Risk factors for invasive aspergillosis in neutropenic patients with hematologic malignancies.

Risk factors for invasive aspergillosis (IA) are incompletely identified and may undergo changes due to differences in medical practice. A cohort of 189 consecutive, adult patients with neutropenia hospitalized in the hemato-oncology ward of the University hospital Berne between 1995 and 1999 were included in a retrospective study to assess risk factors for IA. In total, 45 IA cases (nine proven, three probable, 33 possible), 11 patients with refractory fever and 133 controls were analyzed. IA cases had more often acute leukemia or myelodysplastic syndrome (MDS) (88 vs 38%, P < 0.001) and a longer duration of neutropenia (mean 20.6 vs 9.9 days, P < 0.001). They also had fewer neutropenic episodes during the preceding 6 months (mean 0.42 vs 1.03, P < 0.001), that is, confirmed (82%) and probable (73%) IA occurred most often during the induction cycle. A short time interval ( < or = 14 days) between neutropenic episodes increased the risk of IA four-fold (P = 0.06). Bacteremia, however, was not related to the number of preceding neutropenic episodes. Therefore, neutropenic patients with leukemia or MDS have the highest risk of IA. The risk is highest during the first induction cycle of treatment and increases with short-time intervals between treatment cycles.     

Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole.

This study analyses invasive fungal infections in neutropenic patients with haematological malignancies during antifungal prophylaxis with itraconazole. From September 1994 to December 1998 20 patients developed fungal infections. Two patients suffered from disseminated infections by yeasts and 18 patients suffered from pulmonary infections by moulds (eight proven, 10 highly probable in high-resolution CT scans). In these patients the itraconazole trough concentrations exceeded 500 ng ml-1 (measured by high performance liquid chromatography) significantly less often (median 48%, interquartile range 0-100%) than in another group of 150 leukaemia patients without invasive fungal infections who received 287 courses of prophylaxis with itraconazole at our institution (median 100%, interquartile range 38-100%, P = 0.039). Twelve patients died, six of these had refractory disease. Patients with fatal invasive fungal infections had lower median itraconazole concentrations immediately before occurrence of the infection than patients with non-fatal infections: 120 (0-478) ng ml-1 versus 690 (305-1908) ng ml-1 (P = 0.039). In conclusion, this analysis of breakthrough invasive fungal infections during prophylaxis with itraconazole demonstrates that patients with itraconazole trough concentrations below 500 ng ml-1 were significantly more likely to develop fungal infections and that the last itraconazole trough concentration before occurrence of the infection was significantly lower in patients with fatal invasive fungal infections.     

Diagnosis and treatment of fungal infections in patients with hematologic malignancies

A diagnosis of deep-seated mycosis was made in 54 patients with hematologic malignancies, severe neutropenia and fever, based on a set of clinical and laboratory criteria. Standardized antifungal treatment was started in 31 patients who seven days after onset of fever had not responded to antibiotics; the fungal infection was cured in 13, all of whom had a simultaneous remission of neutropenia, whereas the other 18 who did not respond to antifungal treatment, all had a falling or static neutrophil count. None of the 23 patients who were given no or inadequate antifungal treatment survived regardless of the neutrophil count and/or phase of the hematologic disease. We discuss the suitability of utilizing empirical criteria for a diagnosis of disseminated fungal infection as a basis for starting antifungal therapy in this type of patient.     

国产两性霉素B治疗恶性血液病并发侵袭性真菌感染36例

  目的　观察国产两性霉素B对血液系统恶性肿瘤患者并发侵袭性真菌感染（IFI）的临床疗效并评价其安全性。方法　血液系统恶性肿瘤并发IFI患者36例使用国产两性霉素B,剂量2.5～25 mg／d,疗程3～49 d, 中位20 d,并对用药前后患者肝、肾功能及电解质进行监测。结果　国产两性霉素B治疗IFI总有效率72.7 %（24／33）,不良反应发生率为低钾血症63.8 %（23／36）,畏寒、寒战、高热27.8 %（10／36）,肾功能损害19.4 %（7／36）,静脉炎36.1 %（13／36）。结论　国产两性霉素B抗菌谱广,抗菌作用强,且价格便宜,虽其毒副作用较为多见,只要合理用药,密切监测肝肾功能、电解质,并采取一定防治措施,临床应用空间很大。     

Chemoprophylaxis of fungal infections in neutropenic patients

BACKGROUND:: In recent years there has been an increasing incidence and awarenessof mucosal candidiasis and invasive fungal infections in neutropenicpatients. Early diagnosis (before serious morbidity and mortality)is often difficult, emphasizing the continuing need for adequateprophylaxis. DESIGN:: A review of studies on the chemoprophylaxis of fungal infectionsin neutropenic patients. RESULTS:: There is a limited number of large, prospective, well-designedstudies using proper criteria and end points. No antifungaldrug or drug combination has been shown to prevent invasivefungal infection with the exception of fluco-nazole (mainlyCandida Albicans infections) in certain high-risk patient groups. CONCLUSIONS:: Prophylaxis strategies are dependent upon local conditions,patient populations, types of therapies, available resources,etc. Future improvement will be based upon a) improved studyquality, b) new strategies for established drugs, c) developmentof new and safer drugs, d) new strategies to eliminate or reduceimmunosuppression and e) cost-benefit studies. disseminated candidiasis, invasive aspergillosis neutropenia, prophylaxis     

血清半乳甘露聚糖检测诊断恶性血液病患者侵袭性真菌感染的临床意义

 目的　探讨血清半乳甘露聚糖（GM）检测作为侵袭性真菌感染（IFI）快速检测方法的可行性及其对恶性血液病患者早期诊断的意义。方法　选取体温≥38 ℃持续96 h以上,经合理广谱抗生素治疗无效或起初治疗有效但随后体温再次升高,1周内未用过抗真菌药物的恶性血液肿瘤患者39例为研究对象。每周进行2次血清GM检测,连续监测3周。用统计学方法计算GM在IFI早期诊断中的敏感度、特异度等指标,与传统的诊断方法进行比较,并观察其与IFI预后间的关系。结果　39例入组患者中,31例临床诊断IFI,GM实验的阳性率为80.6 %（界值为0.5）,敏感度为87.1 %,特异度62.5 %,阳性预测值（PV+）90 %,阴性预测值（PV-）55.6 %（κ＝0.474）。8例排除IFI诊断中,GM阳性3例。首次血清GM阳性结果出现于临床诊断前24 d至临床诊断后3 d,平均出现于临床诊断前（2.8±4.8）d;抗真菌治疗过程中,感染恶化患者血清GM水平持续升高,治疗好转患者明显下降。结论　作为IFI诊断方法,GM实验结果与临床IFI诊断具有很好的一致性;与传统培养方法相比,具有早期、快速、敏感性和特异性较高的优点。     

Fusarium infections in patients with hematologic malignancies

Two cases of Fusarium infection in patients with refractory hematologic malignancies are reported. In one patient septicemia progressed to death in septic shock. Miconazole showed some effect in clearing the lesions. There is some evidence that mycotoxins are related with Fusarium infections since severe myositis occurred in our patient. The other patient had a T-cell lymphoma, undergoing allogeneic bone marrow transplantation. The course was also complicated by Fusarium infection of the skin. This patient died of multiorgan failure. Recent literature on Fusarium is reviewed.     

Risk factor for invasive zygomycosis in patients with hematologic malignancies

Zygomycosis (mucormycosis) is a relatively uncommon infection in immunocompromised patients most often diagnosed in patients with haematological malignancies and neutropenia. Postmortem series demonstrate a high mortality rate up to 80%. Pulmonary involvement mimicking the more frequently diagnosed invasive aspergillosis is the typical clinical presentation. Other risk factors for the development of zygomycosis that have been described in other patient populations include diabetic ketoacidosis, iron overload, use of deferoxamine and steroids. If these factors are also associated with zygomycosis in patients with haematological malignancies has not been described. In a retrospective case-control study including 13 patients with zygomycosis and 13 control patients with the same underlying diseases, without zygomycosis we determined the frequency of various risk factors. Patients with zygomycosis experienced a longer period of neutropenia (17 vs. 13 days) and lymphopenia (23 vs. 20 days). A relapse of their underlying disease was diagnosed more frequently in patients with zygomycosis (7/13 vs. 3/13) as were a diagnosis of diabetes mellitus (6/13 vs. 3/13) and a cardiovascular disease (6/13 vs. 1/13). The previous use of steroids was more frequent in patients with zygomycosis (8/13 vs. 4/13) as was a systemic antifungal prophylaxis with itraconazole (9/13 vs. 4/13). Knowledge of these risk factors may be of benefit in diagnosing and monitoring zygomycosis in patients with haematological malignancies.     

伊曲康唑注射液治疗恶性血液病侵袭性真菌感染的临床研究

目的研究伊曲康唑注射液治疗血液恶性病患者合并侵润性真菌感染的疗效。方法对30例按标准诊断患者应用伊曲康唑注射液,剂量200~400mg/d第1天,以后200mg/d用药14天。结果临床总有效率为66.7%,确诊病例、临床诊断病例与拟诊病例有效率分别为71.3%、86.3%、25.0%。确诊病例、临床诊断病例与拟诊病例有效率之间相比,有统计学差异(P<0.05);粒细胞减少,应用广谱抗生素及糖皮质激素是发病的主要危险因素;伊曲康唑注射液起效时间3天~7天,中位时间4天。结论伊曲康唑注射液对恶性血液病合并侵袭性真菌感染疗效显著,对存在危险因素的患者早期诊断,积极治疗,可取得良好效果。     

Epidemiology of invasive fungal infections and rationale for antifungal therapy in patients with haematological malignancies

Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7‐month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty‐four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes. Fifty‐two of 117 patients (44%) received antifungal prophylaxis, 81 of 117 (69%) received empirical (31/117; 26%) or pre‐emptive (50/117; 43%) antifungal therapy and four of 117 patients (3.4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre‐emptively. Twenty‐nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections were rare.     

Yield of diagnostic procedures for invasive fungal infections in neutropenic febrile patients with chest computed tomography abnormalities

Haematological patients with neutropenic fever are frequently evaluated with chest computed tomography (CT) to rule out invasive fungal infections (IFI). We retrospectively analysed data from 100 consecutive patients with neutropenic fever and abnormal chest CT from 1998 to 2005 to evaluate their chest CT findings and the yield of diagnostic approaches employed. For their initial CTs, 79% had nodular opacities, with 24.1% associated with the halo sign. Other common CT abnormalities included pleural effusions (48%), ground glass opacities (37%) and consolidation (31%). The CT findings led to a change in antifungal therapy in 54% of the patients. Fifty‐six patients received diagnostic procedures, including 46 bronchoscopies, 25 lung biopsies and seven sinus biopsies, with a diagnostic yield for IFI of 12.8%, 35.0% and 83.3%, respectively. In conclusion, chest CT plays an important role in the evaluation of haematological patients with febrile neutropenia and often leads to a change in antimicrobial therapy. Pulmonary nodules are the most common radiological abnormality. Sinus or lung biopsies have a high‐diagnostic yield for IFI as compared to bronchoscopy. Patients with IFI may not have sinus/chest symptoms, and thus, clinicians should have a low threshold for performing sinus/chest imaging, and if indicated and safe, a biopsy of the abnormal areas.     

Fusarium infections in patients with hematologic malignancies

Two cases of Fusarium infection in patients with refractory hematologic malignancies are reported. In one patient septicemia progressed to death in septic shock. Miconazole showed some effect in clearing the lesions. There is some evidence that mycotoxins are related with Fusarium infections since severe myositis occurred in our patient. The other patient had a T-cell lymphoma, undergoing allogeneic bone marrow transplantation. The course was also complicated by Fusarium infection of the skin. This patient died of multiorgan failure. Recent literature on Fusarium is reviewed.     

Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients

BACKGROUND: Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). METHODS: The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm(3) at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. RESULTS: Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). CONCLUSIONS: A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA.     

Single daily dose ceftriaxone plus amikacin treatment of febrile episodes in neutropenic patients attending day hospital for hematologic malignancies.

Once-a-day ceftriaxone and amikacin was administered in case of fever to 46 neutropenic patients attending day hospital for hematologic malignancies. All patients were admitted to a short-term ward for infective complications, but were discharged in the event of prompt disappearance of fever and of clinical signs of infection continuing their therapy either by daily reporting to the hospital, or at home. Response to the initial empiric therapy was obtained in 37 cases (76%). Twenty-four patients who promptly responded to therapy completed their treatment on an outpatient basis, their mean number of days of hospitalization being reduced to 4.6 versus a mean of 9.6 days in the overall patient population being considered. Since the outpatient treatment accounted for 21% of the antibiotic therapy administered, the above treatment may result in cost containment and better quality of life for patients, provided that these data are confirmed by prospective randomized studies.     

Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20‐year autopsy study

Autopsy studies remain an essential tool for understanding the patterns of fungal disease not detected ante mortem with current diagnostic approaches. We collected data concerning the microbiological trends, patient clinical characteristics and sites of involvement for invasive fungal infections (IFIs) identified at autopsy in a single large cancer treatment centre over a 20‐year period (1989–2008). The autopsy rate and IFI prevalence both declined significantly during the study period. The prevalence of Aspergillus spp. decreased significantly from the first 15 years of the study (from 0.12 to 0.14 cases per 100 autopsies to 0.07 in 2004–2008; P = 0.04), with only Mucorales accounting for a greater proportion of IFIs over the duration of the study period (0.06 to 0.2 cases per 100 autopsies, P = 0.04). After 2003, moulds accounted for the majority of infections identified at autopsy in the spleen, kidney, heart and gastrointestinal tract. Despite a trend of decreasing prevalence from 1989 to 2004, invasive candidiasis increased in prevalence during later periods 2004–2008 (0.02–0.05 per 100 autopsies) with decreasing kidney, heart and spleen involvement. Despite a declining autopsy rate, these data suggest a decreasing prevalence overall of IFIs with changing patterns of dissemination in patients with haematological malignancies.     

氟康唑预防恶性血液病患者侵袭性真菌感染疗效的Meta分析

目的:系统评价氟康唑预防恶性血液病并真菌感染的疗效。方法:计算机检索中国知网(CNKI)、万方、Pubmed、EmBase数据库,采取RevMan 5.3软件进行Meta分析。结果:共纳入研究14篇,共3 767例,氟康唑组预防真菌感染失败率高于伊曲康唑组（P＝0.001）、伏立康唑组（P＝0.009）、泊沙康唑组（P＜0.001）,较空白对照组低（P=0.006）,且差异均有统计学意义。其中氟康唑组同伊曲康唑组和泊沙康唑组进行亚组分析,分别比较了白色念珠菌、曲霉菌感染率,其中泊沙康唑组曲霉菌感染率较氟康唑组低（P＜0.000 1）,且差异有显著统计学意义。伊曲康唑组白色念珠菌感染率、曲霉菌感染率及泊沙康唑组白色念珠菌感染率差异均无显著统计学意义。结论:氟康唑能有效预防恶性血液病并真菌感染发生率,但疗效低于伊曲康唑、伏立康唑、泊沙康唑。     

Neutropenia and invasive fungal infection in patients with hematological malignancies treated with chemotherapy: a multicenter,prospective, non-interventional study in China

In this study, we explored the relationship between neutropenia (absolute neutrophil count (ANC) <1,500/mm³) and invasive fungal infection (IFI) in Chinese patients who had hematological malignancies treated with chemotherapy. We conducted a multicenter, prospective, non-interventional study of consecutive patients with hematological malignancies undergoing chemotherapy in China and determined clinical characteristics of patients who developed neutropenia and IFI. The results indicated that for the 2,177 neutropenic patients, 88 (4.0 %) were diagnosed with IFI. We found that a high risk of IFI (P?<?0.05) is associated with male gender, non-remission of the primary disease, use of two or more broad-spectrum antibiotics, treatment with parenteral nutrition, presence of cardiovascular disease, history of IFI, and neutropenia. When the ANC was less than 1,000, 1,000～500, 500～100, and <100/mm³, the incidence of IFI was 0.5, 5.2, 3.9, and 4.7 %, respectively (ANC?>?1,000/mm³ versus other groups, P?<?0.001). When the ANC was less than 1,000, 500, or 100/mm³ for 10 days or more, the incidence of IFI was 3.2 versus 6.1 % (P?=?0.0052), 3.5 versus 7.1 % (P?=?0.0021), and 3.1 versus 10.0 % (P?<?0.001). When the ANC was less than 100/mm³, taking antifungal prophylaxis reduced the incidence of IFI (P?<?0.05). The IFI-attributable mortality rate was 11.7 %. In conclusion, Chinese patients with IFI, severe and prolonged neutropenia increases the incidence of IFI. The incidence of IFI associated with neutropenia was reduced when antifungal prophylaxis was given. IFI was associated with a significantly increased high mortality rate in hematological malignancy patients with neutropenia.