Brian Fisher

Objective Examine the influence of household income on health‐related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). Design Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. Exposure Household income was self‐reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. Outcome Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. Result Children with AML (n= 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean±SD: 76.0±14 household income< 25,000vs.59.9±17income≥ 75,000; adjusted mean difference: 11.2, 95% CI: 2.2–20.2). Seven percent of …

Background Cytomegalovirus (CMV) commonly reactivates after allogeneic hematopoietic cell transplant (HCT), potentially leading to CMV disease and significant morbidity and mortality. To reduce morbidity and mortality, many centers conduct weekly CMV blood polymerase chain reaction (PCR) surveillance testing with subsequent initiation of antiviral therapy upon CMV DNAemia detection. However, the impact of CMV DNAemia on subsequent hospitalization risk has not been assessed using models accounting for the time‐varying nature of the exposure, outcome, and confounders. Methods All allogeneic HCTs at the Children's Hospital of Philadelphia from January 2004–April 2017 were considered for inclusion. Patients were monitored with CMV surveillance via PCR testing for up to 105 days after HCT receipt. We estimated the association between CMV DNAemia and rate of hospitalization using …

Background Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life‐threatening complications, including septic shock (SS). An area‐based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS‐associated death (SS‐death). Methods Children treated for de novo AML on two Children’s Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS‐death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front‐line therapy, death, relapse, or removal from study. Multivariable‐adjusted Cox regressions estimated …

Background The primary objective was to measure the proportion of episodes where care delivery was inconsistent with selected recommendations of a clinical practice guideline (CPG) on fever and neutropenia (FN) management. The influence of site size on CPG‐inconsistent care delivery, and association between patient outcomes and CPG‐inconsistent care were described. Methods This retrospective, multicenter study included patients less than 21 years old with cancer who were at high risk of poor FN outcomes and were previously enrolled to a Children's Oncology Group (COG) study at participating National Cancer Institute Community Oncology Research Program (NCORP) institutions from January 2014 through December 2015. Patients were randomly selected for chart review by participating sites from a COG‐generated list. Care delivered in each episode was adjudicated (CPG‐consistent or CPG …

Case identification in administrative databases is challenging as diagnosis codes alone are not adequate for case ascertainment. We utilized machine learning (ML) to efficiently identify pediatric patients with newly diagnosed acute lymphoblastic leukemia. We tested nine ML models and validated the best model internally and externally. The optimal model had 97% positive predictive value (PPV) and 99% sensitivity in internal validation; 94% PPV and 82% sensitivity in external validation. Our ML model identified a large cohort of 21,044 patients, demonstrating an efficient approach for cohort assembly and enhancing the usability of administrative data.

Our objective was to update a clinical practice guideline for the prevention and treatment of Clostridioides difficile infection (CDI) in pediatric patients with cancer and hematopoietic cell transplantation recipients. We reconvened an international multi-disciplinary panel. A systematic review of randomized controlled trials (RCTs) for the prevention or treatment of CDI in any population was updated and identified 31 new RCTs. Strong recommendations were made to use either oral metronidazole or oral vancomycin for non-severe CDI treatment, and to use either oral vancomycin or oral fidaxomicin for severe CDI. A strong recommendation that fecal microbiota transplantation should not be routinely used to treat CDI was also made. The panel made two new good practice statements to follow infection control practices including isolation in patients experiencing CDI, and to minimize systemic antibacterial administration …

Previous literature has reported cytomegalovirus (CMV) infection rate disparities among racial/ethnic groups of hematopoietic cell transplantation (HCT) recipients. Because race and ethnicity categorizations are social constructs unlikely to affect biological systems, it is likely there are covariates on the pathway to CMV detection, known as mediators, that can explain the observed disparity. Recent developments in mediation analysis methods enable the analysis of time-to-event outcomes, allowing an investigation of these disparities to also consider the timing of CMV infection detection relative to HCT. This study aimed to explore whether racial and ethnic CMV infection disparities existed within a population of HCT recipients at our center, and whether clinical covariates explained any observed association. The study cohort included all recipients of allogeneic HCT performed at the Children's Hospital of …

Children with sickle cell disease (SCD) are at risk of complications from viral infections, including SARS‐CoV‐2. We present the clinical characteristics and outcomes of pediatric patients with SCD from the Pediatric COVID‐19 United States Registry who developed acute COVID‐19 due to SARS‐CoV‐2 infection (n = 259) or multisystem inflammatory syndrome in children (MIS‐C; n = 4). Nearly half of hospitalized children with SCD and SARS‐CoV‐2 infection required supplemental oxygen, though children with SCD had fewer intensive care (ICU) admissions compared to the general pediatric and immunocompromised populations. All registry patients with both SCD and MIS‐C required ICU admission. Children with SCD are at risk of severe disease with SARS‐CoV‐2 infection, highlighting the importance of vaccination in this vulnerable population.

Introduction Surgical site infections (SSIs) are a common complication in liver transplant(LT) recipients. Lack of pediatric prophylaxis guidelines results in variation in preventative antibiotic regimens. Methods We performed a retrospective observational study of LT recipients under 18 years using a merged dataset that included data from PHIS and UNOS between 2006 and 2017. The exposure was defined as the antibiotic(s) received within 24 hours of LT; with 6 categories, ranging from narrow (category 1: cefazolin), to broad). The primary outcome was presence or absence of SSI in the index admission. Mixed-effects logistic regression compared the effectiveness of each category relative to category 1 in preventing SSI. Results Of the 2586 LT, 284 (11%) met SSI criteria. SSI rate was higher (16.2%) in the younger sub-cohort compared to older (8.6 …

We evaluated disparities in disease burden, organ dysfunction, vital signs, and timing of therapy in children newly presenting with acute leukemia. Among 899 patients with acute leukemia diagnosed at two large children's hospitals, a priori lab‐based definitions of high disease burden, infection risk, renal dysfunction, and coagulopathy were applied to electronic health record data. Black patients with acute myeloid leukemia had increased prevalence of elevated white blood cell count and uric acid; Black patients with acute lymphoblastic leukemia demonstrated increased prevalence of coagulopathy. Black patients’ presentation more frequently included multiple lab abnormalities consistent with advanced physiologic dysfunction. No differences were found in days to therapy initiation.

Background Pediatric allogeneic hematopoietic cell transplant (allo‐HCT) recipients are at risk for morbidity and mortality from human adenovirus (HAdV). HAdV can be detected in an asymptomatic state, referred to as infection or with signs or symptoms of illness, referred to as disease. Standardized case definitions are needed to distinguish infection from disease and allow for consistent reporting in both observational cohort studies and therapeutic clinical trials. Methods A working group of experts in virology, transplant infectious disease, and HCT was assembled to develop HAdV infection and disease definitions with the degree of certainty (i.e., possible, probable, and proven). Definitions were further refined through an iterative process and independently applied by two central review committees (CRCs) to 20 pediatric allo‐HCT recipients with at least one HAdV‐positive PCR. Results Initial HAdV infection …

Invasive fungal disease (IFD) remains a significant cause of morbidity and mortality in children undergoing transplantation. There is a growing armamentarium of novel antifungal agents recently approved for use or in late stages of clinical development. The overarching goal of this review is to discuss the mechanisms of action, spectrum of activity, stage of development, and pediatric-specific data for the following agents: encochleated amphotericin B deoxycholate, fosmanogepix, ibrexafungerp, isavuconazole, olorofim, opelconazole, oteseconazole, and rezafungin. Additionally, key drug attributes of these novel agents and their potential future therapeutic roles in pediatric transplant recipients are discussed.

Revaccination after hematopoietic cell transplantation (HCT) is critical to prevent morbidity and mortality from vaccine-preventable illnesses. The global aim of our quality improvement initiative was to enhance timely, correct, and effective revaccination after pediatric HCT. The SMART aim of our project was to decrease median unvaccinated time by 4 months by decreasing the time to vaccine eligibility, time from eligibility to vaccine initiation, and time to completion of the vaccine series. A multidisciplinary group performed a cross-sectional quantitative and qualitative evaluation of revaccination practices at our institution. We identified factors associated with delayed, incorrect, or incomplete revaccination. Several plan-do-study-act interventions were implemented to address these drivers, including revising immune readiness criteria, increasing auditing of primary care administered immunizations, and, importantly …

Methods: A retrospective cohort including all pediatric (age< 19 years) patients treated for AML from 2011-2019 at 13 institutions in the United States was established and is being actively expanded to include diagnoses through 2023. Data collection was accomplished by detailed chart abstraction performed by trained study personnel. We additionally merged resource utilization data from the Pediatric Health Information System to ascertain patient acuity and cumulative organ toxicity. Analyses were restricted to patients identified in the medical record as Hispanic, non-Hispanic Black (NHB), and non-Hispanic White (NHW) to specifically assess historically marginalized patient populations. Other racial/ethnic groups including multi-racial were excluded due to small numbers. Kaplan-Meier survival curves were generated for RFS by race/ethnicity. Adjusted Cox models compared the hazard of relapse by race/ethnicity …

Background Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non‐invasive biomarkers, such as the beta‐D‐glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta‐D‐glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post‐HCT period. Methods Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post‐HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at the manufacturer cutoff of 80 pg/ml. IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were …

Background Administrative datasets are useful for identifying rare disease cohorts such as pediatric acute myeloid leukemia (AML). Previously, cohorts were assembled using labor‐intensive, manual reviews of patients’ longitudinal chemotherapy data. Methods We utilized a two‐step machine learning (ML) method to (i) identify pediatric patients with newly diagnosed AML, and (ii) among the identified AML patients, their chemotherapy courses, in an administrative/billing database. Using 2558 patients previously manually reviewed, multiple ML algorithms were derived from 75% of the study sample, and the selected model was tested in the remaining hold‐out sample. The selected model was also applied to assemble a new pediatric AML cohort and further assessed in an external validation, using a standalone cohort established by manual chart abstraction. Results For patient identification, the selected …

Background Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown. Methods Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression …

Background Invasive aspergillosis (IA) and invasive mucormycosis (IM) are life-threatening invasive fungal diseases (IFDs) that occur in critically ill and/or immunocompromised patients. Approved treatment options have significant limitations in pediatric patients. This study assessed the safety and outcomes of isavuconazonium sulfate (ISAV) for the treatment of IFD in this patient population. Methods This phase 2, open-label, non-comparative study enrolled patients at 10 centers in Belgium, Spain, and the US between 2019 and 2022. Patients aged 1 to < 18 years with possible, probable or proven IA or IM per the 2008 (EORTC/MSG) criteria received ISAV 10 mg/kg (max. 372 mg) every 8 h on days 1 and 2, and once-daily thereafter (intravenous or oral), for ≤ 84 days (IA) or ≤ 180 days (IM). Primary objectives were safety, including treatment-emergent adverse events (TEAEs …

Background Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy. Objective To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML. Methods We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence …

We review antifungal susceptibility testing and the development of clinical breakpoints, and detail an approach to using antifungal susceptibility results when breakpoints have not been defined. This information may prove helpful when selecting therapy for invasive fungal infections in children.