Invasive aspergillosis (IA) is a rare complication in solid organ transplant (SOT) recipients. Although IA has significant implications on graft and patient survival, data on diagnosis and management ...of this infection in SOT recipients are still limited.
Discussion of current practices and limitations in the diagnosis, prophylaxis, and treatment of IA and proposal of means of assessing treatment response in SOT recipients.
Liver, lung, heart or kidney transplant recipients have common as well as different risk factors to the development of IA, thus each category needs a separate evaluation. Diagnosis of IA in SOT recipients requires a high degree of awareness, because established diagnostic tools may not provide the same sensitivity and specificity observed in the neutropenic population. IA treatment relies primarily on mold-active triazoles, but potential interactions with immunosuppressants and other concomitant therapies need special attention.
Criteria to assess response have not been sufficiently evaluated in the SOT population and CT lesion dynamics, and serologic markers may be influenced by the underlying disease and type and severity of immunosuppression. There is a need for well-orchestrated efforts to study IA diagnosis and management in SOT recipients and to develop comprehensive guidelines for this population.
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Bloodstream infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are associated with treatment failure and increased mortality. Detection of CPE from blood cultures (BC) by standard ...methods takes 16-72 hours, which can delay the initiation of appropriate antimicrobial therapy and compromise patient outcome. In the present study, we developed and evaluated a new method for the rapid detection of carbapenemases directly from positive BC using a new multiplex immunochromatographic test (ICT). The new ICT was assessed using 170 molecularly characterized Enterobacteriaceae clinical isolates including 126 CPE (OXA-48-like (N = 79), KPC (N = 18) and NDM (N = 29)). After spiking with bacteria and incubation in a BC system, blood from positive BC bottles was hemolyzed, bacteria concentrated by centrifugation and lysed. The lysate was transferred to the RESIST-3 O.K.N. ICT (Coris BioConcept, Gembloux, Belgium), which detects OXA-48-like, KPC and NDM carbapenemases. The final results of the ICT were read when they became positive, at the latest after 15 min. All CPE isolates (126/126) were correctly detected with the new protocol (100% sensitivity, 100% specificity). There was perfect concordance between ICT results and molecular characterization. Total time to result was 20-45 min.
This proof-of-principle study demonstrates that with the newly developed method, OXA-48-like, KPC and NDM carbapenemases can be reliably detected directly from positive BC bottles. The new method is more rapid than other currently available assays and can be performed in any routine microbiology laboratory. This can help to rapidly identify patients with CPE BSI and optimize the management of patients with these difficult-to-treat infections. Further studies are needed to assess the performance of the ICT in routine diagnostics.
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Background
Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment‐related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The ...two main types of prophylactic regimens are granulocyte (macrophage) colony‐stimulating factors (G(M)‐CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony‐stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken.
Objectives
To compare the efficacy and safety of G(M)‐CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full‐text and publications. Two review authors independently screened search results.
Selection criteria
We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)‐CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full‐text, s, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross‐over trials, quasi‐randomised trials and post‐hoc retrospective trials.
Data collection and analysis
Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician.
Main results
In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high‐dose chemotherapy and G‐CSF compared to antibiotics, a second one evaluating 155 patients with small‐cell lung cancer receiving GM‐CSF or antibiotics.
We judge the overall risk of bias as high in the G‐CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM‐CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.
For the trial comparing G‐CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection‐related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection‐related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.
There was no evidence of a difference in terms of median survival time in the trial comparing GM‐CSF and antibiotics. Two‐year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM‐CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM‐CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM‐CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non‐haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM‐CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection‐related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial.
Authors' conclusions
As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)‐CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.
1 Klinik I für Innere Medizin, Klinikum der Universität Köln
2 Zentrum für Klinische Studien (01KN0706), Köln
3 Onkologikum Frankfurt am Museumsufer, Frankfurt
4 III. Medizinische Klinik, ...Universitätsklinikum Mannheim gGmbH, Mannheim
5 Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg
6 Klinik für Hämatologie und Onkologie, Klinikum Neuperlach, München
7 Medizinische Klinik 5, Hämatologie und Internistische Onkologie, Universitätsklinikum Erlangen, Erlangen
8 Medizinische Klinik C, Ernst-Moritz-Arndt-Universität, Greifswald
9 Medizinische Klinik Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Potsdam
10 Charité, Campus Benjamin Franklin, Klinik für Hämatologie und Onkologie, Berlin
11 Pädiatrische Hämatologie/Onkologie, Universitätsklinikum Münster, Münster
12 Charité Universitätsmedizin, Campus Charité Mitte, Medizinische Klinik und Poliklinik II, Berlin
13 Schwerpunktpraxis für Hämatologie und Onkologie, Weilheim, Germany
14 Haematological Sciences (CALS), Leech Building, Medical School, Newcastle upon Tyne, United Kingdom
15 Martin-Luther-Universität Halle-Wittenberg, Halle
16 Johannes Gutenberg-Universität, III. Medizinische Klinik, Mainz, Germany
Correspondence: Oliver A. Cornely, MD, Klinikum der Universität zu Köln, Klinik I für Innere Medizin Zentrum für Klinische Studien (BMBF 01KN0706) 50924 Köln, Germany. E-mail: oliver.cornely{at}ctuc.de
There is no widely accepted standard for antifungal prophylaxis in patients with hematologic malignancies. The Infectious Diseases Working Party of the German Society for Haematology and Oncology assigned a committee of hematologists and infectious disease specialists to develop recommendations. Literature data bases were systematically searched for clinical trials on antifungal prophylaxis. The studies identified were shared within the committee. Data were extracted by two of the authors (OAC and MSi). The consensus process was conducted by email communication. Finally, a review committee discussed the proposed recommendations. After consensus was established the recommendations were finalized. A total of 86 trials were identified including 16,922 patients. Only a few trials yielded significant differences in efficacy. Fluconazole 400 mg/d improved the incidence rates of invasive fungal infections and attributable mortality in allogeneic stem cell recipients. Posaconazole 600 mg/d reduced the incidence of IFI and attributable mortality in allogeneic stem cell recipients with severe graft versus host disease, and in patients with acute myelogenous leukemia or myelodysplastic syndrome additionally reduced overall mortality. Aerosolized liposomal amphotericin B reduced the incidence rate of invasive pulmonary aspergillosis. Posaconazole 600 mg/d is recommended in patients with acute myelogenous leukemia/myelodysplastic syndrome or undergoing allogeneic stem cell recipients with graft versus host disease for the prevention of invasive fungal infections and attributable mortality (Level A I). Fluconazole 400 mg/d is recommended in allogeneic stem cell recipients until development of graft versus host disease only (Level A I). Aerosolized liposomal amphotericin B is recommended during prolonged neutropenia (Level B II).
Key words: invasive fungal infection, antifungal prophylaxis, itraconazole, fluconazole, posaconazole, amphotericin B, liposomal.
Well-characterized biomaterials of high quality have great potential for acceleration and quality improvement in translational biomedical research. To improve accessibility of local sample ...collections, efforts have been made to create central biomaterial banks and catalogues. Available technical solutions for creating professional local sample catalogues and connecting them to central systems are cost intensive and/or technically complex to implement. Therefore, the Translational Thematic Unit HIV of the German Center for Infection Research (DZIF) developed a Laboratory Information and Management System (LIMS) called HIV Engaged Research Technology (HEnRY) for implementation into the Translational Platform HIV (TP-HIV) at the DZIF and other research networks.
HEnRY is developed at the University Hospital of Cologne. It is an advanced LIMS to manage processing and storage of samples and aliquots of different sample types. Features include: monitoring of stored samples and associated information data selection via query tools or Structured Query Language (SQL) preparation of summary documents, including scannable search lists centralized management of the practical laboratory part of multicentre studies (e.g. import of drawing schemes and sample processing steps), preparation of aliquot shipments, including associated documents to be added to shipments unique and secure identification of aliquots through use of customizable Quick Response (QR) code labels directly from HEnRY support of aliquot data transmission to central registries. In summary, HEnRY offers all features necessary for a LIMS software. In addition, the structure of HEnRY provides sufficient flexibility to allow the implementation in other research areas.
HEnRY is a free biobanking tool published under the MIT license. While it was developed to support HIV research in Germany, the feature set and language options, allow much broader applications and make this a powerful free research tool.
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Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) ...continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 2.95-5.92 L h.sup.- 1 and central volume of distribution of 4.29 1.81-7.33 L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 7-25 % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude. Keywords: Methotrexate, Pharmacokinetics, Covariates, Dosing
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Awareness is vital for cancer prevention. US studies show a strong link between web searches and cancer incidence. In Europe, the relationship remains unclear. This study characterizes regional and ...temporal relationships between cancer incidence and web searches and investigates the content of searches related to breast, cervical, colorectal, lung, prostate, and testicular cancer, brain tumors, and melanoma in Germany (July 2018-December 2019). Aggregate data from Google Ads Keyword Planner and national cancer registry data were analyzed. Spearman's correlation coefficient (r
) examined associations between cancer incidence and web search, repeated measures correlation (r
) assessed time trends and searches were qualitatively categorized. The frequency of malignancy-related web searches correlated with cancer incidence (r
= 0.88, P = 0.007), e.g., breast cancer had more queries than the lower-incidence cervical cancer. Seasonally, incidence and searches followed similar patterns, peaking in spring and fall, except for melanoma. Correlations between entity incidence and searches (0.037 ≤ r
≤ 0.208) varied regionally. Keywords mainly focused on diagnosis, symptoms, and general information, with variations between entities. In Germany, web searches correlated with regional and seasonal incidence, revealing differences between North/East and South/West. These insights may help improve prevention strategies by identifying regional needs and assessing impact of awareness campaigns.
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The burden of bloodstream infections remains high worldwide and cannot be confined to short-term in-hospital mortality. We aimed to develop scores to predict short-term and long-term mortality in ...patients with bloodstream infections.
The Bloodstream Infection due to Multidrug-resistant Organisms: Multicenter Study on Risk Factors and Clinical Outcomes (BLOOMY) study is a prospective, multicentre cohort study at six German tertiary care university hospitals to develop and validate two scores assessing 14-day and 6-month mortality in patients with bloodstream infections. We excluded patients younger than 18 years or who were admitted to an ophthalmology or psychiatry ward. Microbiological, clinical, laboratory, treatment, and survival data were prospectively collected on day 0 and day 3 and then from day 7 onwards, weekly. Participants were followed up for 6 months. All patients in the derivation cohort who were alive on day 3 were included in the analysis. Predictive scores were developed using logistic regression and Cox proportional hazards models with a machine-learning approach. Validation was completed using the C statistic and predictive accuracy was assessed using sensitivity, specificity, and predictive values.
Between Feb 1, 2017, and Jan 31, 2019, 2568 (61·5%) of 4179 eligible patients were recruited into the derivation cohort. The in-hospital mortality rate was 23·75% (95% CI 22·15–25·44; 610 of 2568 patients) and the 6-month mortality rate was 41·55% (39·54–43·59; 949 of 2284). The model predictors for 14-day mortality (C statistic 0·873, 95% CI 0·849–0·896) and 6-month mortality (0·807, 0·784–0·831) included age, body-mass index, platelet and leukocyte counts, C-reactive protein concentrations, malignancy (ie, comorbidity), in-hospital acquisition, and pathogen. Additional predictors were, for 14-day mortality, mental status, hypotension, and the need for mechanical ventilation on day 3 and, for 6-month mortality, focus of infection, in-hospital complications, and glomerular filtration rate at the end of treatment. The scores were validated in a cohort of 1023 patients with bloodstream infections, recruited between Oct 9, 2019, and Dec 31, 2020. The BLOOMY 14-day score showed a sensitivity of 61·32% (95% CI 51·81–70·04), a specificity of 86·36% (83·80–88·58), a positive predictive value (PPV) of 37·57% (30·70–44·99), and a negative predictive value (NPV) of 94·35% (92·42–95·80). The BLOOMY 6-month score showed a sensitivity of 69·93% (61·97–76·84), a specificity of 66·44% (61·86–70·73), a PPV of 40·82% (34·85–47·07), and a NPV of 86·97% (82·91–90·18).
The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections.
DZIF German Center for Infection Research.
For the German translation of the abstract see Supplementary Materials section.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Lean European Open Survey on SARS-CoV-2 Infected Patients (LEOSS) is a European registry for studying the epidemiology and clinical course of COVID-19. To support evidence-generation at the rapid ...pace required in a pandemic, LEOSS follows an Open Science approach, making data available to the public in real-time. To protect patient privacy, quantitative anonymization procedures are used to protect the continuously published data stream consisting of 16 variables on the course and therapy of COVID-19 from singling out, inference and linkage attacks. We investigated the bias introduced by this process and found that it has very little impact on the quality of output data. Current laws do not specify requirements for the application of formal anonymization methods, there is a lack of guidelines with clear recommendations and few real-world applications of quantitative anonymization procedures have been described in the literature. We therefore believe that our work can help others with developing urgently needed anonymization pipelines for their projects.
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