Treatment of Invasive Pulmonary Aspergillosis in Severely Neutropenic Children with Malignant Disorders using Liposomal Amphotericin B (AmBisome), Granulocyte Colony-Stimulating Factor,and Surgery: Report of Five Cases

Five children with malignancies developed invasive pulmonary aspergillosis during chemotherapy-induced neutropenia. All patients were treated with liposomal amphotericin B and human recombinant granulocyte colony-stimulating factor. Two patients did not recover from bone marrow aplasia and died from organ-infiltrating fungal invasion. Two patients who recovered from bone marrow aplasia survived after surgery of the pulmonary lesions. The fifth patient had a complete resolution of invasive pulmonary aspergillosis after neutrophil recovery without surgical intervention. We conclude that not only the antifungal treatment but also the recovery of granulocytes are important in localizing invasive forms of Aspergillus infections in patients with profound immunosuppression.     

Treatment of Invasive Pulmonary Aspergillosis in Severely Neutropenic Children with Malignant Disorders using Liposomal Amphotericin B (AmBisome), Granulocyte Colony-Stimulating Factor, and Surgery: Report of Five Cases

Five children with malignancies developed invasive pulmonary aspergillosis during chemotherapy-induced neutropenia. All patients were treated with liposomal amphotericin B and human recombinant granulocyte colony-stimulating factor. Two patients did not recover from bone marrow aplasia and died from organ-infiltrating fungal invasion. Two patients who recovered from bone marrow aplasia survived after surgery of the pulmonary lesions. The fifth patient had a complete resolution of invasive pulmonary aspergillosis after neutrophil recovery without surgical intervention. We conclude that not only the antifungal treatment but also the recovery of granulocytes are important in localizing invasive forms of Aspergillus infections in patients with profound immunosuppression.     

Double invasive fungal infection and typhlitis in children with acute lymphoblastic leukemia

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.     

DOUBLE INVASIVE FUNGAL INFECTION AND TYPHLITIS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Invasive fungal infection is one of the major causes of morbidity and mortality in immunocompromised patients. The occurrence of two invasive fungal infections in one patient at the same time is quite rare. Here the authors report on two adolescent patients with acute lymphoblastic leukemia who developed combined invasive pulmonary aspergillosis and hepatosplenic candidiasis during chemotherapy. They were treated with liposomal amphotericin B, but one of them died due to massive pulmonary hemorrhage during recovery from neutropenia.     

Invasive esophageal aspergillosis associated with acute myelogenous leukemia: successful therapy with combination caspofungin and liposomal amphotericin B

Aspergillosis is one of the most common invasive fungal infections in patients with leukemia. In this patient group, this form of Aspergillus infection is a life-threatening condition with a mortality of 50-100%. The lungs are most often affected, but the esophagus can also be involved.The authors report the case of a child with leukemia who developed invasive esophageal aspergillosis. The condition was diagnosed by microscopic examination of endoscopic biopsy specimens. The patient was already receiving empirical liposomal amphotericin B when the diagnosis was made, so a second antifungal (caspofungin) was added to the regimen. This combination was successful. This case to demonstrates a case of successful treatment of invasive esophageal aspergillosis using combination therapy of liposomal amphotericin B and caspofungin.     

INVASIVE ESOPHAGEAL ASPERGILLOSIS ASSOCIATED WITH ACUTE MYELOGENOUS LEUKEMIA: Successful Therapy with Combination Caspofungin and Liposomal Amphotericin B

Aspergillosis is one of the most common invasive fungal infections in patients with leukemia. In this patient group, this form of Aspergillus infection is a life-threatening condition with a mortality of 50–100%. The lungs are most often affected, but the esophagus can also be involved.The authors report the case of a child with leukemia who developed invasive esophageal aspergillosis. The condition was diagnosed by microscopic examination of endoscopic biopsy specimens. The patient was already receiving empirical liposomal amphotericin B when the diagnosis was made, so a second antifungal (caspofungin) was added to the regimen. This combination was successful. This case to demonstrates a case of successful treatment of invasive esophageal aspergillosis using combination therapy of liposomal amphotericin B and caspofungin.     

非血液病患儿侵袭性肺曲霉病21例的诊断与治疗

目的 总结非血液病患儿侵袭性肺曲霉病(IPA)的诊断和治疗.方法回顾性分析2002年6月-2008年7月期间北京儿童医院确诊或临床诊断的21例非血液病患儿发生IPA的高危因素、临床和影像学表现、微生物学检查、病理学检查以及治疗和预后.结果 确诊5例,临床诊断16例,其中急件IPA 13例,慢性坏死性肺曲霉病8例.高危因素:确诊原发性免疫缺陷病6例,可疑原发性免疫缺陷病3例;使用广谱抗生素、糖皮质激素5例;有肺部基础疾病3例;白细胞减少1例;3例患儿无明显宿主因素.临床和影像学表现:所有患儿均有发热、咳嗽.所有的急性IPA患儿影像均可见双肺多发结节样或刚块状实变阴影,伴空洞形成,10例有"空气新月征".所有的慢性坏死性肺曲霉病患儿均可见单侧肺大叶实变伴有局部胸膜肥厚,实变区有空洞形成.微生物学检查:急性IPA和慢性坏死性肺曲霉病患儿痰和(或)支气管肺泡灌洗液培养的总阳性率分别为72.1%和22.4%.所有培养阳性的痰液和(或)支气管肺泡灌洗液直接涂片均发现有大量典型的曲霉菌丝.病理学检查:3例慢性坏死性肺曲霉病患儿行肺活检,病理学检查结果 均提示肺组织坏死,有肉芽肿性炎症,PAS染色找到曲霉菌丝和孢子.治疗和预后:15例采用两性霉素B、伏立康唑、伊曲康唑及卡泊芬净单用或联合应用,12例治疗有效;3例治疗无效死亡,该3例患儿均发生肺外播散.6例患儿未接受治疗,均死亡.两性霉素B的不良反应主要为寒战、高热、低钾血症和一过性的BUN升高.患儿对伏立康唑、卡泊芬净耐受性好,未发现明显不良反应.结论 发生于非血液病儿童的IPA绝大多数有高危因素或环境暴露史,影像学表现有相对的提示性.宿主(危险)因素和影像学表现是临床考虑IPA的重要线索,蕈复痰液病原学检查是临床诊断的关键.早期两性霉素B、伏立康唑、伊曲康唑单用或联合用药可控制病情.     

儿童急性白血病併发曲霉菌病的临床诊断和治疗——附7例临床病例报告

目的探讨儿童急性白血病患者曲霉菌感染,尤其是肺曲霉菌病的临床特点及其诊断和治疗。方法对我院血液肿瘤病房7例曲霉菌病进行回顾性分析,观察其发病时间、诱因,临床症状及X线、CT表现及治疗效果。通过血或痰等分泌物培养,X线及CT检查等诊断。所有粒细胞缺乏的发热患者积极抗生素治疗的基础上予大扶康预防或经验治疗,3~7天无效者改用两性霉素B。结果诊断曲霉菌肺炎6例,曲霉菌鼻窦炎2例(1例合并肺炎)。鼻窦炎1例鼻窦冲洗液培养为曲霉菌。另1例口唇坏死组织切片见大量菌丝及孢子。曲霉菌肺炎主要根据肺部CT特征性改变及治疗转归临床诊断。2例原发病未缓解者死亡,其它5例均经两性霉素B治疗好转。两性霉素B副作用主要有:寒战、高热、低钾血症及一过性肾功能损害,均无需停药。结论深部曲霉菌感染临床表现不典型,诊断困难,肺部CT检查对其早期发现、及早治疗有重要意义。曲霉菌肺炎典型CT改变为球形或团块状阴影,伴“晕轮征”或“新月征”。以胸膜为基底的楔形实变影提示发生致命性咯血的可能。两性霉素B疗效肯定,副作用可耐受。原发病的缓解及粒细胞恢复也是真菌感染能否治愈的重要因素。     

Antifungal agents for the treatment of systemic fungal infections in children

Traditionally, the mainstay of systemic antifungal therapy has been amphotericin B deoxycholate (conventional amphotericin B). Newer agents have been developed to fulfill special niches and to compete with conventional amphotericin B by virtue of having more favourable toxicity profiles. Some agents have displaced conventional amphotericin B for the treatment of specific fungal diseases. For example, voriconazole has emerged as the preferred treatment for invasive pulmonary aspergillosis. This notwithstanding, conventional amphotericin B remains a useful agent for the treatment of paediatric fungal infections. Knowledge of the characteristics of the newer agents is important, given the increasing numbers of patients who are being treated with these drugs. Efforts need to be directed at research aimed at generating paediatric data where these are lacking. The antifungal agents herein described are most often used as monotherapy regimens because there is no uniform consensus on the value of combination therapy, except for specific scenarios.     

儿童慢性肺曲霉菌病四例的诊断和治疗

目的 探讨儿童慢性肺曲霉菌病的诊断和治疗。方法 分析4例儿童慢性肺曲霉菌病的表现、诊断和治疗,并复习有关文献。结果 (1)4例均表现为长期或间断发热、咳嗽,病程3月～1年。其中2例合并胸壁脓肿。(2)2例肺部闻及细湿哕音并肝脾肿大,另2例肺部及其他部位检查无异常。(3)2例患儿发病前无基础疾病史,1例患慢性肉芽肿病,1例曾患原发性肺结核。4例患儿IgG、IsA、IgM、IgE,T细胞亚群、总补体和C3、C4、中性粒细胞数量均正常。3例四唑氮蓝试验正常,1例异常。(4)胸部影像学表现：4例在病程中均表现为单侧肺叶实变伴胸膜肥厚。2例病初表现为多发结节影。(5)4例痰液培养均有曲霉菌生长,2例行肺活检,在肺组织中发现曲霉菌菌丝或孢子。2例合并胸壁脓肿者,脓液培养也有曲霉菌生长。(6)4例患儿均联合应用二性霉素B和伊曲康唑治疗,10d～1个月症状控制。结论 对于有长期发热、咳嗽,胸部影像表现为肺叶实变伴胸膜肥厚或为结节性阴影,病情进展缓慢的儿童,应考虑慢性肺曲霉病的可能。确诊依赖于多次痰液培养或肺组织培养或在肺组织中发现曲霉菌生长。一旦确诊,联合应用二性霉素B和伊曲康唑可使病情控制。     

Combined systemic and intrapleural treatment of Aspergillus pulmonary empyema after invasive aspergillosis

A 12-year-old immunocompromised boy was hospitalized because of invasive aspergillosis with lung and central nervous system involvement. He was treated with surgery and liposomal amphotericin B, but he developed a pulmonary empyema and a bronchopleural-cutaneous fistula. A catheter was placed through the fistula, and amphotericin B (up to 50 mg in 10 ml of 5% dextrose) was instilled daily into the pleural cavity for 45 days. Treatment was well-tolerated, and the empyema resolved completely, with no evidence of recurrence after 2 years of follow-up.     

实体瘤患儿行自体外周血干细胞移植治疗中真菌感染情况

目的通过对31例实体瘤患儿行自体外周血干细胞移植(auto-PBSCT)治疗中真菌感染的情况进行分析,总结其临床特点、诊断与治疗经验。方法回顾性分析2006年5月-2009年12月本院儿科收治的31例实体瘤患儿行auto-PBSCT治疗过程中防治真菌感染的过程。结果 1.Ⅳ期进展期神经母细胞瘤患儿2例行自体外周血干细胞移植过程中经微生物学检查明确并肺部真菌感染,其中1例并脑、肝真菌感染;2例患儿血培养均为近平滑假丝酵母菌;4例患儿行肺部CT检查,表现为密度增高、渗出炎症阴影;1例进展期神经母细胞瘤患儿明确真菌感染后应用氟康唑、两性霉素B脂质体、伏立康唑静脉滴注抗真菌治疗有效,体温正常,度过骨髓抑制期,原发病获得部分缓解;1例进展期神经母细胞瘤患儿因存在颅内、骨骼、脊髓、肺、肝多发转移肿瘤,于自体外周血造血干细胞移植9 d后骨髓抑制期死亡。2.部分缓解期Ⅳ期神经母细胞瘤1例及进展期肝母细胞瘤1例患儿表现为发热、咳嗽、抽搐,怀疑侵袭性真菌感染,给予氟康唑、两性霉素B、伏立康唑治疗后好转度过骨髓抑制期,原发病获得部分缓解。3.余27例实体瘤患儿auto-PBSCT治疗中应用氟康唑预防真菌感染,临床未发生侵袭性真菌感染,1例进展期Ⅳ期神经母细胞瘤患儿因有多脏器转移,且有原发心脏损害,大剂量化疗后骨髓抑制期免疫耐受差,导致多脏器衰竭死亡。余26例实体瘤患儿顺利度过骨髓抑制期,病情获得缓解。结论实体瘤患儿auto-PBSCT治疗中易并真菌感染,需结合病史、血培养、G试验及CT、MRI等影像学检查做出诊断,经验性应用氟康唑、伏立康唑、两性霉素B等可防治真菌感染,原发病严重未缓解者预后差。     

Factitious fungus in two children with cancer receiving liposomal amphotericin

Amphotericin B deoxycholate and liposomal formulations of amphotericin are often started and continued empirically, in immunocompromised hosts, based on the computed tomography findings and the patient's clinical picture. The authors describe two patients with presumed fungal pulmonary nodules, which were progressive despite prolonged treatment with liposomal amphotericin B. At subsequent biopsy, neither had evidence of active fungal disease; rather, the nodules revealed reactive changes and lipid-laden macrophages. These cases underscore the importance of establishing a microbiologic diagnosis in cases of presumed fungal infection.     

Recurrent central nervous system blastomycosis in an immunocompetent child treated successfully with sequential liposomal amphotericin B and voriconazole

Central nervous system involvement in infection with Blastomyces dermatitidis is uncommon, except in immunocompromised patients. We report a case of central nervous system blastomycosis occurring 18 months after treatment of pulmonary blastomycosis in an immunocompetent child. Our patient was successfully treated sequentially with liposomal amphotericin B followed by oral voriconazole without need for surgical resection.     

Primary cutaneous aspergillosis (PCA)--a case report

Primary cutaneous aspergillosis is a rare diagnosis. Predisposing factors are immunodeficiency and macerated skin. The mortality of infections with Aspergillus species is high, especially in neonatal intensive care units (NICUs). We present a premature (24 wk of gestation) infant with primary cutaneous aspergillosis appearing on the sixth day of life. Predisposing factors in this patient were prematurity, extremely vulnerable skin, treatment with antibiotics and renovation in the radiology department nearby. The patient was treated with amphotericin B intravenously for a total of 40 d. He did not have, nor develop, disseminated aspergillosis, and suffered no side effects from the treatment. The only remaining trace of his infection was scarring in the affected area.Conclusion: After having treated this patient successfully and having gone through the available literature, we conclude that treating primary cutaneous aspergillosis with intravenous amphotericin B prevents disseminated aspergillosis and is the treatment of choice.     

Pulmonary aspergillosis caused by a pan-azole-resistant Aspergillus fumigatus in a 10-year-old boy

A 10-year-old boy with high-risk acute lymphoblastic leukemia treated with hematopoietic stem-cell transplantation developed pulmonary aspergillosis while receiving prophylactic voriconazole. A transpleural aspirate culture revealed a pan-azole-resistant Aspergillus fumigatus. Treatment with liposomal amphotericin B resulted in complete recovery. As the frequency of azole resistance in A. fumigatus increases, invasive procedures to isolate fungi for species identification and susceptibility testing becomes even more important.     

急性白血病合并侵袭性曲霉病的临床治疗

目的探讨急性白血病合并侵袭性曲霉病患儿抗真菌治疗和连续强烈化疗的治疗经验。方法回顾分析我院2007年7月至2008年7月收治的4例儿童急性白血病合并侵袭性曲霉病的诊断和治疗。结果3例急性淋巴细胞白血病(ALL)诱导缓解化疗和1例急性髓细胞白血病(AML)巩固化疗的患儿合并侵袭性曲霉病,1例确诊,3例拟诊,诊断时CT表现均有晕轮征。抗霉菌初始用药首选伏立康唑或两性霉素B。治疗2～5周病灶好转,4月至1年病灶缓解。4例按计划继续强烈化疗,霉菌感染至继续化疗的平均时间为35d,无霉菌复发。结论CT晕轮征可作为早期诊断侵袭性曲霉病的指标;基于晕轮征的抢先治疗和患者免疫功能的逆转可改善侵袭性曲霉病的预后;化疗同时持续抗霉菌治疗是完成连续强烈化疗而无霉菌复发的保障。     

两性霉素B脂质体联合氟康唑治疗早产儿真菌性中枢感染研究

目的 探讨两性霉素B脂质体联合氟康唑治疗早产儿真菌感染的疗效及安全性.方法 收集2009.10 - 2011.5收治的中枢神经系统真菌感染早产儿7例,均应用两性霉素B脂质体联合氟康唑治疗,总疗程8 ～ 12周,监测治疗过程中患儿临床症状、体征及相关的血清学、脑脊液及影像学检查指标.结果 两性霉素B脂质体联合氟康唑足量长疗程治疗使早产儿真菌感染得到良好控制,除1例放弃治疗外,余6例症状明显改善,血培养均转阴,中枢神经系统病灶较前明显改善.治疗过程中未发现较严重的药物不良反应.结论 两性霉素B脂质体联合氟康唑治疗早产儿真菌性中枢感染有效且相对安全.     

Conventional vs. Liposomal Amphotericin B in Immunosuppressed Children

Invasive fungal infections, mostly caused by Candida and Aspergillus species, are a major cause of early morbidity and mortality in immunocompromised children. 1,2 The treatment of choice for systemic fungal infections is still the early intravenous administration of amphotericin B. 3 However, conventional AMB therapy is often limited by severe side effects such as fever, chills, bronchospasm, and nephrotoxicity. 2 In recent reports liposomal AMB (AmBisome) was shown to be effective in the treatment of severe systemic fungal infections. 4,5 So far, clinical experience with AmBisome in children is still anecdotal and no comparative study is yet available. In the following we report on 11 immunosuppressed children who were treated with conventional or liposomal AMB for longer than 3 weeks.     

两性霉素B脂质体治疗早产儿侵袭性真菌感染的疗效

目的分析早产儿侵袭性真菌感染的高危因素、临床特征,观察两性霉素B脂质体治疗的有效性和安全性。方法回顾性分析21例侵袭性真菌感染早产儿的临床资料,根据临床特点、实验室检查确诊病例10例,临床诊断11例。应用两性霉素B脂质体治疗,剂量由0.1mg.kg-1.d-1开始,后每天或隔天加0.1mg.kg-1,每周复查1,3-β-D葡聚糖,结合临床继续增加至1～3mg.kg-1.d-1。同时每周监测肝肾功能及血常规。结果早产儿侵袭性真菌感染的高危因素是低胎龄儿、极低出生体质量儿、使用中心静脉导管、胃肠外营养、气管插管及长期应用抗生素。临床特征非特异性,各种体液培养以白色念珠菌为主;血1,3-β-D葡聚糖检测均>1500pg.L-1。本组治愈17例,有效2例,放弃、死亡各1例;未见明显不良反应。结论NICU中侵袭性真菌感染发病率日益增高,应重视其发病高危因素,血1,3-β-D葡聚糖监测非常必要,两性霉素B脂质体治疗早产儿侵袭性真菌感染安全、有效。