Primary intestinal aspergillosis after high-dose chemotherapy and autologous stem cell rescue

Primary invasive aspergillosis of the gut is a rare event and is associated with high mortality. We report for the first time on a patient who had isolated aspergillosis of the small bowel after autologous stem cell transplantation. Diagnosis of invasive aspergillosis of the gut was based on abdominal pain, galactomannan antigenemia and isolation of Aspergillus fumigatus from the stool and was later confirmed by pathohistologic examination. No other site of invasive aspergillosis was evident. The patient was successfully treated with early surgery and combination antifungal therapy.     

Accuracy of percutaneous lung biopsy for invasive pulmonary aspergillosis

Background. Invasive pulmonary aspergillosis is fulminant and often fatal in immunosuppressed patients. Percutaneous biopsy may select patients who could benefit from surgical resection. Objective. We sought to determine the accuracy of percutaneous biopsy for pediatric invasive pulmonary aspergillosis. Materials and methods. We retrospectively reviewed 28 imaging-guided percutaneous biopsies of the lungs of 24 children with suspected pulmonary aspergillosis. Twenty-two were being treated for malignancy and two for congenital immunodeficiency; 15 had received bone-marrow transplants. The accuracy of the percutaneous lung biopsy was determined by subsequent surgical resection, autopsy, or clinical course. Results. Histopathological studies showed ten biopsy specimens with septate hyphae, indicating a mold, and seven with Aspergillus flavus colonies in culture. The remaining 18 biopsies revealed no fungi. No patient had progressive aspergillosis after negative biopsy. Invasive pulmonary mold was detected by percutaneous biopsy with 100 % (10/10) sensitivity and 100 % (18/18) specificity. Percutaneous biopsy results influenced the surgical decision in 86 % (24 of 28) of the cases. Bleeding complicated the biopsy in 46 % (13/28) and hastened one death. Conclusion. Percutaneous biopsy of the lung is an accurate technique for the diagnosis of invasive pulmonary aspergillosis and correctly determines which immunosuppressed pediatric patients would benefit from therapeutic pulmonary resection. Received: 18 August 2000 Accepted: 2 November 2000     

Galactomannan antigenemia in pediatric oncology patients with invasive aspergillosis

BACKGROUND: Diagnosing invasive aspergillosis is difficult but might be improved by detection of circulating galactomannan. Although galactomannan antigenemia has been well studied in the detection of invasive aspergillosis in adult patients, little is known about the expression of circulating galactomannan in immunocompromised children with invasive aspergillosis. METHODS: We studied the expression of galactomannan antigen by enzyme immunoassay (EIA) in 990 serum samples from 56 pediatric oncology patients (ages 3 months to 18 years) of whom 17 had proven or probable invasive aspergillosis defined by the European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria. Any sample with a galactomannan EIA Galactomannan index value of > or = 0.5 was considered positive. RESULTS: At least 1 serum sample was positive for 11 of 17 pediatric oncology patients (65.7% sensitivity, 95% confidence interval: 38.3-85.7) with invasive aspergillosis. Galactomannan EIA was positive in 99 of 304 samples from patients with proven or probable invasive aspergillosis, and 7 of 686 (1.0%) samples from 39 control subjects resulted in a positive galactomannan EIA result. At least 1 sample tested positive in 5 of the 39 controls (12.8%, 95% confidence interval: 4.3-27.4). No significant association between accuracy and patient age was observed. Among the 7 evaluable galactomannan-positive patients with IA, the galactomannan EIA produced a positive result before clinical or radiographic evidence of infection in 6 cases, with a lead-time to diagnosis ranging from 1 day to 34 days (median: 10 days). In the remaining case, a positive galactomannan was observed on the same day as diagnosis by non-EIA methods. CONCLUSIONS: The presence of circulating galactomannan is predictive of invasive aspergillosis in most pediatric oncology patients. Galactomannan antigenemia may precede clinical, microbiologic, or radiographic evidence of invasive aspergillosis.     

血清半乳甘露聚糖检测对儿童侵袭性肺曲霉病的诊断价值

目的 评价血清半乳甘露聚糖检测(简称GM实验)对儿童侵袭性肺曲霉病(IPA)的诊断价值.方法 88例患儿纳入试验研究,共检测标本215份.其中确诊或临床诊断的IPA患儿14例、其他侵袭性肺部真菌感染16例、非真菌性肺部感染息儿58例(细菌性肺炎23例、支原体肺炎20例、肺结核15例).采用双夹心酶联免疫法检测血清GM的含量,结果以血清GM吸光度指数(Ⅰ值)判断.对IPA组中6例GM Ⅰ值阳性患儿治疗7 d后重复检测.结果 IPA组血清GM Ⅰ值[1.03(0.16～3.73)]明显高于其他IPFIs组[0.30(0.04～1.28)]以及非真菌性肺炎组[0.24(0.08～0.69)](P<0.05).以试剂盒推荐的GM Ⅰ值0.5为阳性界值,GM实验对IPA诊断的敏感性为71.4%,特异性为91.9%,诊断总符合率为88.6%.GM实验阳性可比痰培养阳性提前2～18 d.若将阳性界值提高到0.8,则GM实验对IPA诊断的敏感性为64.2%,特异性为98.6%,诊断总符合率为93.2%.对6例IPA患儿治疗7 d后重复检测,3例病情缓解者GM Ⅰ值明显下降,2例病情加重者GM Ⅰ值无下降,另1例临床症状好转,而血清GM Ⅰ值较治疗前无明显下降.结论 血清GM实验对儿童IPA具有一定的早期诊断价值.     

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.     

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。     

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.     

Clinical manifestations and diagnosis of invasive aspergillosis in immunocompromised children

Invasive aspergillosis (IA) is a serious life-threatening complication in immunocompromised children. The commonest risk groups are children with acquired immunodeficiency syndrome, leukaemia, corticosteroid and other immunosuppressive therapy, chronic granulomatous disease and severe combined immunodeficiency as well as neonates. The clinical manifestations are heterogeneous and many organ systems can be involved. Diagnosis based on the clinical presentation alone is cumbersome. Innovative and sensitive laboratory test systems which detect fungal antigens or DNA in clinical specimens have been recently developed. Specific Aspergillus antibody detection using recombinant antigen technique has also been introduced. Although each individual technique has drawbacks, the combined use of culture with antigen and antibody ELISA as well as PCR should result in an earlier and more definitive diagnosis of IA in children presenting with clinical and/or radiological signs of aspergillosis. In high risk children these methods are valuable for serial screening and early detection of Aspergillus infection. The implementation of accurate diagnostic criteria and standardised diagnostic flow charts in children at risk will lead to a better outcome of IA in the future. CONCLUSION: definite, well-timed early diagnosis and sufficient therapy is elementary for a successful outcome of invasive aspergillosis in immunocompromised children. To date, the diagnosis of invasive aspergillosis remains a combination of clinical presentation, radiology and microbiological tests.     

Successful treatment of pulmonary and cerebral aspergillosis in an immunosuppressed child

A favourable outcome was observed in a 12 year-old boy who developed invasive pulmonary and cerebral aspergillosis during antineoplastic treatment for central nervous system relapse of acute lymphoblastic leukemia. Combination therapy with amphotericin B and 5-Fluorocytosine led to complete regression of pulmonary infiltrates. Despite enlargement of the cerebral lesion monitored by computerized tomography, no viable fungi were found in the completely resected abscess after a 4 weeks' course of antifungal treatment preceeding neurosurgery. Histological examination confirmed the diagnosis of an aspergillotic abscess. The initially severe neurological symptoms disappeared after successful surgery. Aspergillus fumigatus was detected in the soil of a potted ornamental plant in the mother's living room, suggesting that this might have been the source of the infectious agent.Supported by the Stiftung Volkswagenwerk     

Fatal cerebral and pulmonary aspergillosis in acute leukemia in a child

Immediately after induction therapy for acute lymphoblastic leukemia, a 2 1/2-year-old child developed invasive pulmonary aspergillosis revealed by pneumothorax, an unusual manifestation. Despite treatment with amphotericin B, status epilepticus occurred; this manifestation was related to diffuse ischemic cerebral lesions probably caused by cerebral aspergillosis. Outcome was fatal. Early invasive pulmonary aspergillosis is responsible for non-specific pneumonia. Thoracic CT scan and fiberoptic bronchoscopy are informative investigations. At recovery of bone marrow aplasia, the occurrence of hemoptysis and the discovery of excavated lesions on roentgenograms are suggestive of the diagnosis. Cerebral aspergillosis should be routinely considered whenever neurologic symptoms develop in a patient with agranulocytosis, fever, and pneumonia. The prognosis of invasive aspergillosis depends above all on the promptness of treatment; amphotericin B should be given intravenously whenever broad spectrum antimicrobial therapy fails to induce apyrexia in a patient with agranulocytosis.     

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35 d,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。［中国当代儿科杂志,2009,11（11）：901-904］     

CNS-manifestation of aspergillosis in an extremely low-birth-weight infant

Invasive aspergillosis is a rare condition in term and preterm infants. We present here the fatal case of a 28-week gestational age preterm baby who developed pulmonary, hepatic and central nervous system aspergillosis during the first days of life. A hyperechogenic lesion adjacent to the lateral ventricle was diagnosed by ultrasound and initially considered to represent periventricular leukomalacia. Within several days the lesion increased in size and was then falsely considered to be an intraventricular haemorrhage. Aspergillus fumigatus was ultimately isolated in the tracheal aspirates, ascites and in material recovered by open brain biopsy. Despite treatment with conventional and liposomal amphotericin B the infant patient died. Conclusion. Invasive aspergillosis has to be considered in the differential diagnosis of an unusual hyperechogenic brain lesion in very low-birth-weight infants with persistent symptoms and signs of systemic infection despite broad-spectrum antibacterial therapy. Consideration of this diagnosis should result in an aggressive diagnostic work-up to allow early initiation of an appropriate treatment.     

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.     

Mixed Invasive Aspergillosis and Candidiasis in a Fatal Case of Leukemia

A fatal case of leukemia complicated by mixed invasive aspergillosis and candidiasis is presented. Mixed fungal infections may occur in any immunocompromised patients. We should be careful to look for different morphologies of fungi in diagnostic examinations of lesions in these patients.     

婴幼儿急性侵袭性肺曲霉病八例临床分析

目的 分析婴幼儿急性侵袭性肺曲霉病的临床特征,以期提高对该病的早期识别及诊治能力.方法 回顾性研究2010年8月至2011年2月华中科技大学同济医学院附属同济医院普通儿科病房内收治的8例15个月以下婴幼儿急性侵袭性肺曲霉病的临床资料,分析宿主高危因素、临床表现、实验室检查、诊治经过及转归情况.结果 ①诊断依据:5例血清曲霉半乳甘露聚糖实验吸光度指数(GMI)为1.92 ～3.27,2例2次痰培养检出烟曲霉菌,1例GMI 2.85同时1次痰培养检出烟曲霉菌者,均符合临床诊断.②危险因素:7例病前有静脉用广谱抗生素或加糖皮质激素治疗史(6例住院,1例门诊治疗);1例1月龄幼婴父母有严重足癣.③临床特点:4例高热型临床表现为持续高热,早期无明显呼吸道症状体征而肺部CT病变严重,杆状核粒细胞比率明显升高(0.25～0.68),与WBC总数和超敏CRP值正常明显不相称;4例非高热型病例WBC总数、超敏CRP及杆状核粒细胞比率都正常,3例有低热,呼吸道症状体征和肺部CT病变较严重;另1例1月龄幼婴仅有精神反应差.④影像学特点:肺部CT表现以不规则散在分布条索状致密影及小片结节影(6例)和单侧大片团块样实变影(1例)为多见,部分累及胸膜;1例表现为双侧主支气管周围病变伴主支气管狭窄.⑤临床转归:首例患儿并发严重脓毒症,死于多器官功能衰竭;另7例在临床诊断或拟诊后立即伏立康唑治疗,1～3d内病情迅速缓解.结论 广谱抗生素和糖皮质激素滥用使婴幼儿发生侵袭性肺曲霉病的危险性增加;普通儿科病房内可能存在曲霉菌院内感染和传播风险;高热型病例早期具有症状体征轻而肺部CT病变重和外周血杆状核粒细胞明显增高而WBC总数和超敏CRP正常等临床特征;尽早伏立康唑治疗可获显著疗效并有效降低病死率.     

Sinopulmonary aspergillosis in children with hematological malignancy

Invasive pulmonary aspergillosis is a serious infectious complication in immunocompromised especially neutropenic patients. Despite improvements in early diagnosis and effective treatment, invasive pulmonary aspergillosis is still a devastating opportunistic infection. These infections also interfere with the anticancer treatment. We report our experience in the diagnosis and therapeutic management of sinopulmonary aspergillosis in 4 children with hematologic malignancy. All patients except the first were neutropenic when sinopulmonary aspergillosis was diagnosed. Clinical signs included fever, cough, respiratory distress, swallowing difficulty, headache, facial pain-edema and hard palate necrosis. Radiodiagnostic methods showed bilateral multiple nodular infiltrations, soft tissue densities filling all the paranasal sinuses, and bronchiectasis. Diagnosis of aspergillosis was established by bronchoalveolar lavage in one case, tissue biopsy, positive sputum and positive cytology, respectively, in the other 3 cases. One patient was treated with liposomal amphotericin B and other 3 cases were treated with liposomal amphotericin B + itraconozole. Outcome was favorable in all cases except the one who died due to respiratory failure. Early diagnosis, appropriate treatment and primary disease status are important factors on prognosis of Aspergillus infections in children with hematological malignancy.     

Successful antifungal combination therapy with voriconazole and caspofungin

A 12-year-old boy in third remission of an acute lymphoblastic leukaemia developed infection of lung and paranasal sinuses with Aspergillus flavus in neutropenia. Because of the high risk of leukaemia-relapse bone marrow transplantation (BMT) from a matched unrelated donor was carried out despite invasive pulmonary aspergillosis (IPA). It is the first reported patient with IPA, who was successfully treated by the antifungal combination therapy with voriconazole and caspofungin therapy during myeloablative BMT. Despite 6 weeks of aplasia, a dramatic decrease of lesions highly suggestive of aspergillosis was observed after BMT. Since discharge-oral voriconazole monotherapy has been continued.     

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。     

Don’t forget other causes of wheeze. ABPA in a boy with asthma. A case report and review of the literature

Allergic bronchopulmonary aspergillosis (ABPA) is a rare pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus. The prevalence is estimated to be about 1–2% in adult patients with asthma and 2–15% in patients with cystic fibrosis. In paediatric patients with asthma, only single case reports on ABPA exist. We report on a 13‐year‐old boy with allergic asthma complicated by ABPA. Despite the presentation of typical clinical symptoms, it took 6 years before he was diagnosed. The clinical course improved rapidly after ABPA therapy was started, and 12 months after diagnosis, the boy is still free of symptoms. Clinical symptoms of ABPA may be unspecific making a rapid diagnosis difficult in some cases. Conclusion: A delay in diagnosis and treatment increases the risk for irreversible lung damage. Once bronchiectasis has developed, the outcome is unfavourable. Thus, ABPA has to be considered in patients whose asthma remains uncontrolled despite adequate therapy.     

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.