类抗生素使用率高达95%;47%患儿曾全身激素治疗;所有患儿均有侵入性操作史,其中47%患儿接受过气管插管及机械通气治疗;所有患儿临床症状及体征不典型,影像学检查无特异性。真菌培养共检出致病真菌56株,以白色念珠菌为主（41%）,其次为曲霉菌（25%）和毛霉菌（20%）;所有患儿及时予以高效抗真菌药物治疗,治愈15例,好转16例,有效率为82%,不良反应发生率为16%。结论：呼吸道为最常见IFI感染部位;白色念珠菌为主要病原;多数患儿有严重基础疾病、广谱抗生素及糖皮质激素的使用史和侵入性操作史;早期诊断、及时使用高效抗真菌药物可改善预后。     

Invasive fungal infections in pediatric patients with hematologic malignancies receiving oral amphotericin B solution and early intravenous administration of fluconazole

This study aimed to determine the frequency of invasive fungal infection (IFI) in pediatric patients with hematologic malignancy who received amphotericin B oral suspension and early intravenous fluconazole during the neutropenic phase as prophylaxis for IFI. Records of 743 neutropenic episodes induced by cytotoxic chemotherapy between 1997 and 2008 were retrospectively reviewed to determine risk factors for and frequency of IFI. The overall frequency of IFI was 0.8% (n=6) and frequencies of proven, probable, and possible infections were 0.3% (n=2), 0.4% (n=3), and 0.1% (n=1), respectively. During 351 episodes of profound neutropenia (neutrophil count <500/μL for ≥ 14 d), overall incidence of IFI was 1.71% (n=6). Pulmonary aspergillosis was the most common causative agent, and no patients showed candidemia, or hepatosplenic candidiasis. Cytotoxic chemotherapy regimens for acute myelogenous leukemia and profound neutropenia were significantly associated with IFI (P=0.004 and P=0.009, respectively). No IFI-attributable deaths or breakthrough fungal infections occurred. Our results indicate that amphotericin B oral solution and early intravenous fluconazole may be effective in reducing the incidence and mortality of IFI in pediatric patients with hematologic malignancies.     

血浆1,3-β-D葡聚糖检测对儿童侵袭性真菌感染诊断价值

目的 评价血浆1,3-β-D葡聚糖（BG）检测（G试验）对儿童侵袭性真菌感染（IFI）的诊断价值。方法 回顾性分析2008年1月至2011年8月在首都医科大学附属北京儿童医院住院,抗生素应用时间>10 d,并行G试验患儿的临床资料,排除拟诊IFI者。根据IFI诊断标准,将研究对象分为IFI组和非IFI组。G试验测定采用GKT-5M Set动态真菌检测试剂盒,血浆BG浓度≥10 pg·mL-1判定G试验阳性。采用四格表计算G试验诊断IFI的敏感度、特异度、阳性预测值和阴性预测值。对G试验结果进行受试者特征工作曲线（ROC曲线）分析,并计算曲线下面积。结果 研究期间共有525例患儿行G试验,排除拟诊IFI者129例,最终396例患儿纳入分析。IFI组43例,非IFI组353例。IFI组G试验阳性31/43例,阳性率为72.1%;阴性12/43例,假阴性率为27.9%。非IFI组G试验阳性48/353例,假阳性率为13.6%。G试验诊断IFI的敏感度、特异度、阳性预测值和阴性预测值分别为72.1%、 86.4%、39.2%和96.2%。根据G试验结果绘制ROC曲线,曲线下面积为0.815（95%CI：0.732~0.898）。结论 G试验对儿童IFI具有中等诊断价值。适当提高诊断界值或连续监测可很大程度消除假阳性。     

Vincristine disposition in children with acute lymphoblastic leukemia

Vincristine (VCR) has been widely used to treat childhood malignancies for over thirty years, but its plasma disposition has not yet been well-defined. Therefore, we conducted a pharmacokinetic study of VCR in 17 children with acute lymphoblastic leukemia (ALL) receiving the first dose of VCR. A new high-performance liquid chromatographic assay was used for the measurement of VCR in plasma. A two-compartment pharmacokinetic model was fit to the data by nonlinear least-squares regression. Estimated pharmacokinetic parameters were highly variable; mean (S.D.) volume of distribution at steady-state was 360 (176) L.m^?2; total body clearance was 431 (238) ml. min^?1.m^?2, and elimination half-life was 823 (390) min. These results were compared to data from eight adults with lung cancer. Mean volume of distribution in adults and children were similar, but VCR clearance was significantly larger in children (P = 0.01), resulting in a significantly longer elimination half-life in the adults (P < 0.01). We conclude that administration of a standard dosage of VCR to children with ALL results in a highly variable systemic drug exposure, which may have implications for the oncolytic effect and/or toxicity in individual patients. Comparison of data from children and adults suggests that VCR elimination rate is a function of age; this could account for more severe neurotoxicity in older patients. However, it cannot be excluded that differences between the children and adults may be due to other variables than age. Future studies should focus on the possible influence of multidrug resistance modulating agents on VCR pharmacokinetics and on pharmacokinetic-pharmacodynamic relationships in individual patients. © 1995 Wi1ey-Liss Inc.     

长春新碱对激素依赖型肾病综合征的治疗

目的：目前对于激素依赖型肾病综合征的治疗仍较困难,我们回顾性地评价了长春新碱对用过环磷酰胺治疗后而仍有复发的激素依赖型肾病综合征患儿的治疗效果。方法：14例口服过一个疗程以上环磷酰胺而仍有复发的激素依赖型肾病综合征患儿接受了长春新碱治疗。长春新碱的用法为每周静脉注射1次,连用4周,然后每月1次,连用4月,每次剂量为1~1.5 mg/m2。结果：13例完成了长春新碱的整个疗程。正处于肾病复发期的8例患儿,6例(75%)完全缓解,蛋白尿在用长春新碱治疗2~3剂后消失。在疗程结束后对处于肾病缓解状态的12例患儿随访,发现4例(33.3%)未再复发,持续保持缓解9~40月(中位数为13.5月);半年内的肾病复发次数由治疗前的1.67次降至0.67次(P<0.05);8例再复发者,7例再次注射长春新碱(1 mg/m2)1~2剂后蛋白尿均消失。除用1.5 mg/m2剂量时腹痛较显著外患儿未出现其他明显副作用。结论：长春新碱能诱导激素依赖型肾病综合征复发患儿的完全缓解,还有可能降低复发频率。对于再复发患儿,少数几次长春新碱的使用可能优于口服一个疗程的泼尼松龙或环孢素。[中国当代儿科杂志,2005,7(6):495-498]     

Conidiobolomycosis in relapsed acute lymphoblastic leukemia

Invasive fungal infections in immunocompromised children suffering from hematological malignancies have been a major cause of morbidity and mortality. In recent years fungi other than aspergillus and candida are gaining importance. These emerging fungal infections have distinct epidemiological features and management issues especially in immunocompromised patients. Here we report the isolation of Conidiobolus coronatus, a rarely reported zygomycetes infection in a patient suffering from acute lymphoblastic leukemia. Conidiobolus generally causes indolent infection in the sino‐respiratory tract. They are known to be angioinvasive and can disseminate. There is no consensus regarding appropriate antifungal treatment for Conidiobolus infection. Pediatr Blood Cancer 2009; 53:1321–1323. © 2009 Wiley‐Liss, Inc.     

Fungal brain abscesses in leukemia

Invasive fungal infections remain a life threatening complication in children with hematological malignancies. The brain represents a common site of hematogenously disseminated infections from an extracranial focus. We report our experience in the diagnosis, radiological aspects and therapeutic approach of fungal brain abscesses in 2 children receiving chemotherapy for acute lymphoblastic leukemia (ALL).     

Invasive fungal infections in pediatric heart transplant recipients: incidence, risk factors, and outcomes

There are limited data on the incidence or risk factors for IFI in pediatric heart transplant recipients. The purpose of this study was to describe the incidence and types of IFI, to determine risk factors for outcomes of IFI, and to assist in decision-making concerning the need for prophylactic strategies in pediatric heart transplant recipients. Data from a multi-institutional registry of 1854 patients transplanted between 01/93 and 12/04 were analyzed to determine risk factors and outcomes of children with IFI post-heart transplantation. One hundred and thirty-nine episodes of IFI occurred in 123 patients and made up 6.8% of the total number of post-transplant infections. IFI was most commonly attributed to yeast (66.2%), followed by mold (15.8%) and Pneumocystis jiroveci (13%). Ninety percent of the yeast infections were caused by Candida spp., and Aspergillus spp. was causative in 82% of the mold infections. There was a significantly increased risk of fungal infection associated with pretransplant invasive procedures (e.g., ECMO, prior surgery, VAD, mechanical ventilation) with an incremental risk with increasing numbers of invasive procedures (early phase 0 vs. 1, RR 1.3; 0 vs. 3, RR 2.3; p<0.001). In multivariate analysis, previous surgery (p=0.05) and mechanical support at transplantation (p=0.01) remained significant. Forty-nine percent of recipients with IFI died, all within six months post-transplant. Invasive fungal infections are uncommon in pediatric heart transplant recipients. Risk and mortality are highest in the first six months post-transplant especially in patients with previous surgery and those requiring mechanical support. Prophylactic strategies for high-risk patients should be considered and warrants further study.     

血浆β-葡聚糖检测儿童侵袭性真菌感染早期诊断价值探讨

目的:随着免疫受损个体生存期的延长,侵袭性真菌感染（invasive fungal infection, IFI）发病率持续上升。本研究目的在于了解儿童真菌感染高危人群并发IFI的发病情况,评价血液1,3-β-D葡聚糖(1,3-β-D-glucan, BG)（G试验）诊断价值。方法:选择2007年11月至2008年6月在我院儿童ICU、血液肿瘤科住院治疗的持续发热4~7 d以上高危感染患儿进行G试验;每周检测1～2次,直至症状好转,或排除真菌感染,或死亡。G试验采用GKT-5M Set动态真菌检测试剂盒检测,阳性定义为血浆BG水平≥10 pg/mL。结果:① 共计130例入选研究。确诊IFI（proven）2例,均为念珠菌血症。临床诊断（probable）20例,拟诊（possible）7例,排除101例;② IFI组住院天数较非IFI组延长（P＜0.05）,不良预后率明显增加（P＜0.05）;③ IFI组血浆BG水平高于非IFI组(P＜0.01）。G试验诊断敏感度81.8%,特异度82.4%,阳性预测值48.6%,阴性预测值95.7%;④72.2% 病例G试验阳性结果较培养或影像学阳性结果提前或同时发生。结论:儿童高危患者IFI不少见。血液G试验无衡量标准有助于高危患者的筛查,具有早期辅助诊断、指导合理治疗干预的价值。［中国当代儿科杂志,2009,11（11）：905-908］     

PICU侵袭性真菌感染现状

PICU侵袭性真菌感染（ invasive fungal infection,IFI）呈现逐年升高趋势。念珠菌和曲霉是最常见的病因,儿童重症侵袭性念珠菌感染（ ICI）发病率约为侵袭性曲霉感染（ IAI）的5倍。ICI和IAI归因死亡率有所不同,主要是基础疾病存在差异。既往健康的危重症患儿各种侵入性导管、静脉营养、血液透析、机械通气和长时间使用抗生素是ICI发病危险因素。实体肿瘤和白血病患儿使用免疫抑制剂、干细胞移植和广谱抗生素是发生IAI的高危因素。对高风险患儿采取针对性预防,早期识别IFI并予以抢先治疗,仍然是管理PICU危重症患儿的重要挑战。     

Idiopathic thrombocytopenic purpura in childhood: Twenty years of experience in a single center

Background: Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder with a variable clinical course. Methods: A retrospective analysis was carried out of ITP patients presenting to a pediatric hematology‐oncology department during a period of 20 years, with a focus on treatment and outcome. Results: One hundred and twenty‐four cases were recorded (mean patient age, 8.4 years). Forty‐nine children (39.5%) had platelet counts <10 000/µL at diagnosis. No episode of severe bleeding was observed. Peak incidence was observed during spring and summer. Respiratory infections proceeded in 58% of cases. Treatment consisted of i.v. immunoglobulin (IVIG) in 93 children at four dosing schedules. Sixteen children received corticosteroids, 10 children received anti‐D immunoglobulin and 14 received no treatment. Recovery was observed in 67% of children on IVIG and in 50% on anti‐D globulin. Eight patients did not respond initially and received corticosteroids. Three children with refractory thrombocytopenia received anti‐CD20 (rituximab). Fourteen children (11%) had persistent/chronic disease. In 10 of them recovery was observed in 13 months–8 years. Splenectomy was performed in six children with resistant/chronic disease. Conclusion: ITP has a benign course in the majority of cases. Anti‐D globulin can effectively be used as an alternative first‐line treatment. Rituximab can successfully be used in refractory cases, while splenectomy has currently limited indications.     

应用微滴式数字PCR技术快速诊断新生儿侵袭性真菌病

目的 探讨微滴式数字PCR（ddPCR）技术在快速、精确诊断新生儿侵袭性真菌感染（IFI）中的临床应用价值。方法 选择真菌高度保守序列18S rRNA为目标序列，通过引物设计，建立ddPCR检测真菌体系。在深圳一家医院新生儿重症监护室采集了有IFI高危因素和/或临床症状的83例患者血样（n=83），采用血培养及ddPCR法分别对血样进行真菌检测。结果 ddPCR检测真菌体系的特异性为100%，灵敏度可以达到3.2 copies/μL，重复性良好。临床试验中，22例确诊/临床诊断IFI患儿血样中，ddPCR检测阳性19例。61例拟诊/非IFI患儿血样中，ddPCR法检测结果有2例阳性。结论 初步证明ddPCR技术可用于新生儿IFI的检测，该技术是新生儿IFI筛查甚至诊断很有前途的工具。     

Prevention and monitoring of invasive fungal infections in pediatric patients with cancer and hematologic disorders

BACKGROUND: The occurrence of invasive fungal infection (IFIs) in a pediatric hematology/oncology unit after renovation of the ventilation system, and initiating routine azole antifungal prophylaxis was monitored. In addition, the value of serial screening for Aspergillus galactomannan (GM) for diagnosing invasive aspergillosis was assessed. PROCEDURE: A total of 98 consecutive high-risk pediatric patients were prospectively surveyed for signs of IFI and weekly monitored for serum GM. The data was not made available to treating physicians. RESULTS: Only 2 patients had proven and 27 possible IFI based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions. The incidence of proven IFI was 1/31 (3.2%) in the allogeneic stem cell transplant (SCT) (Aspergillus spp), 0/26 in the autologous SCT, and 1/60 (1.6%) in the induction therapy group (C. krusei). GM was detected at least in one tested sample in 12/98 patients (12.2%), in five patients in two or more sequential samples. In the latter group, IFI was proven in one patient and could not be excluded in the others. Four of the five patients belonged to the 31 allogeneic and one to the 26 autologous SCT patients. In patients with only one positive GM test none developed signs of IFI and only one received empirical amphotericin B. CONCLUSIONS: With the currently used preventative and prophylactic measures, IFI is uncommon in children with high-risk for infection. Regular screening for GM could be useful among allogeneic SCT patients and two positive samples should prompt further investigative procedures and pre-emptive antifungal therapy.     

Micafungin: A brief review of pharmacology,safety, and antifungal efficacy in pediatric patients

Invasive fungal infections are a major cause of morbidity and mortality in children with hematological malignancies and those undergoing allogeneic hematopoietic stem‐cell transplantation (HSCT). Although several new antifungal compounds recently became available, some are not yet approved for the use in the pediatric population. Among the new class of echinocandins, micafungin has been licensed in Europe and Japan for children including neonates. Because micafungin is well tolerated and exhibits few clinical relevant drug–drug interactions, the compound is of particular interest for prophylaxis and treatment of invasive mycoses in pediatric patients with cancer or following allogeneic HSCT. This review will focus on the currently available pediatric data of micafungin with emphasis on pharmacokinetics, efficacy, and safety. Pediatr Blood Cancer. 2010;55:229–232. © 2010 Wiley–Liss, Inc.     

儿童侵袭性真菌感染临床流行病学及早期实验室诊断进展

侵袭性真菌感染(IFI)逐年增多,成为儿科特别是重症医学临床难题之一.IFT常发生于新生儿和存在免疫功能障碍的儿童.念珠菌属、曲霉菌是儿童IFI的最常见两大病原菌.早期诊断可提高时的预后.对高危患儿采用1,3-β-D-葡聚糖(G)试验、半乳甘露聚糖抗原试验、分子生物学试验等能帮助早期发现IFI.     

血液肿瘤患儿合并侵袭性真菌感染研究进展

侵袭性真菌病(invasive fungal disease,IFD)已经成为血液肿瘤患儿致病和致死的重要原因.虽然白假丝酵母菌仍是目前儿童侵袭性真菌感染中最常见的致病真菌,但近年来非白假丝酵母菌所致感染和侵袭性曲霉菌感染有显著上升.早期治疗和及时的抗真菌治疗是控制IFD的关键.该文对血液肿瘤患儿合并IFD的诊断及治疗进行综述,以期为临床医生提供帮助.