Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients: an EBMT Transplant Complications Working Party study.

The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome.

Concordance in measurable residual disease result after first and second induction cycle in acute myeloid leukemia: An outcome- and cost-analysis.

Measurable residual disease (MRD) measured using multiparameter flow-cytometry (MFC) has proven to be an important prognostic biomarker in acute myeloid leukemia (AML). In addition, MRD is increasingly used to guide consolidation treatment towards a non-allogenic stem cell transplantation treatment for MRD-negative patients in the ELN-2017 intermediate risk group. Currently, measurement of MFC-MRD in bone marrow is used for clinical decision making after 2 cycles of induction chemotherapy. However, measurement after 1 cycle has also been shown to have prognostic value, so the optimal time point remains a question of debate. We assessed the independent prognostic value of MRD results at either time point and concordance between these for 273 AML patients treated within and according to the HOVON-SAKK 92, 102, 103 and 132 trials. Cumulative incidence of relapse, event free survival and overall survival were significantly better for MRD-negative (<0.1%) patients compared to MRD-positive patients after cycle 1 and cycle 2 (p ≤ 0.002, for all comparisons). A total of 196 patients (71.8%) were MRD-negative after cycle 1, of which the vast majority remained negative after cycle 2 (180 patients; 91.8%). In contrast, of the 77 MRD-positive patients after cycle 1, only 41 patients (53.2%) remained positive. A cost reduction of -€571,751 per 100 patients could be achieved by initiating the donor search based on the MRD-result after cycle 1. This equals to a 50.7% cost reduction compared to the current care strategy in which the donor search is initiated for all patients. These results show that MRD after cycle 1 has prognostic value and is highly concordant with MRD status after cycle 2. When MRD-MFC is used to guide consolidation treatment (allo vs non-allo) in intermediate risk patients, allogeneic donor search may be postponed or omitted after cycle 1. Since the majority of MRD-negative patients remain negative after cycle 2, this could safely reduce the number of allogeneic donor searches and reduce costs.

Prospective assessment of breakthrough infections and neurotoxicity and their association with cefepime trough concentrations in patients with febrile neutropenia.

Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) and free cefepime trough concentration were 101 (85-112) mL/min/1.73m2 and 8.6 (4.9-16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P < 0.001). This study provides real-world clinical data showing that high cefepime dosage is efficacious and safe in FN patients. Routine TDM does not appear to be needed in FN patients with preserved renal function. However, TDM might be reserved for FN patients at high risk of cefepime-induced neurotoxicity or when intended to cover pathogens with a minimum inhibitory concentration >1 mg/L.

Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people.

BACKGROUND: This is an update of the original review published in the Cochrane Database of Systematic Reviews Issue 10, 2015.Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently, there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Increasingly, newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are being investigated. OBJECTIVES: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people. SEARCH METHODS: We searched MEDLINE (1946 to June 2015) and Embase (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. For this review update we updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 3) in the Cochrane Library; MEDLINE via Ovid (June 2015 to March week 2 2018); and Embase via Ovid (June 2015 to 2018 week 12). SELECTION CRITERIA: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control and retrospective studies were excluded from the analysis. DATA COLLECTION AND ANALYSIS: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity. MAIN RESULTS: We included 29 primary studies (18 from the original review and 11 from this update), corresponding to 34 data sets, published between 2000 and 2018 in the meta-analyses, with a mean prevalence of proven or probable IA of 16.3 (median prevalence 11.1% , range 2.5% to 57.1%). Most patients had received chemotherapy for haematological malignancy or had undergone hematopoietic stem cell transplantation. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The summary estimates of sensitivity and specificity were 79.2% (95% confidence interval (CI) 71.0 to 85.5) and 79.6% (95% CI 69.9 to 86.6) for a single positive test result, and 59.6% (95% CI 40.7 to 76.0) and 95.1% (95% CI 87.0 to 98.2) for two consecutive positive test results. AUTHORS' CONCLUSIONS: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as the diagnostic criterion for IA in a population of 100 people with a disease prevalence of 16.3% (overall mean prevalence), three people with IA would be missed (sensitivity 79.2%, 20.8% false negatives), and 17 people would be unnecessarily treated or referred for further tests (specificity of 79.6%, 21.4% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that nine IA people would be missed (sensitivity 59.6%, 40.4% false negatives) and four people would be unnecessarily treated or referred for further tests (specificity of 95.1%, 4.9% false positives). Like galactomannan, PCR has good NPV for excluding disease, but the low prevalence of disease limits the ability to rule in a diagnosis. As these biomarkers detect different markers of disease, combining them is likely to prove more useful.

The eGVHD App has the potential to improve the accuracy of graft-versus-host disease assessment: a multicenter randomized controlled trial.

Graft-versus-host disease (GvHD) assessment has been shown to be a challenge for healthcare professionals, leading to the development of the eGVHD App (www.uzleuven.be/egvhd). In this study, we formally evaluated the accuracy of using the App compared to traditional assessment methods to assess GvHD. Our national multicenter randomized controlled trial involved seven Belgian transplantation centers and 78 healthcare professionals selected using a 2-stage convenience sampling approach between January and April 2017. Using a 1:1 randomization stratified by profession, healthcare professionals were assigned to use either the App ("APP") or their usual GvHD assessment aids ("No APP") to assess the diagnosis and severity score of 10 expert-validated clinical vignettes. Our main outcome measure was the difference in accuracy for GvHD severity scoring between both groups. The odds of being correct were 6.14 (95%CI: 2.83-13.34) and 6.29 (95%CI: 4.32-9.15) times higher in favor of the "APP" group for diagnosis and scoring, respectively (P<0.001). App-assisted GvHD severity scoring was significantly superior for both acute and chronic GvHD, with an Odds Ratio of 17.89 and 4.34 respectively (P<0.001) and showed a significantly increased inter-observer agreement compared to standard practice. Despite a mean increase of 24 minutes (95%CI: 20.45-26.97) in the time needed to score the whole GvHD test package in the "APP" group (P<0.001), usability feedback was positive. The eGVHD App shows superior GvHD assessment accuracy compared to standard practice and has the potential to improve the quality of outcome data registration in allogeneic stem cell transplantation.

A Multimodal Imaging Approach Enables In Vivo Assessment of Antifungal Treatment in a Mouse Model of Invasive Pulmonary Aspergillosis.

Aspergillus fumigatus causes life-threatening lung infections in immunocompromised patients. Mouse models are extensively used in research to assess the in vivo efficacies of antifungals. In recent years, there has been an increasing interest in the use of noninvasive imaging techniques to evaluate experimental infections. However, single imaging modalities have limitations concerning the type of information they can provide. In this study, magnetic resonance imaging and bioluminescence imaging were combined to obtain longitudinal information on the extent of developing lesions and fungal load in a leukopenic mouse model of invasive pulmonary aspergillosis (IPA). This multimodal imaging approach was used to assess changes occurring within lungs of infected mice receiving voriconazole treatment starting at different time points after infection. The results showed that IPA development depends on the inoculum size used to infect animals and that disease can be successfully prevented or treated by initiating intervention during early stages of infection. Furthermore, we demonstrated that a reduction in fungal load is not necessarily associated with the disappearance of lesions on anatomical lung images, especially when antifungal treatment coincides with immune recovery. In conclusion, multimodal imaging allows an investigation of different aspects of disease progression or recovery by providing complementary information on dynamic processes, which are highly useful for assessing the efficacy of (novel) therapeutic compounds in a time- and labor-efficient manner.

Retrospective chart review of hospitalizations and costs associated with the treatment of adults with Philadelphia-negative B-cell relapsed or refractory acute lymphoblastic leukemia in Belgium.

OBJECTIVES: To quantify hospitalizations and costs among adults with Philadelphia-negative relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) who received current salvage chemotherapies in Belgium. METHODS: A retrospective chart review identified patients aged ≥18 years and hospitalized between 2005 and 2015 for Ph-negative R/R B-cell ALL. Data were collected from the index date (first diagnosis of R/R ALL) until death or loss to follow-up. The salvage chemotherapy period was defined as the first chemotherapy hospitalization after the index date to the earliest of death, loss to follow-up, last chemotherapy dose plus 30 days, or initiation of hematological stem cell transplantation (HSCT). The primary endpoint was the percent of time in the hospital during the salvage chemotherapy period. Hospitalization costs were reported from the public health care payer perspective. RESULTS: Nineteen patients were included, with median age of 37 years. The average proportion of time patients spent in the hospital during the salvage chemotherapy period was 50.5%. From the index date to death, patients received a mean of 1.8 lines of chemotherapy, most commonly hyper-CVAD (31%). There was a mean of 5.5 inpatient hospitalizations and 40.1 outpatient visits with 40.8 outpatient lab tests. Mean costs per patient were €79,973 for hospitalization (excluding HSCT), €26,337 for HSCT, €21,007 for chemotherapy drugs, and €6,341 for outpatient management, resulting in a total cost from the payer's perspective of €133,965 per patient. CONCLUSION: Adults with Ph-negative R/R ALL spend half the time receiving salvage chemotherapy in the hospital. Their treatment is associated with large reimbursement costs in Belgium.

Cost-effectiveness analysis of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis in Spain.

OBJECTIVE: According to a recent randomized, double-blind clinical trial comparing the combination of voriconazole and anidulafungin (VOR+ANI) with VOR monotherapy for invasive aspergillosis (IA) in patients with hematologic disease or with hematopoietic stem cell transplant, mortality was lower after 6 weeks with VOR+ANI than with VOR monotherapy in a post hoc analysis of patients with galactomannan-based IA. The objective of this study was to compare the cost-effectiveness of VOR+ANI with VOR, from the perspective of hospitals in the Spanish National Health System. METHODS: An economic model with deterministic and probabilistic analyses was used to determine costs per life-year gained (LYG) for VOR+ANI versus VOR in patients with galactomannan-based IA. Mortality, adverse event rates, and life expectancy were obtained from clinical trial data. The costs (in 2015 euros [€]) of the drugs and the adverse event-related costs were obtained from Spanish sources. A Tornado plot and a Monte Carlo simulation (1,000 iterations) were used to assess uncertainty of all model variables. RESULTS: According to the deterministic analysis, for each patient treated with VOR+ANI compared with VOR monotherapy, there would be a total of 0.348 LYG (2.529 vs 2.181 years, respectively) at an incremental cost of €5,493 (€17,902 vs €12,409, respectively). Consequently, the additional cost per LYG with VOR+ANI compared with VOR would be €15,785. Deterministic sensitivity analyses confirmed the robustness of these findings. In the probabilistic analysis, the cost per LYG with VOR+ANI was €15,774 (95% confidence interval: €15,763-16,692). The probability of VOR+ANI being cost-effective compared with VOR was estimated at 82.5% and 91.9%, based on local cost-effectiveness thresholds of €30,000 and €45,000, respectively. CONCLUSION: According to the present economic study, combination therapy with VOR+ANI is cost-effective as primary therapy of IA in galactomannan-positive patients in Spain who have hematologic disease or hematopoietic stem cell transplant, compared with VOR monotherapy.

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging.

Invasive aspergillosis is an emerging threat to public health due to the increasing use of immune suppressive drugs and the emergence of resistance against antifungal drugs. To deal with this threat, research on experimental disease models provides insight into the pathogenesis of infections caused by susceptible and resistant Aspergillus strains and by assessing their response to antifungal drugs. However, standard techniques used to evaluate infection in a preclinical setting are severely limited by their invasive character, thereby precluding evaluation of disease extent and therapy effects in the same animal. To enable non-invasive, longitudinal monitoring of invasive pulmonary aspergillosis in mice, we optimized computed tomography (CT) and magnetic resonance imaging (MRI) techniques for daily follow-up of neutropenic BALB/c mice intranasally infected with A. fumigatus spores. Based on the images, lung parameters (signal intensity, lung tissue volume and total lung volume) were quantified to obtain objective information on disease onset, progression and extent for each animal individually. Fungal lung lesions present in infected animals were successfully visualized and quantified by both CT and MRI. By using an advanced MR pulse sequence with ultrashort echo times, pathological changes within the infected lung became visually and quantitatively detectable at earlier disease stages, thereby providing valuable information on disease onset and progression with high sensitivity. In conclusion, these non-invasive imaging techniques prove to be valuable tools for the longitudinal evaluation of dynamic disease-related changes and differences in disease severity in individual animals that might be readily applied for rapid and cost-efficient drug screening in preclinical models in vivo.

Burden of serious fungal infections in Belgium.

We aimed to estimate the total number of serious fungal infections occurring yearly in Belgium. The number of cryptococcal infections was retrieved from the National Reference Center for Mycosis. Populations at risk and fungal infections frequencies in these populations were used to estimate incidence or prevalence of other fungal infections. The Belgian population consists of 11.10 million people. Cryptococcal meningitis is rare. In all, 15 of the 1227 newly diagnosed HIV/AIDS cases presented with Pneumocystis jirovecii pneumonia. This accounts for ±14% of total PCP cases (n = 120). The incidence of candidaemia is estimated as 5/100,000 resulting in 555 cases and 213 deaths. A total number of 675 invasive aspergillosis cases and ≥169 deaths attributed to this infection were calculated. Chronic pulmonary aspergillosis is estimated to be prevalent in 662 cases. Allergic bronchopulmonary aspergillosis cases were estimated to be 23,119 applying a 2.5% and 15% rate in adult asthma and cystic fibrosis patients respectively. Severe asthma with fungal sensitisation cases was estimated to be 30,402. There were 174,760 women with recurrent Candida vaginitis assuming a 6% rate in women aged between 15 and 50. Approximately 233,000 people of the Belgian population (2.1%) are estimated to suffer from a fungal infection on a yearly basis.

Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people.

BACKGROUND: Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are increasingly being investigated. OBJECTIVES: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people. SEARCH METHODS: We searched MEDLINE (1946 to June 2015) and EMBASE (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. SELECTION CRITERIA: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control studies were excluded from the analysis. DATA COLLECTION AND ANALYSIS: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity. MAIN RESULTS: Eighteen primary studies, corresponding to 19 cohorts and 22 data sets, published between 2000 and 2013 were included in the meta-analyses, with a median prevalence of IA (proven or probable) of 12.0% (range 2.5 to 30.8 %). The majority of people had received chemotherapy for a haematological malignancy or had undergone a hematopoietic stem cell transplant. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The mean sensitivity and specificity were 80.5% (95% CI; 73.0 to 86.3) and 78.5% (67.8 to 86.4) for a single positive test result, and 58.0% (36.5 to 76.8) and 96.2% (89.6 to 98.6) for two consecutive positive test results. AUTHORS' CONCLUSIONS: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as diagnostic criterion for IA in a population of 100 people with a disease prevalence of 13.0% (overall mean prevalence), three people with IA would be missed (sensitivity 80.5%, 19.5% false negatives), and 19 people would be unnecessarily treated or referred for further tests (specificity of 78.5%, 21.5% false positives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that six IA people would be missed (sensitivity 58.0%, 42.1% false negatives) and three people would be unnecessarily treated or referred for further tests (specificity of 96.2%, 3.8% false positives). Galactomannan and PCR have good NPV for excluding disease but the low prevalence of disease limits the ability to rule in a diagnosis. The biomarkers are detecting different aspects of disease and the combination of both together is likely to be more useful.

Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people.

BACKGROUND: Invasive aspergillosis (IA) is the most common life-threatening opportunistic invasive mould infection in immunocompromised people. Early diagnosis of IA and prompt administration of appropriate antifungal treatment are critical to the survival of people with IA. Antifungal drugs can be given as prophylaxis or empirical therapy, instigated on the basis of a diagnostic strategy (the pre-emptive approach) or for treating established disease. Consequently there is an urgent need for research into both new diagnostic tools and drug treatment strategies. Newer methods such as polymerase chain reaction (PCR) to detect fungal nucleic acids are increasingly being investigated. OBJECTIVES: To provide an overall summary of the diagnostic accuracy of PCR-based tests on blood specimens for the diagnosis of IA in immunocompromised people. SEARCH METHODS: We searched MEDLINE (1946 to June 2015) and EMBASE (1980 to June 2015). We also searched LILACS, DARE, Health Technology Assessment, Web of Science and Scopus to June 2015. We checked the reference lists of all the studies identified by the above methods and contacted relevant authors and researchers in the field. SELECTION CRITERIA: We included studies that: i) compared the results of blood PCR tests with the reference standard published by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG); ii) reported data on false-positive, true-positive, false-negative and true-negative results of the diagnostic tests under investigation separately; and iii) evaluated the test(s) prospectively in cohorts of people from a relevant clinical population, defined as a group of individuals at high risk for invasive aspergillosis. Case-control studies were excluded from the analysis. DATA COLLECTION AND ANALYSIS: Authors independently assessed quality and extracted data. For PCR assays, we evaluated the requirement for either one or two consecutive samples to be positive for diagnostic accuracy. We investigated heterogeneity by subgroup analyses. We plotted estimates of sensitivity and specificity from each study in receiver operating characteristics (ROC) space and constructed forest plots for visual examination of variation in test accuracy. We performed meta-analyses using the bivariate model to produce summary estimates of sensitivity and specificity. MAIN RESULTS: Eighteen primary studies, corresponding to 19 cohorts and 22 data sets, published between 2000 and 2013 were included in the meta-analyses, with a median prevalence of IA (proven or probable) of 12.0% (range 2.5 to 30.8 %). The majority of people had received chemotherapy for a haematological malignancy or had undergone a hematopoietic stem cell transplant. Several PCR techniques were used among the included studies. The sensitivity and specificity of PCR for the diagnosis of IA varied according to the interpretative criteria used to define a test as positive. The mean sensitivity and specificity were 80.5% (95% CI; 73.0 to 86.3) and 78.5% (67.8 to 86.4) for a single positive test result, and 58.0% (36.5 to 76.8) and 96.2% (89.6 to 98.6) for two consecutive positive test results. AUTHORS' CONCLUSIONS: PCR shows moderate diagnostic accuracy when used as screening tests for IA in high-risk patient groups. Importantly the sensitivity of the test confers a high negative predictive value (NPV) such that a negative test allows the diagnosis to be excluded. Consecutive positives show good specificity in diagnosis of IA and could be used to trigger radiological and other investigations or for pre-emptive therapy in the absence of specific radiological signs when the clinical suspicion of infection is high. When a single PCR positive test is used as diagnostic criterion for IA in a population of 100 people with a disease prevalence of 13.0% (overall mean prevalence), three people with IA would be missed (sensitivity 80.5%, 19.5% false negatives), and 19 people would be unnecessarily treated or referred for further tests (specificity of 78.5%, 21.5% false negatives). If we use the two positive test requirement in a population with the same disease prevalence, it would mean that six IA people would be missed (sensitivity 58.0%, 42.1% false negatives) and three people would be unnecessarily treated or referred for further tests (specificity of 96.2%, 3.8% false negatives). Galactamannan and PCR have good NPV for excluding disease but the low prevalence of disease limits the ability to rule in a diagnosis. The biomarkers are detecting different aspects of disease and the combination of both together is likely to be more useful.

Economic Comparison of an Empirical Versus Diagnostic-Driven Strategy for Treating Invasive Fungal Disease in Immunocompromised Patients.

PURPOSE: Patients with persistent or recurrent neutropenic fevers at risk of invasive fungal disease (IFD) are treated empirically with antifungal therapy (AFT). Early treatment using a diagnostic-driven (DD) strategy may reduce clinical and economic burdens. We compared costs and outcomes of both strategies from a UK perspective. METHODS: An empirical strategy with conventional amphotericin B deoxycholate (C-AmB), liposomal amphotericin B (L-AmB), or caspofungin was compared with a DD strategy (initiated based on positive ELISA results for galactomannan antigen) and/or positive results for Aspergillus species on polymerase chain reaction assay) using C-AmB, voriconazole, or L-AmB in a decision-analytic model. Rates of IFD incidence, overall mortality, and IFD-related mortality in adults expected to be neutropenic for ≥10 days were obtained. The empirical strategy was assumed to identify 30% of IFD and targeted AFT to improve survival by a hazard ratio of 0.589. AFT-specific adverse events were obtained from a summary of product characteristics. Resource use was obtained, and costs were estimated by using standard UK costing sources. All costs are presented in 2012 British pounds sterling. FINDINGS: Total costs were 32% lower for the DD strategy (£1561.29) versus the empirical strategy (£2301.93) due to a reduced incidence of adverse events and decreased use of AFT. Administration of AFT was reduced by 41% (DD strategy, 74 of 1000; empirical strategy, 125 of 1000), with similar survival rates. IMPLICATIONS: This study suggests that a DD strategy is likely to be cost-saving versus empirical treatment for immunocompromised patients with persistent or recurrent neutropenic fevers.

Predicting febrile neutropenic patients at low risk using the MASCC score: does bacteremia matter?

BACKGROUND: Febrile neutropenic cancer patients represent a heterogeneous population with a limited proportion at risk of serious medical complications. The Multinational Association for Supportive Care in Cancer (MASCC) score has been developed and validated for identifying low-risk patients at the onset of febrile neutropenia. Since bacteremia, although not documented at baseline, is a predictor of pejorative outcome, the purpose of this study was to investigate the possible interaction between the MASCC score and bacteremic status and to assess whether, assuming that bacteremic status could be predicted at onset of febrile neutropenia, adding bacteremia as a covariate in a risk model would improve the accuracy of low-risk patients identification. METHODS: Two consecutive multicentric observational studies were carried out from 1994 till 2005 involving 2,142 febrile neutropenic patients. The study data bases were retrospectively used for the present analysis. RESULTS: A predictive value was found for the MASCC score in all strata obtained by stratification for the bacteremic status with odds ratios for successful outcome being, in patients with a score ≥21, respectively, 6.06 (95%CI: 4.51-8.15), 3.42 (95%CI: 1.95-5.98), and 6.04 (95%CI: 3.01-12.09) in patients without bacteremia, gram-positive bacteremia, and gram-negative bacteremia. No interaction between the MASCC score and the bacteremic status was present. A clinical prediction rule integrating the MASCC score and the bacteremic status was not helpful in improving the identification of low-risk patients. This rule may then be used in a general population of patients with febrile neutropenia without having concerns for a lower predictive value in bacteremic patients. CONCLUSIONS: Our results suggest that the knowledge, provided we could find a model to predict it at fever onset, of a bacteremic etiology of the fever would be of little additional value to the MASCC score when attempting to identify low-risk patients.