Severe Sepsis During Treatment for Childhood Leukemia and Sequelae Among Adult Survivors.

Importance: Children undergoing treatment for leukemia are at increased risk of severe sepsis, a dysregulated immune response to infection leading to acute organ dysfunction. As cancer survivors, they face a high burden of long-term adverse effects. The association between sepsis during anticancer therapy and long-term organ dysfunction in adult survivors of childhood cancer has not been examined. Objective: To determine whether severe sepsis during therapy for leukemia in childhood is associated with subsequent chronic health conditions in adult survivors. Design, Setting, and Participants: This cohort study included 644 adult survivors of childhood leukemia who were diagnosed between January 1, 1985, and July 19, 2010, and participated in the St Jude Lifetime Cohort Study. Participants were excluded if they received hematopoietic cell transplant or had relapsed leukemia. Data collection ended June 30, 2017. Data were analyzed from July 1, 2020, to January 5, 2024. Exposures: Severe sepsis episodes, defined according to consensus criteria as septic shock, acute respiratory distress syndrome, or multiorgan dysfunction associated with infection occurring during anticancer therapy, were abstracted by medical record review for all participants. Main Outcomes and Measures: Common Terminology Criteria for Adverse Events-defined chronic health condition outcomes were independently abstracted. Associations between sepsis and cumulative incidence of chronic health conditions (eg, cardiovascular, pulmonary, kidney, neurological, and neurocognitive outcomes) were compared by adjusted hazard ratios from Cox proportional hazards logistic regression. Inverse propensity score weighting was used to adjust for potential confounders, including age, year of diagnosis, and leukemia type. Results: The study sample consisted of 644 adult survivors of pediatric leukemia (329 women [51.1%] and 315 men [48.9%]; including 56 with a history of acute myeloid leukemia and 585 with a history of acute lymphoblastic leukemia) who were most recently evaluated at a median age of 24.7 (IQR, 21.2-28.3) years at a median time after leukemia diagnosis of 17.3 (IQR, 13.7-21.9) years. Severe sepsis during treatment of acute childhood leukemia occurred in 46 participants (7.1%). Participants who experienced severe sepsis during treatment were more likely to develop moderate to severe neurocognitive impairment (29 of 46 [63.0%] vs 310 of 598 [51.8%]; adjusted hazard ratio, 1.86 [95% CI, 1.61-2.16]; P < .001) significantly affecting attention, executive function, memory and visuospatial domains. Sepsis was not associated with long-term risk of cardiovascular, pulmonary, kidney, or neurological chronic health conditions. Conclusions and Relevance: In this cohort study of long-term outcomes in survivors of pediatric leukemia, severe sepsis during anticancer therapy for leukemia was associated with a selectively increased risk for development of serious neurocognitive sequelae. Efforts to reduce the effects of anticancer therapy on long-term function and quality of life in survivors might include prevention of severe sepsis during therapy and early detection or amelioration of neurocognitive deficits in survivors of sepsis.

Short-Course Empiric Antibiotics in Children Undergoing Allogeneic Hematopoietic Cell Transplantation.

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for short-course EA during the intervention and preintervention period (n = 24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.

Successful Use of Fosmanogepix for Treatment of Rare Highly Resistant Cutaneous Fusariosis in a Pediatric Patient With STAT3 Hyper-Immunoglobulin E Syndrome and End-Stage Kidney Disease.

We describe the successful use of the novel antifungal drug fosmanogepix to treat a chronic case of multidrug-resistant cutaneous Fusarium suttonianum infection in a pediatric patient with STAT3 hyper-IgE syndrome and end-stage kidney disease on peritoneal dialysis.

Lemierre's Syndrome Due to the Zoonotic Anaerobe Bacteroides pyogenes: Case Report and Literature Review.

Although Fusobacterium necrophorum is well described as an emerging pathogen of acute mastoiditis in young children, infection with other anaerobes can lead to similar severe sequelae including intracranial and extracranial suppurative thrombophlebitis and sepsis. We describe a patient whose unremarkable exposure history assumed increased significance upon obtaining the results of 16S next generation sequencing from a surgical specimen. The novel pathogen Bacteroides pyogenes is reviewed herein.

Evaluation of Plasma Microbial Cell-Free DNA Sequencing to Predict Bloodstream Infection in Pediatric Patients With Relapsed or Refractory Cancer.

Importance: Bloodstream infection (BSI) is a common, life-threatening complication of treatment for cancer. Predicting BSI before onset of clinical symptoms would enable preemptive therapy, but there is no reliable screening test. Objective: To estimate sensitivity and specificity of plasma microbial cell-free DNA sequencing (mcfDNA-seq) for predicting BSI in patients at high risk of life-threatening infection. Design, Setting, and Participants: A prospective pilot cohort study of mcfDNA-seq for predicting BSI in pediatric patients (<25 years of age) with relapsed or refractory cancers at St Jude Children's Research Hospital, a specialist quaternary pediatric hematology-oncology referral center. Remnant clinical blood samples were collected during chemotherapy and hematopoietic cell transplantation. Samples collected during the 7 days before and at onset of BSI episodes, along with negative control samples from study participants, underwent blinded testing using a mcfDNA-seq test in a Clinical Laboratory Improvement Amendments/College of American Pathologists-approved laboratory. Main Outcomes and Measures: The primary outcomes were sensitivity of mcfDNA-seq for detecting a BSI pathogen during the 3 days before BSI onset and specificity of mcfDNA-seq in the absence of fever or infection in the preceding or subsequent 7 days. Results: Between August 9, 2017, and June 4, 2018, 47 participants (27 [57%] male; median age [IQR], 10 [5-14] years) were enrolled; 19 BSI episodes occurred in 12 participants, and predictive samples were available for 16 episodes, including 15 bacterial BSI episodes. In the 3 days before the onset of infection, predictive sensitivity of mcfDNA-seq was 75% for all BSIs (12 of 16; 95% CI, 51%-90%) and 80% (12 of 15; 95% CI, 55%-93%) for bacterial BSIs. The specificity of mcfDNA-seq, evaluated on 33 negative control samples from enrolled participants, was 82% (27 of 33; 95% CI, 66%-91%) for any bacterial or fungal organism and 91% (30 of 33; 95% CI, 76%-97%) for any common BSI pathogen, and the concentration of pathogen DNA was lower in control than predictive samples. Conclusions and Relevance: A clinically relevant pathogen can be identified by mcfDNA-seq days before the onset of BSI in a majority of episodes, potentially enabling preemptive treatment. Clinical application appears feasible pending further study. Trial Registration: ClinicalTrials.gov identifier: NCT03226158.