Publications by authors named "Thomas Lehrnbecher"

157 Publications

Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology.

Lancet Infect Dis 2021 Feb 16. Epub 2021 Feb 16.

Faculty of Medicine, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Clinical Trials Center Cologne, University of Cologne, Cologne, Germany; German Centre for Infection Research, partner site Bonn-Cologne, Cologne, Germany; European Confederation of Medical Mycology Council, Basel, Switzerland.

With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management.
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http://dx.doi.org/10.1016/S1473-3099(20)30784-2DOI Listing
February 2021

Invasive Mold Infection of the Central Nervous System in Immunocompromised Children.

J Fungi (Basel) 2020 Oct 16;6(4). Epub 2020 Oct 16.

Department of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University of Frankfurt, 60528 Frankfurt, Germany.

Due to the difficulties in the definite diagnosis, data on brain imaging in pediatric patients with central nervous system (CNS)-invasive mold infection (IMD) are scarce. Our aim was to describe brain imaging abnormalities seen in immunocompromised children with CNS-IMD, and to analyze retrospectively whether specific imaging findings and sequences have a prognostic value. In a retrospective study of 19 pediatric patients with proven or probable CNS-IMD, magnetic resonance imaging (MRI)-findings were described and analyzed. The results were correlated with outcome, namely death, severe sequelae, or no neurological sequelae. : 11 children and 8 adolescents (11/8 with proven/probable CNS-IMD) were included. Seven of the patients died and 12/19 children survived (63%): seven without major neurological sequelae and five with major neurological sequelae. Multifocal ring enhancement and diffusion restriction were the most common brain MRI changes. Diffusion restriction was mostly seen at the core of the lesion. No patient with disease limited to one lobe died. Perivascular microbleeding seen on susceptibility weighted imaging (SWI) and/or gradient-echo/T2* images, as well as infarction, were associated with poor prognosis. The presence of infarction was related to poor outcome. As early microbleeding seems to be associated with poor prognosis, we suggest including SWI in routine diagnostic evaluation of immunocompromised children with suspected CNS-IMD.
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http://dx.doi.org/10.3390/jof6040226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711511PMC
October 2020

Systemic viral infection in children receiving chemotherapy for acute leukemia.

Pediatr Blood Cancer 2020 12 12;67(12):e28673. Epub 2020 Sep 12.

Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, Frankfurt, Germany.

Systemic viral diseases frequently occur in allogeneic hematopoietic stem cell transplantation, but data in children receiving chemotherapy for acute leukemia are scarce. We therefore collected and analyzed the published data on symptomatic infection from cytomegalovirus, herpes simplex virus, varicella zoster virus, parvovirus B19, or adenovirus in pediatric acute leukemia. Reports on 68 children were identified, of whom 16 patients have died from the infection. Further studies have to (1) evaluate the true incidence of these infections in pediatric acute leukemia, (2) their impact on outcome, and (3) whether a subpopulation of patients could benefit from screening and prophylactic strategies.
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http://dx.doi.org/10.1002/pbc.28673DOI Listing
December 2020

Conventional compared to network meta-analysis to evaluate antibiotic prophylaxis in patients with cancer and haematopoietic stem cell transplantation recipients.

BMJ Evid Based Med 2020 Aug 31. Epub 2020 Aug 31.

Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario, Canada

Our purpose was to compare conventional meta-analysis and network meta-analysis to evaluate the efficacy of different prophylactic systemic antibiotic classes in patients undergoing chemotherapy or haematopoietic stem cell transplant (HSCT). We included randomised trials if patients had cancer or were HSCT recipients and the intervention was systemic antibacterial prophylaxis. Three types of control groups were used: (1) placebo, no antibiotic and non-absorbable antibiotic separately; (2) placebo and no antibiotic combined; and (3) all three combined. These gave different network geometries. Strategies synthesised were fluoroquinolone, trimethoprim-sulfamethoxazole, cephalosporin and parenteral glycopeptide versus control groups. In total 113 trials met the eligibility criteria. Where treatment effects could be estimated with both conventional and network meta-analysis, values were generally similar. However, where events were sparse, network meta-analysis could be more precise. For example, trimethoprim-sulfamethoxazole versus placebo for infection-related mortality showed a relative risk ratio (RR) of 0.55, 95% CI (0.21 to 1.44) with conventional, and RR 0.43, 95% credible region (0.20 to 0.82) with network meta-analysis. Cephalosporin versus fluoroquinolone was comparable only indirectly using the network approach and yielded RR 0.59, 95% credible region (0.28 to 1.20) to reduce bacteraemia. Incoherence (difference between direct and indirect estimates raising concerns about network meta-analysis validity) was observed with network geometry where control groups were separated, but not where control groups were combined. In this situation, conventional and network meta-analysis yielded similar results in general. Network meta-analysis results could be more precise when events were rare. Some analysis could only be performed with the network approach. These results identify scenarios in which network meta-analysis may be advantageous.
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http://dx.doi.org/10.1136/bmjebm-2020-111362DOI Listing
August 2020

Pediatric CNS imaging and long-term effects of irradiation in pediatric oncology patients.

Pediatr Int 2021 Jan 5;63(1):81-87. Epub 2020 Dec 5.

Institute of Neuroradiology, Frankfurt, Germany.

Background: The aim of this study was to evaluate post-irradiation changes in the central nervous system (CNS) detected using magnetic resonance (MR) imaging.

Methods: Magnetic resonance images of 15 children with CNS tumors treated through whole-brain irradiation over 10 years were reviewed retrospectively. Variables such as age at the time of irradiation, total radiation dose, treatment length, and time interval between irradiation and MR changes, were evaluated.

Results: All patients included in the study had imaging abnormalities of the CNS. Eight patients (53%) developed CNS abnormalities within a short period of time - only a few months after irradiation (mean 4.8 months). Seven patients (47%) developed CNS abnormalities within a long time interval after treatment (mean 4.6 years). In almost all patients, a T2 increase in supra- and infratentorial white matter was observed. Follow-up examinations showed nine patients (60%) with cerebellar atrophy.

Conclusions: In this sample of pediatric patients who underwent whole-brain irradiation, the time receiving irradiation was not related to the severity of the MR changes. A correlation between the age of the child or the length of the radiotherapy and the extent of the changes could not be confirmed. However, we observed a trend towards stronger brain parenchymal degeneration with cystic changes in the younger age group of children in our sample. Older children who received irradiation seem to be more susceptible to vascular dysplasia with cavernous hemangiomas and microbleeding.
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http://dx.doi.org/10.1111/ped.14409DOI Listing
January 2021

The role of magnetic resonance imaging in the diagnosis of central nervous system involvement in children with acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 10 2;67(10):e28294. Epub 2020 Aug 2.

Institute of Neuroradiology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.

Purpose: Acute lymphoblastic leukemia (ALL) is the most frequent malignancy in childhood. As central nervous system (CNS) involvement requires an intensified CNS-targeted therapy, timely diagnosis is essential. The aim of this retrospective analysis was to evaluate whether cranial magnetic resonance imaging (MRI) examinations findings correlate with cerebrospinal fluid (CSF) analysis on CNS involvement and whether MRI examinations reveal incidental findings with a clinical consequence.

Methods: All pediatric patients with ALL at our institution between 1998 and 2016 were identified. Patients were divided into two groups: de novo and relapsed ALL. Both groups were analyzed separately for the presence of CNS involvement. Incidental findings were also evaluated.

Results: Two hundred fifteen patients with de novo ALL and 31 with relapsed ALL were identified. In the de novo group, no patient was diagnosed CNS positive based on MRI results alone. In relapsed patients, only one patient had a positive MRI with negative CSF results and no neurological symptoms, thus was classified CNS positive solely on the basis of the MRI. In both groups, no patient showed an incidental finding that required therapy.

Conclusion: In our study, MRI examinations do not improve the detection of CNS involvement compared with CSF analysis alone. In addition, the analysis of incidental findings does not add value to the performance of an MRI examination performed prior to treatment. Overall, MRI prior to treatment in pediatric patients with ALL is not necessary.
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http://dx.doi.org/10.1002/pbc.28294DOI Listing
October 2020

Pharmacokinetics and safety of posaconazole intravenous solution and powder for oral suspension in children with neutropenia: an open-label, sequential dose-escalation trial.

Int J Antimicrob Agents 2020 Sep 17;56(3):106084. Epub 2020 Jul 17.

Merck & Co., Inc., Kenilworth, NJ, USA.

Posaconazole is approved for use in adults as an intravenous (IV) solution and two different oral formulations (a suspension and an improved bioavailability tablet). Data on the pharmacokinetics (PK), dosing and safety of posaconazole in children are limited. A novel powder for oral suspension (PFS) offers the bioavailability of the tablet formulated for weight-based dosing in children. A non-randomised, open-label, sequential dose-escalation, phase 1b trial evaluated the PK and safety of posaconazole IV and PFS in children aged 2 to 17 years with documented or expected neutropenia (ClinicalTrials.gov, NCT02452034; MSD protocol number, MK-5592-P097). Participants received posaconazole IV 3.5, 4.5 or 6.0 mg/kg/d for ≥10 days, with an option to switch to posaconazole PFS at the identical dose for ≤18 days. The target exposure was a mean within-dose cohort average steady-state plasma concentration (C) of ~1200 ng/mL, with ~90% of participants achieving C between 500 and 2500 ng/mL. Doses of 4.5 and 6.0 mg/kg/d achieved the PK target of ~90% of participants with a C ≥500 ng/mL. PFS resulted in lower posaconazole exposures than IV across age groups at all doses. Posaconazole IV and PFS were well tolerated and had safety profiles similar to those reported for adults. Posaconazole PK following IV and PFS administration was well characterised by the data and enable selection of appropriate paediatric doses. Both formulations were well tolerated without dose-, exposure- or age-related differences in the safety profiles.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106084DOI Listing
September 2020

Management of children with fever and neutropenia: results of a survey in 51 pediatric cancer centers in Germany, Austria, and Switzerland.

Infection 2020 Aug 10;48(4):607-618. Epub 2020 Jun 10.

Pediatric Oncology and Hematology, Childrens' Hospital Medical Center, Saarland University Clinic, Kirrberger Str. Building 09, 66421, Homburg, Germany.

Purpose: Investigation of the current practice of diagnostics and treatment in pediatric cancer patients with febrile neutropenia.

Methods: On behalf of the German Society for Pediatric Oncology and Hematology and the German Society for Pediatric Infectious Diseases, an Internet-based survey was conducted in 2016 concerning the management of febrile neutropenia in pediatric oncology centers (POC). This survey accompanied the release of the corresponding German guideline to document current practice before its implementation in clinical practice.

Results: In total, 51 POCs participated (response rate 73%; 43 from Germany, and 4 each from Austria and Switzerland). Identified targets for antimicrobial stewardship concerned blood culture diagnostics, documentation of the time to antibiotics, the use of empirical combination therapy, drug monitoring of aminoglycosides, the time to escalation in patients with persisting fever, minimal duration of IV treatment, sequential oral treatment in patients with persisting neutropenia, indication for and choice of empirical antifungal treatment, and the local availability of a pediatric infectious diseases consultation service.

Conclusion: This survey provides useful information for local antibiotic stewardship teams to improve the current practice referring to the corresponding national and international guidelines.
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http://dx.doi.org/10.1007/s15010-020-01462-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395019PMC
August 2020

Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients.

J Clin Oncol 2020 09 27;38(27):3205-3216. Epub 2020 May 27.

Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients.

Methods: Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients.

Results: There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made.

Conclusion: We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.
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http://dx.doi.org/10.1200/JCO.20.00158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499615PMC
September 2020

Step-down and move forward.

Pediatr Blood Cancer 2020 07 8;67(7):e28342. Epub 2020 May 8.

Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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http://dx.doi.org/10.1002/pbc.28342DOI Listing
July 2020

Recent advances and future directions in the management of the immunocompromised host.

Semin Oncol 2020 02 24;47(1):40-47. Epub 2020 Feb 24.

Division for Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University Frankfurt am Main, Frankfurt, Germany. Electronic address:

Infectious complications are still a major cause of morbidity and mortality in children receiving therapy for cancer or undergoing hematopoietic stem cell transplantation. Current supportive care strategies consider numerous factors for defining the risk for an infection, but these risk-prediction models need to be refined to ultimately personalize anti-infective measures for an individual patient. It has been recognized that the performance of diagnostic tools including serum markers and imaging may differ between children and adults, and future studies have to assess in the pediatric population the combination of specific diagnostic tools in order to improve the early and reliable diagnosis of an infection. There is an ongoing debate on systemic anti-bacterial and antifungal prophylaxis, as these strategies have to weigh individual benefits of reducing infectious complications against the risk of increasing resistance rates in patients and within institutions. Although there was considerable progress in supportive anti-infective care strategies in children and adolescents over the last 2 decades, which resulted in the development of pediatric specific clinical practice guidelines, major effort is needed to close the open research gaps.
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http://dx.doi.org/10.1053/j.seminoncol.2020.02.005DOI Listing
February 2020

Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 06 6;55(6):1126-1136. Epub 2020 Feb 6.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University, Frankfurt am Main, Germany.

Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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http://dx.doi.org/10.1038/s41409-020-0818-4DOI Listing
June 2020

Invasive Scedosporium spp. and Lomentospora prolificans infections in pediatric patients: Analysis of 55 cases from FungiScope® and the literature.

Int J Infect Dis 2020 Mar 19;92:114-122. Epub 2019 Dec 19.

Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University, Frankfurt, Germany.

Objectives: Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections.

Methods: Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected.

Results: Fifty-five children (median age 9 years [IQR: 5-14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment. Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3-28] versus 61 days [IQR: 16-148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35-51.40] and HR 6.12 [95% CI 1.52-24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11-0.99] and HR 0.09 [95% CI 0.02-0.40], respectively).

Conclusions: Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome.
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http://dx.doi.org/10.1016/j.ijid.2019.12.017DOI Listing
March 2020

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

Clin Infect Dis 2020 Sep;71(6):1367-1376

Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.

Methods: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.

Results: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.

Conclusions: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.
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http://dx.doi.org/10.1093/cid/ciz1008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486838PMC
September 2020

Immunosuppressive Compounds Affect the Fungal Growth and Viability of Defined Species.

Pathogens 2019 Nov 29;8(4). Epub 2019 Nov 29.

Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

Immunosuppressive drugs are administered to a number of patients; e.g., to allogeneic hematopoietic stem cell transplant recipients. Immunosuppressive drugs impair the immune system and thus increase the risk of invasive fungal disease, but may exhibit antifungal activity at the same time. We investigated the impact of various concentrations of three commonly used immunosuppressive compounds-cyclosporin A (CsA), methylprednisolone (mPRED), and mycophenolic acid (MPA)-on the growth and viability of five clinically important species. Methods included disc diffusion, optical density of mycelium, and viability assays such as XTT. MPA and CsA had a species-specific and dose-dependent inhibitory effect on the growth of all spp. tested, although growth inhibition by MPA was highest in and . Both agents exhibited species-specific hyphal damage, which was higher when the immunosuppressants were added to growing conidia than to mycelium. In contrast, mPRED increased the growth of , but had no major impact on the growth and viability of any of the other species tested. Our findings may help to better understand the interaction of drugs with species and ultimately may have an impact on individualizing immunosuppressive therapy.
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http://dx.doi.org/10.3390/pathogens8040273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963520PMC
November 2019

Distinct Effects of Immunosuppressive Drugs on the Anti- Activity of Human Natural Killer Cells.

Pathogens 2019 Nov 19;8(4). Epub 2019 Nov 19.

Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents, University Hospital, Goethe University Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

As the prognosis of invasive aspergillosis remains unacceptably poor in patients undergoing hematopoietic stem cell transplantation (HSCT), there is a growing interest in the adoptive transfer of antifungal effector cells, such as Natural Killer (NK) cells. Because immunosuppressive agents are required in most HSCT recipients, knowledge of the impact of these compounds on the antifungal activity of NK cells is a prerequisite for clinical trials. We, therefore, assessed the effect of methylprednisolone (mPRED), cyclosporin A (CsA) and mycophenolic acid (MPA) at different concentrations on proliferation, apoptosis/necrosis, and the direct and indirect anti- activity of human NK cells. Methylprednisolone decreased proliferation and increased apoptosis of NK cells in a significant manner. After seven days, a reduction of viable NK cells was seen for all three immunosuppressants, which was significant for MPA only. Cyclosporin A significantly inhibited the direct hyphal damage by NK cells in a dose-dependent manner. None of the immunosuppressive compounds had a major impact on the measured levels of interferon-γ, granulocyte-macrophage colony-stimulating factor and RANTES (regulated on activation, normal T cell expressed and secreted; CCL5). Our data demonstrate that commonly used immunosuppressive compounds have distinct effects on proliferation, viability and antifungal activity of human NK cells, which should be considered in designing studies on the use of NK cells for adoptive antifungal immunotherapy.
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http://dx.doi.org/10.3390/pathogens8040246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963337PMC
November 2019

Etiology and Outcome of Candidemia in Neonates and Children in Europe: An 11-year Multinational Retrospective Study.

Pediatr Infect Dis J 2020 02;39(2):114-120

Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University 96 School of Health Sciences, Thessaloniki, Greece.

Background: Data on Candida bloodstream infections in pediatric patients in Europe are limited. We performed a retrospective multicenter European study of the epidemiology and outcome of neonatal and pediatric candidemia.

Material And Methods: All first positive blood cultures from patients ≤ 18 years of age with candidemia were registered. Patients' demographic and clinical characteristics and causative Candida species were collected and analyzed. Regression analysis was used to identify factors independently associated with mortality.

Results: One thousand three hundred ninety-five episodes of candidemia (57.8% male) were reported from 23 hospitals in 10 European countries. Of the 1395 episodes, 36.4% occurred in neonates (≤ 44 weeks postmenstrual age), 13.8% in infants (> 44 weeks postmenstrual age to 1 year) and 49.8% in children and adolescents. Candida albicans (52.5%) and Candida parapsilosis (28%) were the predominant species. A higher proportion of candidemia caused by C. albicans was observed among neonatal patients (60.2%) with highest rates of C. parapsilosis seen among infants (42%). Children admitted to hematology-oncology wards presented the highest rates of non-albicans Candida species. Candidemia because of C. albicans was more frequent than non-albicans Candida in Northern versus Southern Europe (odds ratio, 2.3; 95% confidence interval, 1.8-2.9; P < 0.001). The all-cause mortality at 30 days was 14.4%. All-cause mortality was higher among patients admitted to the neonatal or pediatric intensive care units than other wards. Over time, no significant changes in species distribution were observed.

Conclusions: This first multicenter European study shows unique characteristics of the epidemiology of pediatric candidemia. The insights obtained from this study will be useful to guide clinical management and antifungal stewardship.
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http://dx.doi.org/10.1097/INF.0000000000002530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208278PMC
February 2020

Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium.

Lancet Infect Dis 2019 12 5;19(12):e405-e421. Epub 2019 Nov 5.

Department of Medical Microbiology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Mucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health-care settings. From January, 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the "One World One Guideline" initiative of the European Confederation of Medical Mycology (ECMM). Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings. Management of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.
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http://dx.doi.org/10.1016/S1473-3099(19)30312-3DOI Listing
December 2019

Guideline for Antibacterial Prophylaxis Administration in Pediatric Cancer and Hematopoietic Stem Cell Transplantation.

Clin Infect Dis 2020 Jun;71(1):226-236

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Bacteremia and other invasive bacterial infections are common among children with cancer receiving intensive chemotherapy and in pediatric recipients of hematopoietic stem cell transplantation (HSCT). Systemic antibacterial prophylaxis is one approach that can be used to reduce the risk of these infections. Our purpose was to develop a clinical practice guideline (CPG) for systemic antibacterial prophylaxis administration in pediatric patients with cancer and those undergoing HSCT.

Methods: An international and multidisciplinary panel was convened with representation from pediatric hematology/oncology and HSCT, pediatric infectious diseases (including antibiotic stewardship), nursing, pharmacy, a patient advocate, and a CPG methodologist. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to generate recommendations based on the results of a systematic review of the literature.

Results: The systematic review identified 114 eligible randomized trials of antibiotic prophylaxis. The panel made a weak recommendation for systemic antibacterial prophylaxis for children receiving intensive chemotherapy for acute myeloid leukemia and relapsed acute lymphoblastic leukemia (ALL). Weak recommendations against the routine use of systemic antibacterial prophylaxis were made for children undergoing induction chemotherapy for ALL, autologous HSCT and allogeneic HSCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin was recommended during severe neutropenia.

Conclusions: We present a CPG for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients. Future research should evaluate the long-term effectiveness and adverse effects of prophylaxis.
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http://dx.doi.org/10.1093/cid/ciz1082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312235PMC
June 2020

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.

J Clin Oncol 2019 11 12;37(31):2857-2865. Epub 2019 Sep 12.

Trousseau Hospital, Paris, France.

Purpose: Off-label use of vemurafenib (VMF) to treat mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.

Patients And Methods: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score.

Results: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the clone.

Conclusion: VMF seemed safe and effective in children with refractory -positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
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http://dx.doi.org/10.1200/JCO.19.00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823889PMC
November 2019

Galactomannan and PCR in the Central Nervous System to Detect Invasive Mold Disease - A Retrospective Analysis in Immunocompromised Children.

Sci Rep 2019 09 10;9(1):12950. Epub 2019 Sep 10.

University of Lübeck, Department of Paediatrics, Paediatric Haematology and Oncology, Lübeck, Germany.

Invasive mold disease (IMD) of the central nervous system (CNS) is a severe infectious complication in immunocompromised patients, but early microbiological diagnosis is difficult. As data on the value of biomarkers in the CNS are scarce, in particular in children, we retrospectively analyzed the performance of galactomannan (GM) and PCR assays in CNS samples of 15 children with proven and probable CNS IMD and of 32 immunocompromised children without fungal infection. Galactomannan in the cerebrospinal fluid (CSF) was assessed in nine of the 15 pediatric patients and was positive in five of them. Polymerase chain reaction (PCR) was performed in eight of the 15 patients and detected nucleic acids from molds in six patients. Galactomannan and PCR in CNS samples were the only positive microbiologic parameter in the CNS in three and two patients, respectively. In four patients, PCR specified the pathogen detected in microscopy. Galactomannan and PCR results remained negative in the CSF of all immunocompromised children without evidence for CNS IMD. Our data suggest that GM and PCR in CNS specimens are valuable additional tools in diagnosing CNS IMD and should be included in the work up of all pediatric patients with suspected mold disease of the CNS.
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http://dx.doi.org/10.1038/s41598-019-49426-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736859PMC
September 2019

Efficacy of antibiotic prophylaxis in patients with cancer and hematopoietic stem cell transplantation recipients: A systematic review of randomized trials.

Cancer Med 2019 08 5;8(10):4536-4546. Epub 2019 Jul 5.

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Purpose: To determine the efficacy and safety of different prophylactic systemic antibiotics in adult and pediatric patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT).

Methods: We conducted a systematic review and performed searches of Ovid MEDLINE, MEDLINE in-process and Embase; and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were HSCT recipients with anticipated neutropenia, and the intervention was systemic antibacterial prophylaxis. Strategies synthesized included fluoroquinolone vs no antibiotic/nonabsorbable antibiotic; fluoroquinolone vs trimethoprim-sulfamethoxazole; trimethoprim-sulfamethoxazole vs no antibiotic; and cephalosporin vs. no antibiotic. Fluoroquinolone vs cephalosporin and levofloxacin vs ciprofloxacin were compared by network meta-analysis. Primary outcome was bacteremia.

Results: Of 20 984 citations screened, 113 studies comparing prophylactic antibiotic to control were included. The following were effective in reducing bacteremia: fluoroquinolone vs no antibiotic/nonabsorbable antibiotic (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.41-0.76), trimethoprim-sulfamethoxazole vs no antibiotic (RR 0.59, 95% CI 0.41-0.85) and cephalosporin vs no antibiotic (RR 0.30, 95% CI 0.16-0.58). Fluoroquinolone was not significantly associated with increased Clostridium difficile infection (RR 0.62, 95% CI 0.31-1.24) or invasive fungal disease (RR 1.28, 95% CI 0.79-2.08) but did increase resistance to fluoroquinolone among bacteremia isolates (RR 3.35, 95% CI 1.12 to 10.03). Heterogeneity in fluoroquinolone effect on bacteremia was not explained by evaluated study, population, or methodological factors. Network meta-analysis revealed no direct comparisons for pre-specified analyses; superior regimens were not identified.

Conclusions: Fluoroquinolone, trimethoprim-sulfamethoxazole, and cephalosporin prophylaxis reduced bacteremia. A clinical practice guideline to facilitate prophylactic antibiotic decision-making is required.
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http://dx.doi.org/10.1002/cam4.2395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712447PMC
August 2019

Pre-emptive versus empirical antifungal therapy in immunocompromised children.

Lancet Child Adolesc Health 2019 08 13;3(8):518-520. Epub 2019 Jun 13.

Center for Bone Marrow Transplantation and Department of Paediatric Haematology and Oncology, University Children's Hospital Münster, Münster, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2352-4642(19)30191-9DOI Listing
August 2019

The clinical management of invasive mold infection in children with cancer or undergoing hematopoietic stem cell transplantation.

Expert Rev Anti Infect Ther 2019 07 8;17(7):489-499. Epub 2019 Jun 8.

a Division of Pediatric Hematology and Oncology, Hospital for Children and Adolescents , Johann Wolfgang Goethe-University , Frankfurt , Germany.

: Invasive fungal disease (IFD) is a significant cause for morbidity and mortality in children receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT). As compared to adults, children may differ from adults in specific aspects regarding epidemiology, diagnosis and management of IFD. : The review provides an overview over the epidemiology of IFD in children with cancer or undergoing HSCT, diagnostic tools, preventive and therapeutic strategies. : Whereas the risk for IFD is highest in children with acute myeloid leukemia, relapse of acute leukemia, and allogeneic HSCT, the individual risk for IFD needs to be better defined in the large and heterogenous group of children with acute lymphoblastic leukemia. In contrast to galactomannan, pediatric data on beta-D-glucan and PCR testing are scarce. Findings of imaging studies in children are often not typical, but may prompt invasive diagnostic procedures. No substantial differences exist between children and adult regarding antifungal chemoprophylaxis, empirical, pre-emptive and specific therapy. However, antifungal strategies in children are limited as a number of antifungal compounds are not licensed for children or their pediatric dosage is unknown.
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http://dx.doi.org/10.1080/14787210.2019.1626718DOI Listing
July 2019

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia-A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP.

Am J Hematol 2019 08 29;94(8):880-890. Epub 2019 May 29.

St. Anna Kinderspital and Children's Cancer Research Institute (CCRI), Department of Paediatrics, Medical University of Vienna, Vienna, Austria.

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.
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http://dx.doi.org/10.1002/ajh.25511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772138PMC
August 2019

Extended Dosing Regimens for Fungal Prophylaxis.

Clin Microbiol Rev 2019 06 15;32(3). Epub 2019 May 15.

Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, Münster, Germany.

Invasive fungal diseases carry high morbidity and mortality in patients undergoing chemotherapy for hematological malignancies or allogeneic hematopoietic stem cell transplantation. In order to prevent these life-threatening infections, antifungal chemoprophylaxis plays an important role in daily clinical practice. Broad-spectrum antifungal triazoles are widely used but exhibit disadvantages such as relevant drug-drug interactions. Therefore, amphotericin B products or echinocandins can be an alternative in selected patient populations. As these compounds are available as intravenous formulations only, there is growing interest in extended dosing regimens. Although not approved for these agents, this strategy is a rational option, as these compounds have properties suitable for this strategy, including dose-proportional pharmacokinetics, prolonged elimination half-life, and a large therapeutic window. As the use of extended dosing regimens in antifungal prophylaxis is expanding in clinical practice, we reviewed the pharmacokinetic and pharmacodynamic rationale for this strategy, animal model data, dose escalation studies, and clinical trials supporting this concept.
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http://dx.doi.org/10.1128/CMR.00010-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589864PMC
June 2019

Invasive mold disease of the central nervous system in children and adolescents with cancer or undergoing hematopoietic stem cell transplantation: Analysis of 29 contemporary patients.

Pediatr Blood Cancer 2019 08 7;66(8):e27806. Epub 2019 May 7.

Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Infectious Disease Research Program, Münster, Germany.

Background: Invasive mold disease (IMD) is a severe infectious complication in immunocompromised patients. The outcome of central nervous system (CNS) IMD is poor, but contemporary data, in particular in the pediatric setting, are lacking.

Procedure: For this retrospective multicenter analysis, pediatric patients < 18 years with proven or probable CNS IMD receiving chemotherapy or undergoing allogeneic HSCT were reported by the local investigator. CNS IMD had to be diagnosed between 2007 and 2016. Proven CNS IMD was defined as compatible CNS imaging or macroscopic autopsy findings in conjunction with a positive microscopic or microbiological result in the brain tissue or cerebrospinal fluid. Probable CNS IMD was defined as compatible CNS imaging findings in combination with proven or probable IMD at a site outside the CNS.

Results And Conclusions: A total of 29 patients (median age, 14 years; 14 allogeneic HSCT recipients) were diagnosed with proven (n = 12) or probable (n = 17) CNS IMD. Aspergillus spp. was the most common fungal pathogen. All but one patient had IMD sites outside the CNS and eight patients (27.6%) were neurologically asymptomatic at diagnosis of CNS IMD. Forty-nine percent of the patients survived CNS IMD; however, 46.7% of the survivors suffered from severe long-term neurological sequelae. Our data suggest that (1) outcome of CNS IMD has improved in children as compared with previous series, (2) half of surviving patients suffer from severe neurological sequelae, and (3) imaging of the CNS should be performed in all children with IMD irrespective of neurological symptoms.
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http://dx.doi.org/10.1002/pbc.27806DOI Listing
August 2019