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In contrast to transplant recipients, there is a paucity of data regarding frequency and clinical significance of viraemia in children receiving conventional chemotherapy. In a prospective observational study, we assessed the frequency of and clinical impact of viraemia with cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, human herpesvirus-6 (HHV6) and herpes-simplex virus 1/2 (HSV1/2) in paediatric cancer patients at diagnosis, at a routine examination during intensive chemotherapy, and during febrile neutropenia (FN). Seventy-nine patients (median age 6 years; 66 children with haematological malignancies) were included in the study. Overall, 362 blood samples were analysed, 72 from the time at diagnosis (11.1% with positive PCR result), 118 during a regular control after chemotherapy (11.0% positive), and 159 during FN (8.8% positive). The overall positivity rate was 9.6% (CMV 3.3%, HHV6 2.7%, HSV 2.2%, EBV 0.8% and adenovirus 0.3%). There were no significant differences between FN episodes with and without viraemia in terms of duration of fever or neutropenia/lymphopenia, severity of mucositis (> II 0 ), incidence of diarrhea and ICU admission. Our results indicate that viraemia in paediatric cancer patients generally does not have a major clinical impact, and may help in the decision regarding the indication of routine evaluation for viraemia in febrile neutropenic, but otherwise asymptomatic children., (© 2024. The Author(s).)

Background: Vaccination against SARS-CoV-2 is recommended for cancer patients. However, long-term data on the effectiveness in the pediatric setting are lacking., Methods: Pediatric patients < 18 years on active treatment for cancer and without prior SARS-CoV-2 infection received three doses of an mRNA vaccine. The clinical course and humoral and cellular immunity were evaluated at the end of the follow-up period of ≥ 1 year after the third dose of vaccine., Results: SARS-CoV-2 infection occurred in 17 of 19 analyzed patients (median age 16.5 years) during the follow-up period (median 17 months), but no severe symptoms were seen. At ≥ 1 year after the last SARS-CoV-2 antigen exposure, 4 of 17 patients had received the recommended booster vaccine. At the end of the follow-up period, all evaluable 15 patients had anti-SARS-CoV-2 receptor-binding domain IgG antibodies. Twelve of the 15 patients had neutralizing antibody titers ≥ 1:10 against the Delta variant and 12/15 and 13/15 against the BA.1 and BA.5 variants, respectively. Specific T cells against SARS-CoV-2 antigens were seen in 9/13 patients., Conclusions: Most SARS-CoV-2-vaccinated pediatric cancer patients had SARS-CoV-2 infections and limited interest in booster vaccination. At 1 year after the last antigen exposure, which was mostly an infection, humoral immune responses remained strong., Trial Registration: German Clinical Trials Register DRKS00025254, May 26, 2021., (© 2024. The Author(s).)

Background: The current German guidance from 2016 recommends a Time to Antibiotics (TTA) of<60 min in children and adolescents with febrile neutropenia (FN)., Methods: Critical analysis of available studies and recent meta-analyses, and discussion of the practical consequences in the FN working group of the German Societies for Paediatric Oncology and Haematology and Paediatric Infectious Diseases., Results: The available evidence does not support a clinically significant outcome benefit of a TTA<60 min in all paediatric patients with FN. Studies suggesting such a benefit are biased (mainly triage bias), use different TTA definitions and display further methodical limitations. In any case, a TTA<60 min remains an essential component of the 1st hour-bundle in paediatric cancer patients with septic shock or sepsis with organ dysfunction., Conclusion: Provided that all paediatric FN patients receive a structured medical history and physical examination (including vital signs) by experienced and trained medical personnel in a timely fashion, and provided that a sepsis triage and management bundle is established and implemented, a TTA lower than 3 hours is sufficient and reasonable in stable paediatric cancer patients with FN., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients., Methods: The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered., Results: We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients., Conclusion: The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care.

Introduction: Infectious complications, particularly invasive bacterial and fungal infections, are still a major cause of morbidity in pediatric cancer patients and are associated with significant mortality. Over the last few years, there has been much effort in defining risk groups to tailor antimicrobial therapy, and in establishing pediatric-specific guidelines for antimicrobial strategies., Areas Covered: This review provides a critical overview of defining risk groups for infection, diagnostic work-up, antimicrobial prophylaxis, empirical therapy, and treatment of established infections., Expert Opinion: To date, no generalizable risk prediction model has been established for pediatric cancer patients. There is growing interest in defining the impact of the individual genetic background on infectious complications. New diagnostic tools have been developed over the last few years, but they need to be validated in pediatric cancer patients. International, pediatric-specific guidelines for antimicrobial prophylaxis, empirical therapy, and treatment of established infections have recently been published and will harmonize antimicrobial strategies in the future.

Our study in 21 pediatric cancer patients demonstrates that 3 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine (BioNTech/Pfizer) elicited both humoral and cellular immunity in most patients during chemotherapy. Immunity was stronger in children with solid tumors and during maintenance therapy compared to those with hematological malignancies or during intensive chemotherapy. Clinical Trials Registration.ȃGerman Registry for Clinical Trials (DRKS00025254)., Competing Interests: Potential conflicts of interest. T. L. received consulting fees and honoraria from Pfizer. S. C. received consulting fees and honorarium from BioNTech for serving on an advisory board. C. J. reports payment for expert testimony from Landschaftsverband Rheinland, Department for Social Decompensation and Institut für Medizinische und Pharmazeutische Prüfungsfragen. J. H. K. reports grants or contracts unrelated to this work from Deutsche Forschungsgemeinschaft (KL2374/3-1, KL2374/5-1), European Research Council for the European Union’s Horizon 2020 research and innovation program (grant agreement number 714226), St Baldrick’s Robert Arceci Innovations Award (551589), and the German Federal Ministry of Education and Research (01GM1911D myPred); consulting fees from Bluebird Bio, Novartis, Roche, and Jazz Pharmaceuticals; and participation on a data safety and monitoring board or advisory board for Bluebird Bio, Novartis, Roche, and Jazz Pharmaceuticals. S. Ho. reports speaker’s fees from Streamedup GmbH and Sanofi Genzyme and receipt of materials and reagents for other study from Roche Diagnostics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Epidemiology of Clostridioides difficile infection (CDI) in paediatric cancer patients is uncertain. The primary objective was to describe the prevalence of CDI outcomes among paediatric patients receiving cancer treatments. Secondary objectives were to describe clinical features of CDI, propose a definition of severe CDI and to determine risk factors for CDI clinical outcomes., Methods: A multi-centre retrospective cohort study that included paediatric patients (1-18 years of age) receiving cancer treatments with CDI. Severe CDI definition was achieved by consensus. Univariable and multivariable regression was conducted to evaluate risk factors for CDI outcomes., Results: There were 627 eligible patients who experienced 721 CDI episodes. The prevalence of clinical cure was 82.9%, recurrence was 9.6%, global cure was 75.0% and repeated new CDI episode was 12.8%. The proposed definition of severe CDI was the presence of colitis, pneumatosis intestinalis, pseudomembranous colitis, ileus or surgery for CDI, occurring in 70 (9.7%) episodes. In univariable regression, initial oral metronidazole or initial oral vancomycin were not significantly associated with failure to achieve clinical cure or CDI recurrence. In multiple regression, oral metronidazole was significantly associated with higher odds (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.0-2.7) and oral vancomycin was significantly associated with lower odds (OR 0.4, 95% CI 0.2-0.8) of repeated new episodes., Conclusion: The prevalence of clinical cure was 82.9% and recurrence was 9.6% in pediatric patients receiving cancer treatments. Severe CDI, as per our proposed definition, occurred in 9.7% episodes. Initial oral vancomycin was significantly associated with a reduction in repeated new CDI episodes., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andreas H Groll has research support from Gilead Sciences, Merck Sharp and Dohme, and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; and served at the speakers’ bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme, and Pfizer; Thomas Lehrnbecher has an unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas, and Roche; and serves at the speakers’ bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer, and GlaxoSmithKline. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 in Wuhan challenges pediatric oncologists in an unexpected way. We provide a comprehensive overview, which systematically summarizes and grades evidence (QoE) on SARS-CoV-2 infections in pediatric cancer patients at 1.5 years of pandemic. A systematic literature search in PubMed combined with an additional exploratory literature review in other international databases was conducted to identify studies on children (aged < 18 years) with a malignant disease and COVID-19 infections. In total, 45 reports on 1003 pediatric cancer patients with SARS-CoV-2 infections were identified out of 1397 reports analyzed. The clinical course of COVID-19 was reported mild or moderate in 358 patients (41.7%), whereas 11.1% of patients showed severe COVID-19. In 12.7% of patients, chemotherapy was postponed, whereas 19% of patients with different underlying malignancies received chemotherapy during SARS-CoV-2 infection. Twenty-five patients with SARS-CoV-2 infections died, potentially related to COVID-19., Conclusion: Despite a favorable COVID-19 outcome in most pediatric cancer patients, the morbidity is reported higher than in children without comorbidities. However, no severe COVID-19 complications were associated to the continuation of chemotherapy in some cohort studies and reports on two patients. Therefore, the risk of cancer progress or relapse due to interruption of chemotherapy has carefully to be weighed against the risk of severe COVID-19 disease with potentially fatal outcome., What Is Known: • Most of pediatric patients with malignant diseases show an asymptomatic, mild or moderate clinical course of SARS-CoV-2 infection. • Current need for a basis for decision-making, whether to stop or interrupt cancer treatment in a patient infected with SARS-CoV-2, and when to continue chemotherapy., What Is New: • Review results comprising over 1000 pediatric COVID-19 cancer patients confirm mild courses of SARS-CoV-2 infection in most patients but also show the attributable mortality is at least 10 times higher compared to reports on hospitalized children without comorbidities. • Review identifies that chemotherapy was continued despite SARS-CoV-2 positivity in 18% of patients with individual chemotherapy modification according to the clinical course of SARS-CoV-2 infection and existing comorbidities. On this basis, no severe COVID-19 complications were associated to the continuation of chemotherapy in several cohort studies and two case reports., (© 2022. The Author(s).)

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., Competing Interests: Competing interests: BF’s institution receives research funding from Pfizer and Merck, and he serves on a Data Safety Monitoring Board for Astellas. TL has received research grants from Gilead Sciences, is a consultant to Astellas, Basilea, Gilead Sciences and Merck/MSD, and served at the speaker's bureau of Astellas, Gilead Sciences, Merck/MSD and Pfizer., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Conflict of interest statement A.H.G. has research support from Gilead Sciences, Merck Sharp and Dohme and Pfizer; is a consultant for Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer; and served at the speakers' bureau of Astellas, Basilea, F2G, Gilead Sciences, Merck Sharp and Dohme and Pfizer. A.A. is a consultant for Jazz Pharmaceuticals, Amgen, Novartis, Gilead Sciences and MSD/Merck and served at the speakers' bureau of Jazz Pharmaceuticals, Amgen and Novartis. T.L. has an unrestricted research support from Gilead Sciences; is a consultant for Gilead Sciences, Merck Sharp and Dohme, Pfizer, Astellas and Roche; and serves at the speakers' bureau of Gilead Sciences, Merck Sharp and Dohme, Astellas, Pfizer and GlaxoSmithKline. All the other authors do not have to declare a conflict of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., Competing Interests: TL erhielt Vortragshonorare von Astellas, Gilead Sciences, GSK, Merck/MSD und Pfizer, Honorare für Beratertätigkeiten von Astellas, Gilead Sciences, Merck/MSD und Pfizer sowie Forschungsunterstützung von Gilead Sciences. HJL erhielt Vortragshonorare und Reisekostenunterstützung von CSL Behring, Pfizer und Bayer sowie Honorare für Beratertätigkeiten von CSL Behring. AA erhielt Vortragshonorare und Reisekostenunterstützung von Jazz Pharmaceuticals und Pfizer sowie Honorare für Beratertätigkeiten von Gilead Sciences, Jazz Pharmaceuticals und Novartis. AHG erhielt Vortragshonorare von Astellas, Basilea, F2G, Gilead Scviences, Merck/MSD und Pfizer, Honorare für Beratertätigkeiten von Amplyx, Astellas, Basilea, F2G, Gilead Sciences, Merck/MSD und Pfizer sowie Forschungsunterstützung von Gilead Sciences, Merck/MSD und Pfizer. Alle anderen Autoren haben keine Interessenskonflikte., (Thieme. All rights reserved.)

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.

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

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.

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

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., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction : 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. Areas covered : The review provides an overview over the epidemiology of IFD in children with cancer or undergoing HSCT, diagnostic tools, preventive and therapeutic strategies. Expert opinion : 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.

Purpose of Review: Fever during neutropenia is a common occurrence in children with cancer. A number of studies have recently been performed to refine algorithms regarding initiation, modification, and termination of antimicrobial treatment and are the basis for international pediatric-specific guidelines for the treatment of fever and neutropenia in children with cancer., Recent Findings: Although hospitalization and prompt initiation of intravenous broad-spectrum antibiotics remains the mainstay in the treatment of febrile neutropenic children with cancer, recent research has addressed a number of questions to optimize the management of these patients. Risk prediction rules have been evaluated to allow for individualized treatment intensity and to evaluate the safety of early discontinuation of empirical antibiotic therapy. In addition, the use of preemptive antifungal therapy has been evaluated to decrease the use of antifungal agents., Summary: Based on the results of studies in children, pediatric-specific guidelines have been established and are regularly updated.

Background: Although a number of risk factors have been associated with invasive fungal disease (IFD), a systematic review of the literature to document pediatric-specific factors has not been performed., Methods: We used the Ovid SP platform to search Medline, Medline In-Process, and Embase for studies that identified risk factors for IFD in children with cancer or those who undergo hematopoietic stem cell transplantation (HSCT). We included studies if they consisted of children or adolescents (<25 years) who were receiving treatment for cancer or undergoing HSCT and if the study evaluated risk factors among patients with and those without IFD., Results: Among the 3566 studies screened, 22 studies were included. A number of pediatric factors commonly associated with an increased risk for IFD were confirmed, including prolonged neutropenia, high-dose steroid exposure, intensive-timing chemotherapy for acute myeloid leukemia, and acute and chronic graft-versus-host disease. Increasing age, a factor not commonly associated with IFD risk, was identified as a risk factor in multiple published cohorts., Conclusions: With this systematic review, we have confirmed IFD risk factors that are considered routinely in daily clinical practice. Increasing age should also be considered when assessing patient risk for IFD. Future efforts should focus on defining more precise thresholds for a particular risk factor (ie, age, neutropenia duration) and on development of prediction rules inclusive of individual factors to further refine the risk prediction.

Immunocompromised children and adolescents receiving treatment for cancer have a considerably increased risk for infection. Neutropenia is the most important single risk factor for infectious complications, and fever in neutropenia is considered as an emergency. Whereas guidelines for the management of fever in neutropenic adults have been established for decades, specific pediatric guidelines have not been developed until recently. As children differ in many aspects from adults such as in the underlying malignancy or in the availability and dosing of antimicrobial compounds, guidelines for pediatric patients are important. This article reviews similarities and differences between the recently published German interdisciplinary guideline of the German Societies of Pediatric Infectious Diseases and Pediatric Oncology and Hematology and a guideline developed by a panel of international experts for the management of fever in neutropenia in children and adolescents., Competing Interests: TL erhielt Vortragshonorare von Astellas, Gilead Sciences, Merck/MSD und Pfizer, Honorare für Beratertätigkeiten von Astellas, Basilea, Gilead Sciences und Merck/MSD sowie Forschungsunterstützung von Gilead Sciences.AHG erhielt Vortragshonorare von Astellas, Basilea, Gilead Sciences, Merck/MSD und Pfizer, Honorare für Beratertätigkeiten von Amplyx, Astellas, Basilea, Gilead Sciences und Merck/MSD sowie Forschungsunterstützung von Gilead Sciences, Merck/MSD und Pfizer. AA erhielt Vortragshonorare und Reisekostenunterstützung von Jazz Pharmaceuticals und Pfizer sowie Honorare für Beratertätigkeiten von Jazz Pharmaceuticals. AH hat Vortragshonorare von Astellas, MSD und Pfizer erhalten. HJL erhielt Vortragshonorare und Reisekostenunterstützung von CSL Behring, Pfizer und Bayer, Honorare für Beratertätigkeiten von Astellas, Shire und CSL Behring sowie Forschungsunterstützung von CSL Behring. MS erhielt Vortragshonorare von Merck/MSD. Alle anderen Autoren haben keine Interessenskonflikte., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients. Methods The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low. Results Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN. Conclusion Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.

We systematically reviewed and analyzed the available data for galactomannan (GM), β-D-glucan (BG), and polymerase chain reaction (PCR)-based assays to detect invasive fungal disease (IFD) in patients with pediatric cancer or undergoing hematopoietic stem cell transplantation when used as screening tools during immunosuppression or as diagnostic tests in patients presenting with symptoms such as fever during neutropenia (FN). Of 1532 studies screened, 25 studies reported on GM (n = 19), BG (n = 3), and PCR (n = 11). All fungal biomarkers demonstrated highly variable sensitivity, specificity, and positive predictive values, and these were generally poor in both clinical settings. GM negative predictive values were high, ranging from 85% to 100% for screening and 70% to 100% in the diagnostic setting, but failure to identify non-Aspergillus molds limits its usefulness. Future work could focus on the usefulness of combinations of fungal biomarkers in pediatric cancer and HSCT., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Risk-stratified management of febrile neutropenia (FN) allows intensive management of high-risk cases and early discharge of low-risk cases. Most risk stratification systems predicting severe infection from admission variables have been derived from childhood or adult populations and consequently their value in adolescents/young adults (AYA) may vary. Our objective was to determine their value in this population., Methods: Data from the 'predicting infectious complications in children with cancer' (PICNICC) individual participant data collaboration were used to evaluate six previously described risk stratification schema in the AYA population. Complete case analyses were undertaken for five 'paediatric' rules, with imputation for specific missing variables of the 'adult' rule. The predictive performance of the rules or the outcome microbiologically defined infection (sensitivity, specificity and predictive values) were compared., Results: Among the 5,127 episodes of FN in 3,504 patients in the PICNICC collaboration data set, 603 episodes of FN from 478 patients in 20 studies were of patients 16-25 years old. The six rules demonstrated variable sensitivity (33-96%) and specificity (13-83%). Their overall discriminatory ability was poor (area under the receiver operator curve estimates 0.514-0.593)., Conclusions: Both paediatric and adult FN risk stratification schema perform poorly in AYA with cancer. An alternative rule or clinical recognition of their limitations is required., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To describe treatment failure and mortality rates with different antibiotic regimens and different management strategies for empirical treatment of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients., Methods: We conducted a systematic review and performed searches of MEDLINE, Embase, PubMed, and Cochrane Central Register of Controlled Trials. Studies were included if pediatric patients had cancer or were HSCT recipients and the intervention was related to the management of FN. Strategies synthesized were monotherapy versus aminoglycoside-containing combination therapy; antipseudomonal penicillin monotherapy versus fourth-generation cephalosporin monotherapy; inpatient versus outpatient management; oral versus intravenous antibiotics; and addition of colony-stimulating factors., Results: Of 11,469 citations screened, 68 studies randomly assigning 7,265 episodes were included. When compared with monotherapy, aminoglycoside-containing combination therapy did not decrease treatment failures (risk ratio, 1.13; 95% CI, 0.92 to 1.38; P = 0.23), and no difference in mortality was observed. Antipseudomonal penicillin and fourth-generation cephalosporin monotherapy were associated with similar failure and mortality rates. Outpatient management and oral antibiotics were safe in low-risk FN with no infection-related mortality observed in any patient and no significant differences in outcomes compared with inpatient management and intravenous therapy. Therapeutic colony-stimulating factors were associated with a 1.42-day reduction in hospitalization (95% CI, 0.62 to 2.22 days; P < .001)., Conclusion: There were a moderate number of pediatric randomized trials of FN management. Monotherapy for high-risk FN and outpatient and oral management for low-risk FN are effective strategies. These findings will provide the basis for guideline recommendations in pediatric FN., (© 2016 by American Society of Clinical Oncology.)

Purpose of Review: Invasive fungal disease (IFD) is an important cause of morbidity and mortality in immunocompromised patients. In contrast to adults, detailed information of pharmacokinetics and pharmacodynamics of many antifungal compounds is lacking in pediatric patients, and antifungal agents that have been proven to be effective in adults have not been licensed for children. We therefore review the current literature on drugs and dosing for antifungal prophylaxis in the pediatric age group., Recent Findings: Although there are only few compounds approved for antifungal prophylaxis in children, an increasing number of reports describe safety and suggest efficacy of agents given to prevent IFD in the pediatric population. Owing to the small number of children included in most studies, however, evidence for efficacy has to be extrapolated from studies in adults. In addition, most studies do not address the optimal dosage of a compound to prevent IFD (optimal balance between efficacy and toxicity)., Summary: Although there is a wide use of prophylactic antifungal agents in children, future studies need to establish the optimal dosing of each compound.

Treatment-related mortality is an important outcome in paediatric cancer clinical trials. An international group of experts in supportive care in paediatric cancer developed a consensus-based definition of treatment-related mortality and a cause-of-death attribution system. The reliability and validity of the system was tested in 30 deaths, which were independently assessed by two clinical research associates and two paediatric oncologists. We defined treatment-related mortality as death occurring in the absence of progressive cancer. Of the 30 reviewed deaths, the reliability of classification for treatment-related mortality was noted as excellent by clinical research associates (κ=0·83, 95% CI 0·60-1·00) and paediatric oncologists (0·84, 0·63-1·00). Criterion validity was established because agreement between the consensus classifications by clinical research associates and paediatric oncologists was almost perfect (0·92, 0·78-1·00). Our approach should allow comparison of treatment-related mortality across trials and across time., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Invasive aspergillosis (IA) is a life-threatening complication in hematological cancer patients. Voriconazole (VCZ) is the established first-line treatment of IA. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, therapeutic drug monitoring (TDM) of VCZ may help to improve treatment results in IA patients, but evidence-based data on the clinical use of TDM in patients treated with VCZ for IA are scarce. Evidence-based guidance is needed to support decisions on the use of TDM in routine VCZ therapy of IA. Our present analysis assessed published studies for evidence-based criteria for TDM of VCZ to improve efficacy and safety of IA therapy in cancer patients. Literature searches of MEDLINE and Cochrane database were performed. We identified 27 clinical studies reporting on the use of plasma level monitoring and/or TDM for VCZ. For each study, strength of recommendation and quality of evidence were categorized according to predefined criteria. A number of studies were published on plasma level monitoring (PLM) and TDM in VCZ therapy of IA. Across studies, VCZ levels >5-5.5 mg/L were found to be associated with toxicity, while reaching minimum levels of >1-2 mg/L appeared to improve efficacy. Timing, frequency, and intervention thresholds and dosage increments of VCZ for adjustment of plasma levels remain to be established. Currently, there is still no conclusive evidence for recommendations in routine clinical practice. More data from prospective randomized studies with TDM are desirable to provide a solid evidence basis for these approaches.

Purpose: The objective of this study was to describe the diagnostic yield and complication rate of bronchoalveolar lavage (BAL) and lung biopsy in the evaluation of pulmonary lesions in patients with cancer and recipients of hematopoietic stem-cell transplantation (HSCT)., Methods: We conducted a systematic literature review and performed electronic searches of Ovid MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were recipients of HSCT, and if they underwent BAL or lung biopsy for the evaluation of pulmonary lesions. Only English language publications were included., Results: In all, 14,148 studies were screened; 72 studies of BAL and 31 of lung biopsy were included. The proportion of procedures leading to any diagnosis was similar by procedure type (0.53 v 0.54; P = .94) but an infectious diagnosis was more common with BAL compared with lung biopsy (0.49 v 0.34; P < .001). Lung biopsy more commonly led to a noninfectious diagnosis (0.43 v 0.07; P < .001) and was more likely to change how the patient was managed (0.48 v 0.31; P = .002) compared with BAL. However, complications were more common with lung biopsy (0.15 v 0.08; P = .006), and procedure-related mortality was four-fold higher for lung biopsy (0.0078) compared with BAL (0.0018)., Conclusion: BAL may be the preferred diagnostic modality for the evaluation of potentially infectious pulmonary lesions because of lower complication and mortality rates; thus, choice of procedure depends on clinical suspicion of infection. Guidelines to promote consistency in the approach to the evaluation of lung infiltrates may improve clinical care of patients., (© 2015 by American Society of Clinical Oncology.)

Background: Intensive chemotherapy in children with cancer results in long-term impairment of humoral immunity. Whereas most studies to date focused on children with acute lymphoblastic leukemia (ALL), little data have been published on patients suffering from Hodgkin disease or from solid tumors. We therefore analyzed the loss of protective immunity (defined as immunity at the time of diagnosis and lack of immunity after completion of therapy) against vaccine-preventable diseases in children treated for various malignancies., Methods: Children and adolescents <21 years of age at diagnosis and treated between 2001 and 2010 for various malignancies in the Department of Pediatric Hematology and Oncology, University of Frankfurt, were included in the retrospective chart review. Antibody levels against measles, mumps, rubella and varicella-zoster-virus (VZV) were routinely assessed at the time of diagnosis and within 12 months after completion of therapy., Results: The study population consisted of 195 children (122 male); 80 patients had ALL, 15 acute myelogenous leukemia (AML), 18 non-Hodgkin lymphoma (NHL), 22 Hodgkin disease, and 60 various solid tumors. Overall, 27%, 47%, 19%, and 17% of the patients lost their humoral immunity against measles, mumps, rubella, and VZV, respectively. The risk of losing protective antibody titers depended on age with a higher risk in younger children. The loss of protective humoral immunity occurred significantly more often in patients with ALL compared to patients with any other underlying malignant disease (hematological malignancies such AML and NHL, Hodgkin disease or solid tumors)., Conclusions: Our data demonstrate that a significant number of children lose pre-existing humoral immunity against measles, mumps, rubella, and VZV after completion of chemotherapy. This loss occurs more often in children with ALL than in children with AML, solid tumors and Hodgkin disease. Our results underline the need for post-chemotherapy revaccination of childhood cancer survivors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To develop an evidence-based guideline for the empiric management of pediatric fever and neutropenia (FN)., Methods: The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group composed of experts in pediatric oncology and infectious disease as well as a patient advocate. The Panel was convened for the purpose of creating this guideline. We followed previously validated procedures for creating evidence-based guidelines. Working groups focused on initial presentation, ongoing management, and empiric antifungal therapy. Each working group developed key clinical questions, conducted systematic reviews of the published literature, and compiled evidence summaries. The Grades of Recommendation Assessment, Development, and Evaluation approach was used to generate summaries, and evidence was classified as high, moderate, low, or very low based on methodologic considerations., Results: Recommendations were made related to initial presentation (risk stratification, initial evaluation, and treatment), ongoing management (modification and cessation of empiric antibiotics), and empiric antifungal treatment (risk stratification, evaluation, and treatment) of pediatric FN. For each recommendation, the strength of the recommendation and level of evidence are presented., Conclusion: This guideline represents an evidence-based approach to FN specific to children with cancer. Although some recommendations are similar to adult-based guidelines, there are key distinctions in multiple areas. Implementation will require adaptation to the local context.

Purpose: The utility of peripheral blood cultures in patients with cancer and/or hematopoietic stem cell transplantation (HSCT) recipients with central venous lines (CVL) and suspected blood stream infection (BSI) is controversial. Our main objective was to describe the proportion of bacteremia detected only by the peripheral blood (PB) culture in order to define its role in the evaluation of patients in this setting., Methods: We performed electronic searches of OVID Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for studies of adults or children with cancer and/or HSCT that evaluated concurrent PB and CVL cultures and reported sufficient data to permit calculation of the primary outcome. The proportion of bacteremia identified by site of sample was used as the effect measure. The review was registered in PROSPERO: CRD42011001610., Results: From 149 reviewed articles, 7 were included in the meta-analysis. In a total number of 10,370 paired blood cultures, bacteremia was detected in 17 %. Thirteen percent of BSI were only identified by PB, while 28 % of infections were only identified by CVL., Conclusions: PB cultures identified many episodes of bacteremia not detected in the CVL culture. This finding suggests that PB culture should be considered in the evaluation of patients with cancer and/or HSCT with suspected BSI.

Background: Objectives were to compare systemic mould-active vs fluconazole prophylaxis in cancer patients receiving chemotherapy or haematopoietic stem cell transplantation (HSCT)., Methods: We searched OVID MEDLINE and the Cochrane Central Register of Controlled Trials (1948-August 2011) and EMBASE (1980-August 2011). Randomised controlled trials of mould-active vs fluconazole prophylaxis in cancer or HSCT patients were included. Primary outcome was proven/probable invasive fungal infections (IFI). Analysis was completed by computing relative risks (RRs) using a random-effects model and Mantel-Haenszel method., Results: From 984 reviewed articles, 20 were included in this review. Mould-active compared with fluconazole prophylaxis significantly reduced the number of proven/probable IFI (RR 0.71, 95% CI 0.52 to 0.98; P=0.03). Mould-active prophylaxis also decreased the risk of invasive aspergillosis (IA; RR 0.53, 95% confidence interval (CI) 0.37-0.75; P=0.0004) and IFI-related mortality (RR 0.67, 95% CI 0.47-0.96; P=0.03) but is also associated with an increased risk of adverse events (AEs) leading to antifungal discontinuation (RR 1.95, 95% CI 1.24-3.07; P=0.004). There was no decrease in overall mortality (RR 1.0; 95% CI 0.88-1.13; P=0.96)., Conclusion: Mould-active compared with fluconazole prophylaxis significantly reduces proven/probable IFI, IA, and IFI-related mortality in cancer patients receiving chemotherapy or HSCT, but increases AE and does not affect overall mortality. (PROSPERO Registration: CRD420111174).

Background: Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people., Methods: This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485., Results: We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules., Conclusions: The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study., (© 2012 Phillips et al; licensee BioMed Central Ltd.)

Although various guidelines on antifungal prophylaxis and treatment have been published, the practical approach in the individual clinical setting might considerably differ because of special local circumstances. In addition, there are major differences between paediatric and adult patients regarding antifungal strategies and the use of antifungal compounds. We here present the antifungal approach in the Departments of Hematology and Oncology of the University Hospital of Frankfurt, where per year approximately 350 children and adults are diagnosed with cancer and an additional 100 patients undergo haematopoietic stem cell transplantation. The differences in the approach between the paediatric and adult setting are highlighted.

Background: Recovery of cytomegalovirus (CMV)-specific T cell mediated immunity after allogeneic hematopoietic stem cell transplantation (SCT) is critical for protection against CMV disease. Tetramer-based technologies have been shown to be a sensitive tool in the enumeration of specific T cells, but have the disadvantage of HLA-restriction of the peptides., Patients and Methods: In this pilot study, we tested the feasibility of a panel of 6 CMV-specific tetrameric HLA/CMV-peptide complexes to enumerate CMV-specific CD8 +T cells (CTLs). The reconstitution of CMV-specific CTLs was assessed in 16 children in the first year after allogeneic SCT (median age, 8 years)., Results: The presented assay covered more than 85% of our patients transplanted in the last 3 years. During CMV-reactivation, all 4 of the 16 analyzed patients with a high virus-load showed less than 10 CMV-specific CTLs/microl; out of these, three had not any detectable CMV-CTLs. On the other hand, five of the children with less than 10 CMV-specific CTLs/microl did not develop CMV reactivation. When enumeration of T cells was performed by means of different tetrameric HLA/CMV-peptide complexes simultaneously, the numbers of CMV-specific CTLs cells widely differed according to the HLA-type., Conclusions: Our pilot study suggests that enumeration of CMV-specific T cells by means of a panel of 6 tetramers might be a useful tool in the risk assessment for CMV reactivation in the majority of patients undergoing allogeneic SCT, but future trials have to evaluate whether this method is appropriate in tailoring antiviral therapy in the individual patient.

Background: Infections are significant causes of morbidity and mortality among immunocompromised patients, but little is known about the adherence by the paediatric cancer patients to preventive anti-infective interventions., Methods: A voluntary and anonymised questionnaire was distributed to all patients, completing intensive anticancer therapy. Compliance was analysed by using a panel of eight commonly recommended preventive interventions and semi-quantitative scoring of adherence by the patient and/or its caretaker. Satisfaction with information and belief in the efficacy of the interventions were similarly assessed. Relationships of these factors to compliance were explored by using an overall compliance score and non-parametric correlation and/or ANOVA and logistic regression, respectively., Results: In 216 children and adolescents (mean age: 8 years; 94 girls) included in the study, compliance rates were the highest for food restriction (89.3%), the use of topic antimycotics (88.2%) and trimethoprim/sulfamethoxazole (86.6%), and the lowest for the use of face masks (68.8%), antiseptic mouth rinses (67.1%), non-absorbable antibiotic agents (66.5%) and restrictions in social contacts (65.5%). The most frequent reasons for drug non-compliance were forgetfulness and patient refusal. Compliance correlated with haematological malignancy, younger age and belief in its efficacy, but not with the perceived degree of information, burden of interventions and overall satisfaction with quality of information and medical care., Conclusion: Compliance to recommended anti-infective prophylactic interventions was variable and correlated with haematological malignancy, younger age and belief in efficacy.

Changes of the immune system can be a consequence of an underlying malignancy or induced by antineoplastic treatment. Both influence the risk for infectious complications and relapse. Over the past decade, there have been a series of major developments in the laboratory assessment of immune dysfunction, particularly as it relates to the complex interactions of the distinct components of the immune system. In addition, several new therapeutic strategies that modulate the immune system have been introduced. We review new findings that can affect clinical decision making. Better insights into the impairment of host response could provide the rationale for the development of new therapeutic strategies, for both supportive care and anticancer treatment.

Piperacillin-Tazobactam (Pip-Taz) is an evidence-based empirical treatment of febrile neutropenia in adolescents and adults. No data are available in pediatric cancer patients <25 months of age. In this retrospective, multicenter data survey, the analysis focuses on safety, tolerance, and efficacy. The daily dose administered was 240 mg/kg given in three equally divided doses. Data on 156 Pip-Taz treatment courses in 69 children <25 months from five pediatric cancer treatment centers (2001-2005) were analyzed. The median duration of treatment with Pip-Taz was 5 days (range, 1-23 days; 1-12 Pip-Taz courses per patient). Pip-Taz was started on the first day of fever in 90% of all courses, in 6% in the first 72 h, and in 4% as second- or third-line agent. Forty-five percent of all patients were neutropenic. In all patients, the outcome was favorable independent whether Pip-Taz was given as monotherapy (42 courses; 27%) or in combination. Overall, Pip-Taz was well tolerated and discontinued due to adverse events in only two patients who experienced non-life-threatening allergic reactions (skin rash and wheezing). The results of this study are preliminary due to the methodological limitations of a retrospective survey. Taking this bias into consideration, Pip-Taz appears to be a safe, and feasible alternative in pediatric cancer patients with febrile neutropenia <25 months of age suggesting that the inclusion of children of all age groups in future prospective controlled studies evaluating Pip-Taz is justified.

Infections are serious complications of cytoreductive therapy in pediatric cancer patients presenting with febrile neutropenia. It is standard of care to initiate empirical intravenous broad-spectrum antibiotics until the fever and neutropenia resolve. However, it might be effective and safe to allow for early hospital discharge in certain subgroups of patients. Two strategies for risk stratification of pediatric cancer patients with regard to infectious complications are discussed in this review: (1) clinical risk parameters and laboratory measures to assist therapeutic management at presentation with fever in neutropenia, and (2) investigations of individual genetic susceptibility factors to tailor potential prophylactic approaches. Given the data available from a significant number of small studies, a large prospective non-inferiority trial is essential to assess low-risk clinical factors and additional laboratory or genetic markers for their predictive value., ((c) 2007 Wiley-Liss, Inc.)

Immunotherapy of childhood malignancies has a magic aura of promising an easy way to cure. It is not only the public, but also the medical community, which has caused this hope. Therefore, it was worthwhile to bring together a panel of experts working in the field of immunotherapy in order to discuss ongoing projects, and to show hopes and disappointments. The result was a fascinating symposium sponsored by The Kind Philipp Leukemia Foundation (Mönchengladbach, Germany). The symposium took place in the Reissensburg near Ulm (Germany) which gives the ideal location for such an event.

The rapid institution of empirical broad-spectrum antibiotics has become the gold standard of treatment for febrile neutropenic children undergoing therapy for cancer. With this approach, morbidity and mortality have dropped significantly but have not been eliminated altogether. In recent randomized studies evaluating different drug combinations, there is still a 3-10 % mortality reported in febrile, neutropenic cancer events. Despite improvements in invasive and non-invasive diagnostic procedures, a majority of patients will receive antibiotic therapy despite an inability to identify a specific pathogen or source (fever of unknown origin, FUO). While there are evidence-based guidelines in adult patients with fever and neutropenia, data are less clear in the pediatric population. Experts agree on the early use of empirical antibiotic therapy, which covers Pseudomonas spp. and is initiated at the first sign of fever. The success of this approach has been based upon clinical intervention before the results of the diagnostic evaluation are available. In contrast, the use of aminoglycosides or glycopeptides is still a matter of debate, as it is the duration of antibiotic therapy. Based on published data in pediatric and adult patients with cancer, the current diagnostic procedures and therapeutic strategies will are discussed. The recommendations given are a consensus of the German Society of Pediatric Oncology and Hematology (GPOH) and the German Society of Pediatric Infectious Diseases (DGPI).

Infectious complications are still a major cause of morbidity and mortality in pediatric patients undergoing therapy for malignancy. Therapy-induced neutropenia is the most important risk factor for infectious risk in pediatric patients with cancer, but other factors, such as alterations in skin/mucosal barriers, and defects in cell-mediated or humoral immunity also contribute to the risk for infection. In most centers, about two thirds of bacteremic isolates are gram-positive pathogens, whereas gram-negative organisms are isolated less frequently, but are associated with considerably higher mortality rates. Prolonged neutropenia increases the risk for invasive fungal infection. In most cases, fever is an important and early indication of serious infection, particularly in children with neutropenia. Discrimination between serious and inconsequential infection in febrile children with neutropenia at the time of presentation is difficult, and serum markers have not been proven to reliably indicate infection. Although several groups investigate risk categories based on clinical tests or the genetic background, the current paradigm is to treat all pediatric patients with neutropenia and fever with intravenous broad-spectrum antibiotics. It is hoped that the identification of one or more predictive factors may be useful for tailoring antibiotic prophylaxis and therapy in children with cancer.

Invasive mycoses are important causes for treatment related morbidity and mortality in severely immunocompromised pediatric patients with hematological malignancies or hematopoietic stem cell transplantation. The past decade has witnessed a major expansion of antifungal drug research, which has resulted in the development of the novel class of echinocandin lipopeptides (anidulafungin, micafungin, caspofungin) and a new generation of antifungal triazoles with improved pharmacological properties (posaconazole, ravuconazole, voriconazole). Whereas caspofungin and voriconazole have been licensed in the European Union, the United States, Canada and several other countries throughout the world, posaconazole, ravuconazole, anidulafungin and micafungin are under regulatory review or in advanced stages of clinical development. Caspofungin and voriconazole are increasingly prescribed in pediatric patients, although pediatric dosage finding and safety evaluations have not been completed. This article reviews the clinical pharmacology of the new antifungal agents and the status of their clinical development in immunocompromised pediatric patients.

Background: Infection of anorectal region represents a significant complication of anti-cancer therapy. Anorectal infection occurs in patients receiving aggressive chemotherapy. Untreated infection leads to substantial morbidity and in the past, mortality., Methods: 82 episodes of anorectal infection in 64 patients with malignant diseases occurring over 12 years at the National Cancer Institute (NCI) were retrospectively reviewed., Results: The overall incidence is comparable to the prior NCI experience despite a shift in patient population to a lower percentage of lymphoid/leukemic diagnoses (34% vs 77%). There were no deaths associated with anorectal infection in the 12 years reviewed compared to seven of 44 in the previous decade (p = 0.003). Antibiotic therapy alone was successful in managing 25/82. Only five episodes were treated with surgery alone compared to nearly 45% in the previous decade. There were no major surgical complications. Neutropenia was present in 43/82 episodes. 11 episodes were complicated by bacteremia, predominately with Staphylococcus non- aureus (n = 8). Wound cultures were performed in 36 episodes from 23 patients yielding 99 separate isolates. Gram-negative isolates were most common overall. Modification of antibiotic therapy with further anaerobic coverage was administered successfully in 39/77 episodes., Conclusion: This study illustrates that anorectal infections in cancer patients can be successfully managed with antibiotic therapy and local care; surgery can be withheld unless there is evidence of progressive infection or substantial fluctuance and necrosis.

Background: Since the optimal duration of antibiotic therapy in febrile neutropenic patients is not clear, we evaluated the safety and efficacy of short courses of intravenous antibiotic treatment in selected pediatric cancer patients admitted for fever and neutropenia., Patients and Methods: We retrospectively analyzed the clinical course of children with chemotherapy-induced neutropenia and fever. All patients were treated with empirical intravenous antibiotics. In episodes of fever of unknown origin (FUO), treatment regimen allowed discontinuation of antibiotics and early hospital discharge regardless of absolute neutrophil count (ANC) or evidence of bone marrow recovery as long as patients were afebrile for at least 24 h and had been treated for a minimum of 72 h., Results: 106 episodes of febrile neutropenia occurred in 56 patients. 84 episodes were classified as FUO and intravenous antibiotic therapy was discontinued regardless of ANC when patients met the criteria described above. No death or major complication occurred. None of the patients had to be rehospitalized for recurrent fever or infection., Conclusion: Discontinuation of intravenous antibiotics regardless of ANC or evidence of bone marrow recovery seems safe and effective in pediatric cancer patients with FUO when children are afebrile for at least 24 h and are treated for a minimum of 72 h.

The hematopoietic colony-stimulating factors have been introduced into clinical practice as additional supportive measures that can reduce, but not eliminate infectious complications associated with therapy-induced neutropenia. Over the past decade, we have begun to appreciate the subtler aspects of the proper use of G-CSF and GM-CSF, identifying appropriate indications and contraindications. In the course of evaluating the multitude of studies, a set of formal recommendations have been propagated for the judicious use of these expensive growth factors. To prevent serious infection, the use of G- or GM-CSF is recommended in a subset of pediatric cancer patients shortly after receiving chemotherapy or a marrow transplant. Children with intensive chemotherapy (e.g., children with high risk ALL, NHL or metastatic neuroblastoma) seem to benefit from hematopoietic growth factors whereas it is not clear that this applies to children undergoing therapy for solid tumors such as rhabdomyosarcoma or Ewing's sarcoma. An exciting development is the use of G-CSF and GM-CSF to mobilize peripheral-blood progenitor cells. Future studies in pediatric cancer patients are clearly warranted to address several issues. Prospective clinical trials are still needed to define specific treatment groups who can benefit from growth factor support. In this regard, efforts must be directed at better defining the endpoints and in particular, assigning value to reduction in treatment of possible infectious complications, such as days in hospital, antibiotic usage and costs. In addition, randomized studies are required to evaluate the proper dosage and duration of therapy, which most likely will vary between groups, depending upon underlying malignancy and therapy given. In addition, combinations of different growth factors have to be tested, particularly if ex vivo expansion and the storage of hematopoietic stem cells are to be utilized in a wider spectrum of patients.

Treatment with intensive myelosuppressive therapy results in decreased levels of immunoglobulins. Whereas pediatric cancer patients undergoing chemotherapy do not benefit from the routine administration of intravenous immunoglobulins, prophylactic intravenous immunoglobulins given after bone marrow transplantation or after peripheral stem cell transplantation reduce infectious complications. Still, prospective clinical trials are needed to define specific treatment groups who can benefit from immunoglobulin support. In addition, randomized studies are required to evaluate the proper dosage and duration of therapy. Passive immunization of children potentially incubated with varicella or measles is generally recommended.