Publications by authors named "Andreas H Groll"

164 Publications

Interaction in vitro of pulmonary surfactant with antifungal agents used for treatment and prevention of invasive aspergillosis.

J Antimicrob Chemother 2021 Nov 11. Epub 2021 Nov 11.

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

Background: Optimizing antifungal therapy is important to improve outcomes in severely immunocompromised patients.

Objectives: We analysed the in vitro interaction between pulmonary surfactant and antifungal agents used for management of invasive pulmonary aspergillosis.

Methods: Amphotericin B formulations, mould-active triazoles and echinocandins were tested in vitro against 24 clinical isolates of different Aspergillus spp. with and without the addition of a commercial porcine surfactant (Curosurf®; Poractant alfa, Nycomed, Austria). The data are presented as MIC or minimum effective concentration (MEC) ranges, as MIC or MEC values that inhibited 90% of the isolates (MIC90 or MEC90) and as geometric mean (GM) MIC or MEC values.

Results: For amphotericin B products, addition of surfactant to a final concentration of 10% led to a statistically significant reduction of the GM MIC for all Aspergillus isolates tested after 24 h (0.765 versus 0.552 mg/L; P < 0.05). For the mould-active triazoles, addition of 10% surfactant resulted in a significantly higher GM MIC at 48 h (0.625 versus 0.898 mg/L; P < 0.05). For the echinocandins, the addition of 10% surfactant led to a significantly higher GM MEC after both 24 h (0.409 versus 0.6532 mg/L; P < 0.01) and 48 h (0.527 versus 0.9378 mg/L; P < 0.01). There were no meaningful differences between individual members of the three existing classes of antifungal agents or between the different Aspergillus spp. tested.

Conclusions: Using EUCAST methodology, addition of porcine surfactant up to a concentration of 10% had a minor, and presumably non-relevant, impact on the in vitro activity of antifungal agents used in prophylaxis and treatment of invasive pulmonary aspergillosis.
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http://dx.doi.org/10.1093/jac/dkab422DOI Listing
November 2021

SARS-CoV-2 in children with cancer or after haematopoietic stem cell transplant: An analysis of 131 patients.

Eur J Cancer 2021 Oct 9;159:78-86. Epub 2021 Oct 9.

Paediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe University, Frankfurt, Germany.

Purpose: There are limited data on SARS-CoV-2 (COVID-19) infection in children with cancer or after haematopoietic stem cell transplant (HSCT). We describe the severity and outcomes of SARS-COV-2 in these patients and identify factors associated with severe disease.

Methods: This was a multinational, observational study of children (aged <19 years) with cancer or HSCT and SARS-CoV-2 confirmed by polymerase chain reaction. COVID-19 was classified as asymptomatic, mild, moderate, severe or critical (≥1 organ support). Exact polytomous regression was used to determine the relationship between clinical variables and disease severity.

Results: One hundred and thirty-one patients with COVID-19 across 10 countries were identified (median age 8 years). Seventy-eight (60%) had leukaemia/lymphoma, 48 (37%) had solid tumour and five had primary immunodeficiency and HSCT. Fever (71%), cough (47%) and coryza (29%) were the most frequent symptoms. The median duration of detectable virus was 16 days (range, 1-79 days). Forty-nine patients (37%) were hospitalised for COVID-19 symptoms, and 15 (11%) required intensive care unit-level care. Chemotherapy was delayed/modified in 35% of patients. COVID-19 was asymptomatic in 32% of patients, mild in 47%, moderate in 8%, severe in 4% and critical in 9%. In 124 patients (95%), a full recovery was documented, and four (3%) died due to COVID-19. Any comorbidity (odds ratio, 2.94; 95% confidence interval [CI], 1.81-5.21), any coinfection (1.74; 95% CI 1.03-3.03) and severe baseline neutropenia (1.82; 95% CI 1.13-3.09) were independently and significantly associated with increasing disease severity.

Conclusion: Although most children with cancer had asymptomatic/mild disease, 13% had severe COVID-19 and 3% died. Comorbidity, coinfection and neutropenia may increase the risk of severe disease. Our data may help management decisions in this vulnerable population.
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http://dx.doi.org/10.1016/j.ejca.2021.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501219PMC
October 2021

Infections in Pediatric Patients - Experience at a European Center for Pediatric Hematology and Oncology.

Front Oncol 2021 12;11:752037. Epub 2021 Oct 12.

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

is an important nosocomial pathogen in immunocom-promised individuals and characterized by intrinsic resistance to broad-spectrum antibacterial agents. Limited data exists on its clinical relevance in immunocompromised pediatric patients, particularly those with hematological or oncological disorders. In a retrospective single center cohort study in pediatric patients receiving care at a large european pediatric hematology and oncology department, ten cases of invasive infections (blood stream infections (BSI), 4; BSI and pneumonia, 3, or soft tissue infection, 2; and pneumonia, 1) were identified between 2010 and 2020. Seven patients had lymphoblastic leukemia and/or were post allogeneic hematopoietic cell transplantation. Invasive infections occurred in a setting of indwelling central venous catheters, granulocytopenia, defective mucocutaneous barriers, treatment with broad-spectrum antibacterial agents, and admission to the intensive care unit. Whole genome sequencing based typing revealed no genetic relationship among four individual isolates. The case fatality rate and mortality at 100 days post diagnosis were 40 and 50%, respectively, and three patients died from pulmonary hemorrhage. Invasive infections are an emerging cause of infectious morbidity in patients receiving care at departments of pediatric hematology and oncology and carry a high case fatality rate.
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http://dx.doi.org/10.3389/fonc.2021.752037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547273PMC
October 2021

When to change treatment of acute invasive aspergillosis: an expert viewpoint.

J Antimicrob Chemother 2021 Sep 11. Epub 2021 Sep 11.

Department of Microbiology, Immunology, and Transplantation, K.U. Leuven, Leuven, Belgium.

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status.
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http://dx.doi.org/10.1093/jac/dkab317DOI Listing
September 2021

Antifungal Combination Therapy in Children with Cancer-A 4-Year Analysis of Real-Life Data of Two Major Pediatric Cancer Centers.

J Fungi (Basel) 2021 Jul 26;7(8). Epub 2021 Jul 26.

Pediatric Hematology and Oncology, Hospital for Children and Adolescents, Johann Wolfgang Goethe-University, 60590 Frankfurt, Germany.

Clinical data on antifungal combination therapy are limited, in particular in the pediatric setting. We analyzed real-life data collected in two major pediatric cancer centers over a period of 4 years. Patients were identified in an observational study on children with acute leukemia and lymphoma or undergoing hematopoietic cell transplantation. Out of 438 patients, 19 patients received 21 episodes of antifungal combination therapy. Therapy was mostly started for sepsis ( = 5) or clinical deterioration with pulmonary infiltrates ( = 10), and less often for periorbital swelling with suspected mold infection ( = 2), clinical deterioration and new skin lesions, secondary antifungal prophylaxis, a persistently elevated galactomannan index, or as pre-emptive treatment ( = 1 each). Diagnostics revealed proven, probable, and possible invasive fungal disease in two, seven and four episodes, respectively. Most regimens included caspofungin ( = 19), and treatment was initiated as first line therapy in 10 episodes. The median duration was 13 days (4-46 days). Nine of the 13 patients with proven, probable, or possible invasive fungal disease survived, which was comparable to patients receiving antifungal monotherapy. Our analysis demonstrates that combination therapy has mainly been prescribed in selected immunocompromised patients with clinical deterioration due to suspected invasive fungal disease or those with sepsis, and is well tolerated. Future studies need to better characterize clinical settings in which patients may benefit from antifungal combination therapy.
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http://dx.doi.org/10.3390/jof7080604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396953PMC
July 2021

Global guideline for the diagnosis and management of rare yeast infections: an initiative of the ECMM in cooperation with ISHAM and ASM.

Lancet Infect Dis 2021 Dec 19;21(12):e375-e386. Epub 2021 Aug 19.

Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.
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http://dx.doi.org/10.1016/S1473-3099(21)00203-6DOI Listing
December 2021

Secondary Dysgammaglobulinemia in Children with Hematological Malignancies Treated with Targeted Therapies.

Paediatr Drugs 2021 Sep 22;23(5):445-455. Epub 2021 Jul 22.

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

Targeted therapies have emerged as innovative treatments for patients whose disease does not respond to conventional chemotherapy, and their use has widely expanded in the field of pediatric hematologic malignancies in the last decade. While they carry the promise of improved disease control and survival and are currently investigated in first-line treatment protocols for patients with poor prognostic markers, they are associated with a considerable incidence of specific toxicities, including cytokine-release syndrome, neurotoxicity, hepatotoxicity, nephrotoxicity, cardiotoxicity, endocrine adverse events, and infectious complications. Iatrogenic or secondary dysgammaglobulinemia is a main consequence of targeted therapies using monoclonal antibodies and other antibody-derived treatments that target specific antigens on lymphoid cells (blinatumomab, inotuzumab ozogamicin, rituximab), chimeric antigen receptor T cells, tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) and, to a lesser extent, checkpoint inhibitors (pembrolizumab, nivolumab). This review discusses the diagnosis and incidence of secondary or iatrogenic dysgammaglobulinemia in children treated with targeted therapies for leukemias and lymphomas, and options for monitoring and treatment.
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http://dx.doi.org/10.1007/s40272-021-00461-3DOI Listing
September 2021

State of Medical Mycology at German Academic Medical Centres: A Survey of the German-Speaking Mycological Society (DMYKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG).

Mycoses 2021 Oct 7;64(10):1177-1182. Epub 2021 Jul 7.

Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD), and German Centre for Infection Research (DZIF) Partner Site Bonn-Cologne, University of Cologne, Cologne, Germany.

Background: Little is known about the infrastructure to translate advances in the management of patients at risk to develop invasive opportunistic fungal diseases. To assess the current state of Medical Mycology support in Germany, we conducted a survey among all 36 academic medical centres.

Methods: The survey consisted of a 3-pages questionnaire sent out in the first half of 2019. Information included details of infrastructure, education and teaching; consultation services and interdisciplinary conferences; research activities and participation in network groups; radiology, microbiology and pharmacology support; publication activity; and European Confederation for Medical Mycology (ECMM) Excellence Center designation, if assigned.

Results: Information was returned from 24 centres (67%). Thirteen institutions (54%) reported an independent infectious disease, and two a separate Medical Mycology department (8%); a Medical Mycology working group was reported for nine institutions (38%). An infectious disease consultation service was existent in 16 institutions (67%) and a multidisciplinary conference in 13 (54%). Fifteen institutions reported a separate study office with activities in infectious disease studies (63%). Laboratory capability for fungal identification and susceptibility testing was confirmed by all 24 institutions; testing of galactomannan by 23 (96%), cryptococcal antigen by 21 (88%), ß-D-Glucan by 9 (38%), and panfungal and Pneumocystis PCR by 21 and 22 (88% and 92%), respectively. Therapeutic drug monitoring of voriconazole was reported to be available in 15 (63%) institutions with a turnaround of ≤24 h during weekdays in 10 (42%). Two of the 24 University hospitals (8%) reported ECMM Diamond Excellence Status.

Conclusions: The results of this survey document the continuing need to improve the availability of specialised Medical Mycology support in German academic medical centres.
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http://dx.doi.org/10.1111/myc.13346DOI Listing
October 2021

Extracorporeal Membrane Oxygenation in Children With Cancer or Hematopoietic Cell Transplantation: Single-Center Experience in 20 Consecutive Patients.

Front Oncol 2021 27;11:664928. Epub 2021 Apr 27.

Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for severe respiratory and/or circulatory failure. Few data exist on the potential benefit of ECMO in immunocompromised pediatric patients with cancer and/or hematopoietic cell transplantation (HCT). Over a period of 12 years, eleven (1.9%) of 572 patients with new diagnosis of leukemia/lymphoma and nine (3.5%) of 257 patients post allogeneic HCT underwent ECMO at our center. Five (45%) and two (22%) patients, respectively, survived to hospital discharge with a median event-free survival of 4.2 years. Experiences and outcomes in this cohort may aid clinicians and families when considering ECMO for individual patients.
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http://dx.doi.org/10.3389/fonc.2021.664928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111086PMC
April 2021

[Antibacterial Prophylaxis in Children and Adolescents Undergoing Therapy for Cancer - Statement of the Society of Pediatric Oncology and Hematology (GPOH) and of the German Society for Pediatric Infectious Diseases (DGPI) on Two Current International Guidelines].

Klin Padiatr 2021 May 10;233(3):101-106. Epub 2021 May 10.

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

Immunocompromised children and adolescents receiving treatment for cancer have an increased risk for potentially life-threatening infectious complications such as blood stream infections with Gram-positive and Gram-negative pathogens. Therefore, several centers for Pediatric Hematology and Oncology administer antibacterial prophylaxis to these patients to lower morbidity and mortality. Two pediatric specific guidelines on antibacterial prophylaxis were recently published. One of these guidelines was drawn up by an international group of pediatric experts of Europe, North and South America and Australia. The other guideline was prepared by an European group convened at the Eighth European Conference on Infections in Leukaemia (ECIL-8). In this review article, the working groups "Infections" of the Society of Pediatric Oncology and Hematology (GPOH) and "Fever in the neutropenic host" of the German Society for Pediatric Infectious Diseases" (DGPI) summarize the available data from randomized studies, systematic reviews and meta-analyses on antibacterial prophylaxis as well of current data on the emergence of resistance and discuss methodological aspects and the recommendations of the two guidelines.
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http://dx.doi.org/10.1055/a-1443-6576DOI Listing
May 2021

Infectious Morbidity in Pediatric Patients Receiving Neoadjuvant Chemotherapy for Sarcoma.

Cancers (Basel) 2021 Apr 21;13(9). Epub 2021 Apr 21.

Infectious Disease Research Program, Center for Bone Marrow Transplantation, Department of Pediatric Hematology/Oncology, University Children's Hospital Münster, 48149 Münster, Germany.

The purpose of this retrospective, single-center cohort study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy. The review included all patients with a new diagnosis of Ewing sarcoma, osteosarcoma or soft tissue sarcoma between September 2009 and December 2018 who were enrolled in the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Primary endpoints were the occurrence of febrile neutropenia (FN) and microbiologically documented infection (MDI). Parameters with a potential impact on FN and MDI were also analyzed. A total of 170 sarcoma patients (median age: 13 years, range: 0-21; 96 m/74 f) received 948 chemotherapy courses (median: 6; range: 2-8). Of these patients, 58.8% had ≥1 FN episode and 20.6% ≥ 1 MDI. FN occurred in 272/948 courses (28.7%) with fever of unknown origin (FUO) in 231 courses and 45 MDI and 19 clinically documented infections (CDI) occurring in a total of 57 courses. Patients enrolled in EWING 2008 had significantly more FN ( < 0.001), infections ( = 0.02) and MDI ( = 0.035). No infection-related deaths were observed. Younger age, tumor type and localization, and higher median and maximum mucositis grades were significantly associated with higher numbers of FN ( < 0.001), and younger age ( = 0.024) and higher median mucositis grade ( = 0.017) with MDI. The study shows substantial infectious morbidity in sarcoma patients during neoadjuvant chemotherapy treatment and opportunities to improve prevention and management.
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http://dx.doi.org/10.3390/cancers13091990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122626PMC
April 2021

Antifungal agents and the kidney: pharmacokinetics, clinical nephrotoxicity, and interactions.

Expert Opin Drug Saf 2021 Sep 1;20(9):1061-1074. Epub 2021 Jun 1.

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

Introduction: Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades have seen a considerable expansion in antifungal drug research, resulting in the clinical development of different classes of antifungal agents with different pharmacologic properties. Among drug-specific characteristics of antifungal agents, renal disposition and nephrotoxicity are important clinical considerations as many patients requiring antifungal therapy have compromised organ functions or are receiving other potentially nephrotoxic medications.

Areas Covered: The present article reviews incidence, severity and mechanisms of nephrotoxicity associated with antifungal agents used for prevention and treatment of invasive fungal diseases by discussing distribution, metabolism, elimination and drug-related adverse events in the context of safety data from phase II and III clinical studies.

Expert Opinion: Based on the available data amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.
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http://dx.doi.org/10.1080/14740338.2021.1922667DOI Listing
September 2021

8th European Conference on Infections in Leukaemia: 2020 guidelines for the use of antibiotics in paediatric patients with cancer or post-haematopoietic cell transplantation.

Lancet Oncol 2021 06 31;22(6):e270-e280. Epub 2021 Mar 31.

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

Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review.
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http://dx.doi.org/10.1016/S1470-2045(20)30725-7DOI Listing
June 2021

8th European Conference on Infections in Leukaemia: 2020 guidelines for the diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or post-haematopoietic cell transplantation.

Lancet Oncol 2021 06 31;22(6):e254-e269. Epub 2021 Mar 31.

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

Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review.
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http://dx.doi.org/10.1016/S1470-2045(20)30723-3DOI Listing
June 2021

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies.

J Fungi (Basel) 2021 Mar 5;7(3). Epub 2021 Mar 5.

Pediatric and Adolescent Hematology-Oncology Unit, 2nd Department of Pediatrics, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece.

Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.
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http://dx.doi.org/10.3390/jof7030186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999508PMC
March 2021

Antibiotic Resistant Bloodstream Infections in Pediatric Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant: Factors Associated with Development of Resistance, Intensive Care Admission and Mortality.

Antibiotics (Basel) 2021 Mar 5;10(3). Epub 2021 Mar 5.

Child Health Evaluative Sciences, The Hospital for Sick Children, Peter Gilgan Centre for Research & Learning, Toronto, ON M5G 0A4, Canada.

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of and vancomycin resistance in 40% of . Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.
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http://dx.doi.org/10.3390/antibiotics10030266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000765PMC
March 2021

School and kindergarten attendance and home schooling of pediatric cancer patients before and during the SARS-CoV-2 pandemic: results of a survey of the German Society for Pediatric Oncology and Hematology.

GMS Hyg Infect Control 2021 5;16:Doc10. Epub 2021 Mar 5.

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

In this multicenter survey (July 07 to August 08, 2020) in pediatric oncology centers (POCs) belonging to the German Society for Pediatric Oncology and Hematology (GPOH), 36 POCs participated (response rate 70.6%). Home schooling practice was judged as satisfying by 79% prior to and by 38% during the pandemic (=0.0007). The individual risk of a SARS-CoV-2 infection and the risk of transmission to other patients/caregivers were arguments against attendance. Most POCs recommended regular social participation/school attendance after the end of intensive therapy. 81% stated that persisting restrictions result in serious negative psychosocial consequences for the patients and their families. In-hospital school education, home schooling and re-attendance of school and kindergarten among pediatric cancer patients have suffered a severe setback during the SARS-CoV-2 pandemic. Continuous communication and education concerning protective measures as well as an individual risk assessment are required to avoid the detrimental exclusion of pediatric oncology patients from kindergarten and school.
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http://dx.doi.org/10.3205/dgkh000381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982994PMC
March 2021

Pneumocystis jirovecii Disease: Basis for the Revised EORTC/MSGERC Invasive Fungal Disease Definitions in Individuals Without Human Immunodeficiency Virus.

Clin Infect Dis 2021 03;72(Suppl 2):S114-S120

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

Background: Pneumocystis jirovecii pneumonia (PCP) causes substantive morbidity in immunocompromised patients. The EORTC/MSGERC convened an expert group to elaborate consensus definitions for Pneumocystis disease for the purpose of interventional clinical trials and epidemiological studies and evaluation of diagnostic tests.

Methods: Definitions were based on the triad of host factors, clinical-radiologic features, and mycologic tests with categorization into probable and proven Pneumocystis disease, and to be applicable to immunocompromised adults and children without human immunodeficiency virus (HIV). Definitions were formulated and their criteria debated and adjusted after public consultation. The definitions were published within the 2019 update of the EORTC/MSGERC Consensus Definitions of Invasive Fungal Disease. Here we detail the scientific rationale behind the disease definitions.

Results: The diagnosis of proven PCP is based on clinical and radiologic criteria plus demonstration of P. jirovecii by microscopy using conventional or immunofluorescence staining in tissue or respiratory tract specimens. Probable PCP is defined by the presence of appropriate host factors and clinical-radiologic criteria, plus amplification of P. jirovecii DNA by quantitative real-time polymerase chain reaction (PCR) in respiratory specimens and/or detection of β-d-glucan in serum provided that another invasive fungal disease and a false-positive result can be ruled out. Extrapulmonary Pneumocystis disease requires demonstration of the organism in affected tissue by microscopy and, preferably, PCR.

Conclusions: These updated definitions of Pneumocystis diseases should prove applicable in clinical, diagnostic, and epidemiologic research in a broad range of immunocompromised patients without HIV.
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http://dx.doi.org/10.1093/cid/ciaa1805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243279PMC
March 2021

Long-Term Follow-Up on Systemic Bevacizumab Treatment in Recurrent Respiratory Papillomatosis.

Laryngoscope 2021 06 31;131(6):E1926-E1933. Epub 2020 Dec 31.

Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany.

Objectives/hypothesis: Recurrent respiratory papillomatosis (RRP) is a primarily benign disease affecting the entire respiratory tract. Treatment is challenging and usually involves surgical interventions and adjuvant medications. Previously, promising results on systemic administration of bevacizumab have been reported. However, experience on long-term systemic use in patients with RRP is not yet available. Here, we present our long-term follow-up on RRP patients undergoing systemic bevacizumab treatment.

Study Design: Case series.

Methods: To describe experience on long-term systemic bevacizumab administration, we performed the underlying investigation. Clinical, radiological, and bronchoscopy data were collected.

Results: To date, a total of n = 5 patients has been treated with systemic bevacizumab at Muenster University Hospital. With a median follow-up since first systemic bevacizumab administration of 95.5 months long-term follow-up is illustrated. Following bevacizumab treatment partial remission or very good partial remission were achieved in all patients. After papilloma recurrence/progression due to bevacizumab discontinuation, further response was documented in all patients in whom bevacizumab was started again. In one patient, bevacizumab was discontinued due to loss of efficacy. Lung cancer developed in one patient with pulmonary papillomatosis prior to bevacizumab administration whereas three patients suffered from malignant transformation during bevacizumab treatment. Systemic bevacizumab led to long-term reduction in surgical interventions in all patients. Except from mild proteinuria and hypertension in two patients therapy was well tolerated.

Conclusions: Systemic bevacizumab represents a promising long-term treatment option for aggressive forms of papillomatosis. Rate of malignant transformation under bevacizumab treatment, optimal treatment schedule, and influence on survival should be further evaluated in clinical trials.

Level Of Evidence: 4 Laryngoscope, 131:E1926-E1933, 2021.
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http://dx.doi.org/10.1002/lary.29351DOI Listing
June 2021

Breakthrough Fungemia in an Immuno-Compromised Adolescent: Case Report and Review of the Literature.

J Fungi (Basel) 2020 Dec 21;6(4). Epub 2020 Dec 21.

Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, D-48149 Münster, Germany.

is a rare cause of candidemia that is known for its unique capability to rapidly acquire resistance to amphotericin B. We report the case of an adolescent with grade IV graft-vs.-host disease after hematopoietic cell transplantation who developed catheter-associated candidemia while on therapeutic doses of liposomal amphotericin B. We review the epidemiology of bloodstream infections in adult and pediatric patients, the development of resistance, and its role in breakthrough candidemia. Appropriate species identification, in vitro susceptibility testing, and source control are pivotal to optimal management of candidemia. Initial antifungal therapy may consist of an echinocandin and be guided by in vitro susceptibility and clinical response.
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http://dx.doi.org/10.3390/jof6040380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766689PMC
December 2020

Use of letermovir in off-label indications: Infectious Diseases Working Party of European Society of Blood and Marrow Transplantation retrospective study.

Bone Marrow Transplant 2021 05 7;56(5):1171-1179. Epub 2020 Dec 7.

Department for Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.

Letermovir (LMV) is licensed for prophylaxis of CMV infection in allogeneic hematopoietic cell transplant adult CMV-seropositive patients. Due to its favorable safety profile, LMV brings potential for use in other clinical situations, outside the approved indication. The objective of the study was to analyze the efficacy and safety of the use of LMV in off-label indications in EBMT centers. A total of 49 patients were reported including 44 adults and 5 children. LMV was administered for: secondary prophylaxis (37 adults, 3 children), primary prophylaxis (2 children), pre-emptive treatment (5 adults), and therapy of CMV disease (2 adults; pneumonia, colitis). Cyclosporine was concomitantly used in 26 patients. Overall, LMV was used for a median 112 days (range: 10-473). Cumulative incidence of breakthrough infections during secondary prophylaxis was 10.1% (95% CI = 3.1-21.9). Prophylactic treatment with LMV resulted in 94.9% (95% CI = 81.0-98.7), and 81.9% (95% CI = 65.7-90.9) probability of, respectively, 60 and 120-day survival without CMV infection in patients receiving secondary prophylaxis. During therapy of CMV infection/disease, probability of 60 and 120-day overall survival was 100% and 71.4% (95% CI = 25.8-92.0), respectively. No breakthrough infection occurred in children on LMV prophylaxis. Adverse events were reported in 15/49 (30.4%) patients: the most common being nausea/vomiting (22.4%). In conclusion, the efficacy of the use of LMV as secondary prophylaxis was high, and the preliminary experience with the use of LMV for the treatment of patients with refractory CMV infection/disease was positive. Our data showed that higher dose or prolonged therapy did not result in increased rate of adverse events.
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http://dx.doi.org/10.1038/s41409-020-01166-wDOI Listing
May 2021

Pharmacodynamics of Posaconazole in Experimental Invasive Pulmonary Aspergillosis: Utility of Serum Galactomannan as a Dynamic Endpoint of Antifungal Efficacy.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

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

galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of IPA at doses between 2 and 20 mg/kg per day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day, in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics package in R. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by dynamic Hill functions reflecting growth and killing of the fungus. Through calculations of the area under the concentration-time curve from 0 to 24 h (AUC) at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC of 30 mg · h/liter. All prophylactic doses were able to control the fungal burden. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC greater than 30 mg · h/liter was associated with adequate resolution of the GMI, which well supports previously suggested exposure-response relationships in humans.
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http://dx.doi.org/10.1128/AAC.01574-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848991PMC
January 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

Toxoplasmosis after allogeneic haematopoietic cell transplantation-disease burden and approaches to diagnosis, prevention and management in adults and children.

Clin Microbiol Infect 2021 Mar 13;27(3):378-388. Epub 2020 Oct 13.

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

Background: Toxoplasmosis is a rare but highly lethal opportunistic infection after allogeneic haematopoietic cell transplantation (HCT). Successful management depends on screening, early recognition and effective treatment.

Objectives: To review the current epidemiology and approaches to diagnosis, prevention and treatment of toxoplasmosis in adult and paediatric allogeneic HCT recipients.

Source: Search of the English literature published in MEDLINE up to 30 June 2020 using combinations of broad search terms including toxoplasmosis, transplantation, diagnosis, epidemiology, prevention and treatment. Selection of articles for review and synthesis on the basis of perceived quality and relevance of content.

Content: Toxoplasmosis continues to be a major challenge in the management of allogeneic HCT recipients. Here we provide a summary of published case series of toxoplasmosis in adult and paediatric patients post allogeneic HCT. We review and discuss the pathogenesis, epidemiology, clinical presentation, diagnosis and current recommendations for prevention and treatment. We also discuss impacts of toxoplasmosis in this setting and factors affecting outcome, emphasizing attention to neurological, neuropsychological and neurocognitive late effects in survivors.

Implications: Apart from careful adherence to established strategies of disease prevention through avoidance of primary infection, identification of seropositive patients and implementation of molecular monitoring, future perspectives to improve the control of toxoplasmosis in allogeneic HCT recipients may include the systematic investigation of pre-emptive treatment, development of immunomodulatory approaches, antimicrobial agents with activity against the cyst form and vaccines to prevent chronic infection.
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http://dx.doi.org/10.1016/j.cmi.2020.10.009DOI Listing
March 2021

Guidance regarding COVID-19 for survivors of childhood, adolescent, and young adult cancer: A statement from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Pediatr Blood Cancer 2020 12 23;67(12):e28702. Epub 2020 Sep 23.

Department of Malignant Haematology, Great Ormond Street Hospital for Children NHS Trust, London, UK.

Childhood, adolescent, and young adult (CAYA) cancer survivors may be at risk for a severe course of COVID-19. Little is known about the clinical course of COVID-19 in CAYA cancer survivors, or if additional preventive measures are warranted. We established a working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) to summarize existing evidence and worldwide recommendations regarding evidence about factors/conditions associated with risk for a severe course of COVID-19 in CAYA cancer survivors, and to develop a consensus statement to provide guidance for healthcare practitioners and CAYA cancer survivors regarding COVID-19.
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http://dx.doi.org/10.1002/pbc.28702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537044PMC
December 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

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

Can we optimise doxorubicin treatment regimens for children with cancer? Pharmacokinetic simulations and a Delphi consensus procedure.

BMC Pharmacol Toxicol 2020 05 28;21(1):37. Epub 2020 May 28.

Department of Paediatric Haematology and Oncology, University Children's Hospital Muenster, Albert-Schweitzer-Campus 1, A1, 48149, Muenster, Germany.

Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects.

Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process.

Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended.

Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
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http://dx.doi.org/10.1186/s40360-020-00417-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254632PMC
May 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
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