G试验联合GM试验在恶性血液病侵袭性真菌感染的诊断价值

目的：探讨血浆1,3-β-D葡聚糖检测（G实验）联合曲霉半乳甘露聚糖检测（GM试验）对恶性血液病侵袭性真菌感染（IFI）的诊断价值。方法：应用MB-80微生物动态快速检测系统和酶联免疫吸附法定量检测血浆1,3-β-D葡聚糖及半乳甘露聚糖的含量,将检测结果及临床特征进行分析。按照欧洲癌症研究治疗组织及真菌研究组（EORTC/MSG）诊断标准,在349例患者中,确定诊断2例,临床诊断23例,临床拟诊175例,排除诊断149例。结果：G、GM试验分别以20ng/ml、0.5为诊断界值,G试验的敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）分别为77%、89.9%、91.1%、74.4%。G/GM试验的敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）分别为100%、90.4%、85.9%、100%。结论：G试验联合GM试验是诊断恶性血液病患者IFI的早期、快速的方法。     

What is the role of the (1→3)‐β‐d‐glucan assay in the screening of patients undergoing autologous haematopoietic stem‐cell transplantation?

The aim of this study is to determine the clinical contribution of (1→3)‐β‐d ‐glucan (BDG) screening in the case of patients undergoing autologous haematopoietic stem‐cell transplantation (HSCT). The records at our stem‐cell transplantation centre were reviewed to identify the patients who underwent autologous HSCT between April 2009 and December 2010. Patients were classified as having proven invasive aspergillosis (IA), probable IA, or possible IA on the basis of the criteria established by the European Organization for Research and Treatment of Cancer and Mycoses Study Group (independent of the BDG results). During the study period, the patients were screened for BDG twice a week from transplant (day 0) until engraftment. Three patients were diagnosed with probable IA and five were diagnosed with possible IA. A total of 354 serum samples from79 patients who met the study inclusion criteria were used for statistical analysis. At the cut‐off value of 80 pg ml^?1, the sensitivity was 27.2% [95% confidence interval (CI); 7.3–60.6]; specificity, 94.4% (95% CI; 91.3–96.5); positive predictive value, 6.2%; and negative predictive, 93.7%. The clinical contribution of the BDG assay as a screening test was relatively limited in this cohort of patients undergoing autologous HSCT.     

Detection of (1→3)‐β‐D‐glucan in same‐day urine and serum samples obtained from patients with haematological malignancies

Serum 1,3‐beta‐d ‐glucan (BDG) testing is an established diagnostic marker for invasive fungal infections (IFI) among patients with haematological malignancies. In contrast limited data exist regarding the application of urine BDG testing. Same‐day midstream urine and serum screening samples were collected in adult patients with underlying haematological malignancies. A total of 80 urine samples from 46 patients were investigated: Twenty‐six had positive corresponding serum BDG >120 pg ml^?1, 27 intermediate (60–80 pg ml^?1), and 27 negative serum BDG (<25 pg ml^?1). A significant positive correlation between BDG in serum and urine samples was observed (P = 0.025; r = 0.252). Sensitivity, specificity, positive predictive value and negative predictive value (compared with same‐day serum results) were: 42%, 76%, 46%, 73% when using an 80 pg ml^?1 urine cut‐off, and 35%, 96%, 82%, 75% for a 250 pg ml^?1 cut‐off. Urine BDG seemed to be higher in samples obtained from patients with probable IFI (n = 13, median 145, IQR 22–253) compared to those from patients without IFI (n = 56, median 24, IQR 15–88) but the difference was not significant (P = 0.069). Overall correlation of same‐day urine BDG and serum BDG was moderate. However, urine BDG testing may warrant further investigation in larger studies, as high‐positive urine results correlated with high‐positive corresponding serum levels and clinical performance was comparable to serum BDG.     

The role of surgery in the treatment of invasive fungal infection in paediatric haematology patients: a retrospective single‐centre survey

Surgery may improve the control of fungal disease and patient survival. The aim of this study was to report a single‐centre experience in using surgery for the treatment of paediatric invasive fungal infection (IFI). From 2001 to 2009, 18 paediatric onco‐haematology patients underwent 24 surgical procedures as treatment of IFI. At surgery, severe thrombocytopenia and neutropenia were present in four and one episodes respectively. Complications were one pleural effusion, one pleural effusion and surgical wound infection, one pneumothorax with wound dehiscence and one wound dehiscence. None of them required repeat surgery. The median duration of hospitalisation for four complicated procedures was 11 days, range 3–16, and 7 days, range 2–13, for the 20 uncomplicated procedures. No surgery‐related deaths occurred. Fourteen patients resumed chemotherapy after a median of 26 days, range 9–77, whereas nine patients underwent hematopoietic stem cell transplantation after a median of 42 days, range 27–110. At 3 months from IFI, 17 patients were alive (94%) and one patient (6%) died from mycosis; the 3‐month overall survival (OS) being 94.4%, CI 66.6–99.2. After a median follow‐up of 7.1 years (CI 2.8–7.5), the OS was 54.5%, CI 29.2–74.2. Surgery is a feasible and valuable option in paediatric patients because it is associated with a low incidence of complications and an acceptable delay in resuming the chemotherapeutic plan.     

Comparative evaluation of pan‐fungal real‐time PCR,galactomannan and (1‐3)‐β‐D‐glucan assay for invasive fungal infection in paediatric cancer patients

Limited specific data and investigations are available for the diagnosis of Invasive Fungal Infection (IFI) in paediatrics cancer patients. Three non‐invasive tests; Platelia Aspergillus EIA for galactomannan (GM), β‐D‐glucan (BDG) assay and pan‐fungal real‐time PCR for fungal DNA in blood were evaluated. One hundred twenty‐five paediatrics cancer patients at the high risk of IFI were enrolled. Single blood and serum samples were evaluated by all the three methods. Patients were classified into 10 proven, 52 probable and 63 no IFI cases in accordance with EORTC MSG 2008 revised guidelines. The sensitivity, specificity, PPV and NPV of all the three tests in proven, probable and no IFIs cases were analysed singly and in combination. The sensitivity, specificity, PPV and NPV of GM, BDG and pan‐fungal real‐time PCR were: 87%, 61%, 81%, 69.5% for GM, 88%, 59.5%, 81%, 71.4% for BDG and 89%, 69.2%, 85%, 67.5% for PCR (95% CI). Among different combinations, best combination was found to be GM and PCR with sensitivity, specificity, PPV and NPV of 98.2%, 89.3%, 97.1% and 90% respectively. Single samples must be evaluated by combination of tests.     

Reduction in incidence of invasive fungal infection in patients receiving allogeneic stem cell transplantation using combined diagnostic‐driven approach and itraconazole oral solution

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic‐driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non‐significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic‐driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non‐statistically significant, number of IFI in our medical centre.     

Epidemiology of invasive fungal diseases in children with solid tumours undergoing autologous haematopoietic stem cell transplantation: a 10‐year experience in a tertiary Italian centre

The objective of the study was to determine the incidence of invasive fungal disease (IFD) in children undergoing autologous haematopoietic stem cell transplantation (auHSCT) for solid tumours (ST). Retrospective study on auHSCT was performed in children with ST (January 2006‐December 2015). Data on the number of patient‐days at risk (pdr) during the first 30 and 90 days after auHSCT and cases of proven/probable IFDs were collected. Infection rate (IR, episodes/1000 pdr) and proportions and cumulative risk (CR) of IFD were evaluated. In 186 patients, 270 auHSCT were performed, for a total of 8327 pdr during the first 30 days and 24 366 up to day 90. Median age was 5 years (interquartile range 2;8), 63% were male. At day 30, seven procedures were complicated by IFD, with an IR of 0.84 (95% CI 0.66‐1.02) and aCR of 2.6% (95% CI 1.4‐5.4) at 18 days after HSCT. Within day 90, two further IFDs were detected with an IR of 0.37 (95% CI ?0.49 to 1.23) and a CR of 3.3% (95% CI 1.7‐6.3) at day 69. Children undergoing auHSCT for ST have a low incidence of IFDs in the first 90 days after the procedure.     

Performance of 1,3‐β‐D‐glucan for diagnosing invasive fungal diseases in children

Plasma 1,3‐β‐D‐glucan (BDG) is indicated as a tool for early diagnosis of invasive fungal diseases (IFD). However, data on its diagnostic value are scarce in children. Therefore, definition of BDG test performance in paediatrics is needed. BDG was evaluated in children admitted to “Istituto Giannina Gaslini,” Genoa, Italy, who developed clinical conditions at risk for IFD. Results were analysed for sensitivity, specificity, predictive values, likelihood ratios, accuracy, informedness and probability of missing one case by a negative test. A total of 1577 BDG determinations were performed on 255 patients (49% males, median age 5.4 years). Overall 46 IFD were diagnosed, 72% proven/probable. The test performance was evaluated for 80 pg/mL, 120 pg/mL, 200 pg/mL, 350 pg/mL, 400 pg/mL cut offs. Sensitivity was always <0.80 and specificity > 0.90 only for cut offs ≥200 pg/mL. Negative predictive value was ≥0.90 for all the cut offs evaluated, while positive predictive value resulted barely 0.50 (8% IFD prevalence). Accuracy was never >0.90, and informedness was at best 0.50. The risk of missing one IFD by a negative result was < 10%. Analyses in haemato‐oncological or newborn patients did not show major differences. Detection of serum BDG does not appear a valuable adjunctive diagnostic tool for IFD in paediatrics.     

Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single‐centre study with focus on emerging pathogens

With increased use of expanded‐spectrum triazoles for antifungal prophylaxis, the epidemiology of invasive fungal infections (IFIs) after allogeneic haematopoietic stem cell transplantation (HSCT) continues to evolve. To define the contemporary epidemiology of IFIs in this population, we reviewed all European Organization for Research and Treatment of Cancer‐Mycoses Study Group proven and probable IFIs in adults transplanted from 2002 to 2011 and determined the incidence and risk factors for IFI and post‐IFI mortality. All patients received antifungal prophylaxis. Fifty‐three (14%) of 378 allogeneic HSCT recipients developed an IFI. There were 62 IFI episodes, of which aspergillosis (n = 31; 50%) and candidaemia (n = 15; 24%) were most common. Sixteen episodes (26%) were caused by other fungi, including Mucorales (n = 6; 10%) and the following uncommon pathogens: Trichosporon asahii, Arthrographis sp., Cladosporium sp., Geosmithia argillacea and Hormographiella aspergillata. Independent IFI risk factors were hospitalisation in an intensive care unit [ICU; odds ratio (OR) = 6.0], graft‐versus‐host disease (OR = 5.3), central venous catheter use (OR = 5.2) and hypoalbuminaemia (OR = 0.3 g^?1 dl^?1 increase in albumin). The 90‐day mortality rate after IFI was 57%. Non‐cytomegalovirus systemic viral co‐infection (OR = 3.5) and stay in an ICU (OR = 2.9) were independent risk factors for death. Despite antifungal prophylaxis, IFIs remain common after allogeneic HSCT and previously uncommon pathogens are emerging.     

Empirical caspofungin therapy in clinical practice for suspected invasive fungal disease in adults with acute lymphoblastic leukaemia

Patients with acute lymphoblastic leukaemia (ALL) after cytotoxic chemotherapy or haematopoietic stem cell transplantation (HSCT) are at risk for life‐threatening invasive fungal disease (IFD). The aim was to evaluate the characteristics, antifungal therapy and outcome of adult patients with ALL after chemotherapy or HSCT receiving caspofungin empirically in a clinical setting. Retrospective chart reviews were conducted at nine large tertiary care centres in Germany. Adult patients with ALL treated empirically with caspofungin according to the product label between 2006 and 2012 were eligible. Data were extracted as case reports. In total, 25 patients (12 males, 13 females; median age 37 years; 19 with B‐ALL, 6 with T‐ALL) with 28 treatment episodes because of suspected IFD (18 episodes after chemotherapy, 10 episodes after allogeneic HSCT) were included in the analysis. Empirical caspofungin therapy (median duration: 19 days, range 1–105 days) was given as first‐line monotherapy in 20 (71.4%), second‐line monotherapy in five (17.9%) and combination therapy in three (10.7%) episodes respectively. Therapy rated successful according to the physician's overall assessment (inflammatory parameters, clinical symptoms): 20 (95%) of 21 evaluable episodes with therapy duration of at least 8 days. Empirical caspofungin appears to be an effective therapeutic option in critically ill adult ALL patients with suspected IFD in clinical practice.     

Diagnostic accuracy of the Aspergillus‐specific bronchoalveolar lavage lateral‐flow assay in haematological malignancy patients

We evaluated the performance of the Aspergillus‐specific lateral‐flow device (LFD) test for diagnosing invasive pulmonary aspergillosis (IPA) in patients with underlying haematological malignancies. Participating centres were the two Austrian University Hospitals of Graz and Innsbruck. LFD performance was evaluated with 95 bronchoalveolar lavage fluid (BALF) samples from 72 patients collected prospectively in Graz, and with 24 BALF bio bank samples from 23 patients (21 samples with probable IPA) in Innsbruck. Invasive fungal infections were classified according to the revised European Organization of Research and Treatment of Cancer/Mycoses Study Group criteria. Overall, 27 patients (30 samples) had probable IPA, 32 (43 samples) possible and 36 (46 samples) did not fulfil IPA criteria. The vast majority of patients – in particular those with probable IPA – received mould‐active treatment before bronchoscopy. Sensitivity, specificity, positive predictive value and negative‐predictive‐value for probable IPA diagnosis using the BALF‐LFD test were 71%, 76%, 35% and 94% for the Graz cohort. Sensitivity of the BALF‐LFD test for probable IPA was 57% in Innsbruck bio bank samples. Our results indicate that the BALF‐LFD‐test provides fast results with moderate sensitivities in patients with underlying haematological malignancies. Similar to other diagnostic tests and biomarkers sensitivity of the test may be influenced by ongoing systemic mould‐active treatment.     

Epidemiology and outcome of invasive fungal disease in children after hematopoietic cell transplantation or treated for malignancy: Impact of national programme of antifungal prophylaxis

The objective of the study was the analysis of incidence and outcome of invasive fungal disease (IFD) in children treated for malignancy (PHO, paediatric hematology‐oncology) or undergoing hematopoietic cell transplantation (HCT) over a period of six consecutive years in nationwide study. A total number of 5628 patients with newly diagnosed malignancies and 971 patients after HCT (741 allo‐HCT and 230 auto‐HCT) were screened for infectious complications in biennial reports. IFD incidence was lower among PHO patients: 8.8% vs 21.2% (P < .0001) and survival from IFD was better: 94.2% vs 84.1% (P < .0001). Auto‐HCT patients had lower incidence (10.9% vs 24.4%) and lower mortality than allo‐HCT patients. Introduction of national antifungal prophylaxis programme in HCT and acute leukaemia patients decreased incidence of IFD in HCT (from 23.1% to 13.4%) and AML on conventional chemotherapy (from 36% to 23%) but not in ALL patients during chemotherapy. In multivariate analysis, the incidence of IFD was higher in patients after HCT, diagnosed for ALL, AML or NHL, and in patients > 10 years old. Factors contributing to death with infection were as follows: undergoing HCT, diagnosis of acute leukaemia (ALL or AML) and duration of treatment of infection > 21 days. In conclusion, the incidence of IFD in allo‐HCT and in AML patients on chemotherapy has decreased after introduction of national programme of antifungal prophylaxis, while the incidence of IFD in ALL patients on chemotherapy did not change significantly. The outcome of IFD both in PHO and HCT patients has largely improved in comparison with historical international data.     

Use of (1→3)‐β‐d‐glucan for diagnosis and management of invasive mycoses in HIV‐infected patients

People living with HIV (PLHIV) are highly vulnerable to invasive fungal infections (IFIs) due to their immune dysfunction. Diagnosis and treatment of IFIs remain challenging due to the requirement of deep tissue sampling to visualise and culture fungi before initiating treatment. Such techniques are less practical in resource‐limited settings due to their cost and requirement of relatively invasive procedures. Hence, identification of surrogate markers for the early diagnosis and therapeutic monitoring of IFIs is required. Recent studies have shown that (1→3)‐β‐d ‐glucan (BDG), a major fungal cell wall antigen, represents a promising soluble marker for the presumptive diagnosis and therapeutic monitoring of IFIs in HIV‐infected patients. Herein, we review findings on the merits of BDG assays in the diagnosis of IFIs and monitoring of antifungal therapies for PLHIV. Conversely to other types of immunocompromised patients, HIV infection is associated with gut damage and subsequent bacterial and fungal translocation leading to elevated BDG plasma levels.     

Reliability of serum 1,3‐beta‐d‐glucan assay in patients undergoing renal replacement therapy: a review of the literature

The serum 1,3‐beta‐d ‐glucan (BDG) test is a pan‐fungal serum marker considered to detect the majority of pathogenic fungi, including Aspergillus spp. and Candida spp. For this review we searched for publications dealing with serum BDG levels in patients undergoing renal replacement therapy (RRT). The influence of various different membrane materials used for RRTs in these publications on serum BDG has been reviewed. We found that unmodified cellulose containing membranes increased the serum BDG levels highly, whereas conflicting results have been observed for modified cellulose containing materials. Synthetic materials (e.g. polysuflone) had no influence on serum BDG levels in the majority of the reviewed publications.     

Performance of 1,3‐beta‐D‐glucan in the diagnosis and monitoring of invasive fusariosis

Invasive fusariosis (IF) usually presents with high fungal burden at diagnosis, and this may contribute to its high mortality rate. The use 1,3‐beta‐D‐glucan (BDG) may help to establish the diagnosis at an earlier disease stage and to monitor treatment. To evaluate the performance of BDG in the diagnosis of IF and its kinetics in relation to the outcome, we retrospectively tested serum samples of 13 cases of IF, analysed the temporal relationship between the first positive BDG test and the date of the diagnosis of IF, and the kinetics of BDG in relation to patients’ outcome. We selected 13 controls with similar underlying diseases as cases, at least two serum samples stored, and no invasive fungal disease. Twelve patients with IF had at least one positive BDG (median 4, range 1‐16). The test was positive before the diagnosis of IF in 11 of the 12 patients (91.6%), at a median of 10 days (range 1‐32). The median BDG value increased (from 109 to 316 pg/mL, P = 0.04) in patients who died by day 30, and did not change significantly (99‐101 pg/mL, P = 0.60) in survivors. Using two consecutive BDG tests, sensitivity, specificity, and positive and negative predictive values were 85%, 69%, 7% and 99%, respectively. BDG is positive in the majority of patients with IF, usually before the diagnosis, but the low positive predictive value limits its use to diagnose IF earlier. Once therapy is started, decreasing BDG values suggests treatment response.     

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.     

Five‐year follow‐up of survival and relapse in patients who received cryotherapy during high‐dose chemotherapy for stem cell transplantation shows no safety concerns

SVANBERG A., ÖHRN K. & BIRGEGÅRD G. (2012) European Journal of Cancer Care Five‐year follow‐up of survival and relapse in patients who received cryotherapy during high‐dose chemotherapy for stem cell transplantation shows no safety concerns We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high‐dose chemotherapy for stem cell transplantation. The present study is a 5‐year follow‐up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high‐dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5‐year follow‐up study gave no support for safety concerns with cryotherapy.     

Diagnostic value of serum galactomannan, (1,3)‐β‐d‐glucan,and Aspergillus fumigatus‐specific IgA and IgG assays for invasive pulmonary aspergillosis in non‐neutropenic patients

Detection of serum galactomannan (GM) and (1,3)‐β‐d ‐glucan (BG) is considered useful for non‐culture diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Only few studies evaluated these seromarkers in non‐neutropenic patients suspected of having IPA. The aim of this study was to evaluate both tests together with the Aspergillus fumigatus‐specific serum IgG and IgA (IgAG) test for serological IPA diagnosis in non‐neutropenic patients. Sera from 87 patients suspected of having IPA were retrospectively analysed. Patients were categorised into groups of proven IPA (n = 10), putative IPA (n = 31) and non‐IPA colonisation (n = 46). When the GM, BG and IgAG assays were used for patients included in the study, the sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) were 48.8%/91.3%/83.3%/66.7%, 82.9%/73.9%/73.9%/82.9% and 75.6%/95.7%/93.9%/81.5%, respectively. Thus, the highest specificity and PPV were confirmed for the IgAG assay. Improvements in the sensitivity and NPV were achieved by “at least one positive” analysis with the GM and BG assays, with the sensitivity/specificity/PPV/NPV values being 85.0%/69.6%/71.4%/84.2%. Nevertheless, the highest sensitivity and NPV were achieved by the “at least one positive” analysis combining the GM, BG and IgAG tests (97.6% and 96.8%, respectively). The involvement of the IgAG assay could improve IPA diagnosis in non‐neutropenic patients by increasing the sensitivity and NPV when combined with the GM or BG assays. Furthermore, improvement was achieved by combining the GM, BG and IgAG assays using the “at least one positive test” strategy, especially if doubt exists.