First name
Andreas
Middle name
H
Last name
Groll

Title

Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update.

Year of Publication

2023

Number of Pages

JCO2202224

Date Published

01/2023

ISSN Number

1527-7755

Abstract

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.

DOI

10.1200/JCO.22.02224

Alternate Title

J Clin Oncol

PMID

36689694

Title

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

Year of Publication

2020

Number of Pages

JCO2000158

Date Published

2020 May 27

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients.</p>

<p><strong>METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>CONCLUSION: </strong>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.</p>

DOI

10.1200/JCO.20.00158

Alternate Title

J. Clin. Oncol.

PMID

32459599

Title

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

Year of Publication

2019

Date Published

2019 Dec 05

ISSN Number

1537-6591

Abstract

<p><strong>BACKGROUND: </strong>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.</p>

<p><strong>METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>CONCLUSIONS: </strong>These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.</p>

DOI

10.1093/cid/ciz1008

Alternate Title

Clin. Infect. Dis.

PMID

31802125

Title

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

Year of Publication

2019

Date Published

2019 Nov 02

ISSN Number

1537-6591

Abstract

<p><strong>INTRODUCTION: </strong>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 cancer and HSCT patients.</p>

<p><strong>METHODS: </strong>An international and multi-disciplinary 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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

DOI

10.1093/cid/ciz1082

Alternate Title

Clin. Infect. Dis.

PMID

31676904

Title

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

Year of Publication

2019

Date Published

2019 Nov 04

ISSN Number

1474-4457

Abstract

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

DOI

10.1016/S1473-3099(19)30312-3

Alternate Title

Lancet Infect Dis

PMID

31699664

Title

Epidemiology of Invasive Fungal Disease in Children.

Year of Publication

2017

Number of Pages

S3-S11

Date Published

2017 Sep 01

ISSN Number

2048-7207

Abstract

<p>Considerable progress has been made in the prevention, diagnosis, and management of pediatric patients with invasive fungal disease (IFD). The reported decreasing trend in the incidence of invasive candidiasis (IC) over the past 15 years in both neonates and children has been encouraging. Nevertheless, due to the growing number of immunocompromised children at risk for IFD, this disease continues to be associated with significant morbidity and death and with increased financial burden to the health care system. Therefore, it is important to understand the contemporary epidemiology of IFD. Incidence rates of IFD in children are affected by geographical, population, and time variability. There is an ongoing effort to constantly document and update the incidence of IFD and species distribution among different pediatric populations as a means to direct preventative, diagnostic, and therapeutic resources to the most appropriate subset of patients. Children with a hematologic malignancy or a primary or secondary immunodeficiency, those undergoing solid organ or hematopoietic stem cell transplantation, and premature neonates are the major subsets of pediatric patients at risk of developing IFD. In this review, we focus on fungal disease epidemiology with a specific emphasis on the 2 most common pediatric IFDs, IC and invasive aspergillosis (IA).</p>

DOI

10.1093/jpids/pix046

Alternate Title

J Pediatric Infect Dis Soc

PMID

28927200

Title

Diagnostic Imaging and Invasive Fungal Diseases in Children.

Year of Publication

2017

Number of Pages

S22-S31

Date Published

2017 Sep 01

ISSN Number

2048-7207

Abstract

<p>Invasive fungal disease (IFD) is a life-threatening condition, especially in immunocompromised children. The role of diagnostic imaging in children at risk for an IFD is multifactorial, including initially detecting it, evaluating for dissemination of infection beyond the primary site of disease, monitoring the response to antifungal therapy, and assessing for potential relapse. The objective of this review was to synthesize the published literature relevant to the use of various imaging modalities for the diagnosis and management of IFD in children.</p>

DOI

10.1093/jpids/pix055

Alternate Title

J Pediatric Infect Dis Soc

PMID

28927203

Title

Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update.

Year of Publication

2017

Number of Pages

JCO2016717017

Date Published

2017 May 01

ISSN Number

1527-7755

Abstract

<p>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.</p>

DOI

10.1200/JCO.2016.71.7017

Alternate Title

J. Clin. Oncol.

PMID

28459614

Title

Galactomannan, Beta-D-Glucan and PCR-Based Assays for the Diagnosis of Invasive Fungal Disease in Pediatric Cancer and Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

Year of Publication

2016

Date Published

2016 Nov

ISSN Number

1537-6591

Abstract

<p>We systematically reviewed and analyzed the available data for galactomannan (GM), beta-D-glucan (BG), and polymerase-chain reaction (PCR)-based assays to detect invasive fungal disease (IFD) in pediatric cancer or hematopoietic stem cell transplantation (HSCT) patients when used as screening tools during immunosuppression or as diagnostic tests in patients presenting with symptoms such as fever during neutropenia (FN). Out of 1,532 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 85-100% for screening and 70-100% 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.</p>

DOI

10.1093/cid/ciw592

Alternate Title

Clin. Infect. Dis.

PMID

27567122

Title

Results from a prospective, international, epidemiologic study of invasive candidiasis in children and neonates.

Year of Publication

2012

Number of Pages

1252-7

Date Published

2012 Dec

ISSN Number

1532-0987

Abstract

<p><strong>BACKGROUND: </strong>Candida species are the third most common cause of pediatric health care-associated bloodstream infection in the United States and Europe. To our knowledge, this report from the International Pediatric Fungal Network is the largest prospective, multicenter observational study dedicated to pediatric and neonatal invasive candidiasis.</p>

<p><strong>METHODS: </strong>From 2007 to 2011, we enrolled 196 pediatric and 25 neonatal patients with invasive candidiasis.</p>

<p><strong>RESULTS: </strong>Non-albicans Candida species predominated in pediatric (56%) and neonatal (52%) age groups, yet Candida albicans was the most common species in both groups. Successful treatment responses were observed in pediatric (76%) and neonatal patients (92%). Infection with Candida parapsilosis led to successful responses in pediatric (92%) and neonatal (100%) patients, whereas infection with Candida glabrata was associated with a lower successful outcome in pediatric patients (55%). The most commonly used primary antifungal therapies for pediatric invasive candidiasis were fluconazole (21%), liposomal amphotericin B (20%) and micafungin (18%). Outcome of pediatric invasive candidiasis was similar in response to polyenes (73%), triazoles (67%) and echinocandins (73%). The most commonly used primary antifungal therapies for neonatal invasive candidiasis were fluconazole (32%), caspofungin (24%) and liposomal amphotericin B (16%) and micafungin (8%). Outcomes of neonatal candidiasis by antifungal class again revealed similar response rates among the classes.</p>

<p><strong>CONCLUSIONS: </strong>We found a predominance of non-albicans Candida infection in children and similar outcomes based on antifungal class used. This international collaborative study sets the foundation for large epidemiologic studies focusing on the unique features of neonatal and pediatric candidiasis and comparative studies of therapeutic interventions in these populations.</p>

DOI

10.1097/INF.0b013e3182737427

Alternate Title

Pediatr. Infect. Dis. J.

PMID

22982980

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