Frequency of Treatment Failure of UTIs in Children With Congenital Urinary Tract Anomalies.

OBJECTIVES: Children with certain congenital anomalies of the kidney and urinary tract and neurogenic bladder (CAKUT/NGB) are at higher risk of treatment failure for urinary tract infections (UTIs) than children with normal genitourinary anatomy, but the literature describing treatment and outcomes is limited. The objectives of this study were to describe the rate of treatment failure in children with CAKUT/NGB and compare duration of antibiotics between those with and without treatment failure. METHODS: Multicenter retrospective cohort of children 0 to 17 years old with CAKUT/NGB who presented to the emergency department with fever or hypothermia and were diagnosed with UTI between 2017 and 2018. The outcome of interest was treatment failure, defined as subsequent emergency department visit or hospitalization for UTI because of the same pathogen within 30 days of the index encounter. Descriptive statistics and univariates analyses were used to compare covariates between groups. RESULTS: Of the 2014 patient encounters identified, 482 were included. Twenty-nine (6.0%) of the 482 included encounters had treatment failure. There was no difference in the mean duration of intravenous antibiotics (3.4 ± 2.5 days, 3.5 ± 2.8 days, P = .87) or total antibiotics between children with and without treatment failure (10.2 ± 3.8 days, 10.8 ± 4.0 days, P = .39) Of note, there was a higher rate of bacteremia in children with treatment failure (P = .04). CONCLUSIONS: In children with CAKUT/NGB and UTI, 6.0% of encounters had treatment failure. Duration of antibiotics was not associated with treatment failure. Larger studies are needed to assess whether bacteremia modifies the risk of treatment failure.

Frequency, Characteristics, and Outcomes of Patients Requiring Early PICU Readmission.

OBJECTIVES: Readmission to the PICU is associated with worse outcomes, but factors associated with PICU readmission within the same hospitalization remain unclear. We sought to describe the prevalence of, and identify factors associated with, early PICU readmission. METHODS: We performed a retrospective analysis of PICU admissions for patients aged 0 to 26 years in 48 tertiary care children's hospitals between January 1, 2016 and December 31, 2019 in the Pediatric Health Information System. We defined early readmission as return to the PICU within 2 calendar days of floor transfer during the same hospitalization. Generalized linear mixed models were used to analyze associations between patient and clinical variables, including complex chronic conditions (CCC) and early PICU readmission. RESULTS: The results included 389 219 PICU admissions; early PICU readmission rate was 2.5%. Factors with highest odds of early PICU readmission were CCC, with ≥4 CCCs (reference: no CCC[s]) as highest odds of readmission (adjusted odds ratio [95% confidence interval]: 4.2 [3.8-4.5]), parenteral nutrition (2.3 [2.1-2.4]), and ventriculoperitoneal shunt (1.9 [1.7-2.2]). Factors with decreased odds of PICU readmission included extracorporeal membrane oxygenation (0.4 [0.3-0.6]) and cardiopulmonary resuscitation (0.8 [0.7-0.9]). Patients with early PICU readmissions had longer overall length of stay (geometric mean [geometric SD]: 18.2 [0.9] vs 5.0 [1.1] days, P < .001) and increased odds of mortality (1.7 [1.5-1.9]). CONCLUSIONS: Although early PICU readmissions within the same hospitalization are uncommon, they are associated with significantly worse clinical outcomes. Patients with medical complexity and technology dependence are especially vulnerable.

Urogenital urobiome of healthy children does not differ from that of children with bladder and bowel dysfunction.

INTRODUCTION: The pediatric urinary microbiome (urobiome) has been studied in the context of healthy children and children with genitourinary pathologies including neuropathic bladder, urinary tract infection (UTI) and nephrolithiasis. Little is known about the urobiome of children with bladder and bowel dysfunction (BBD), a condition that is an established risk factor of UTI. We hypothesized that the symptoms of a child with BBD may be related to urobiome composition. OBJECTIVE: To evaluate the urogenital urobiome's role in BBD, we compared the urogenital urobiomes of children with and without BBD. STUDY DESIGN: We performed a prospective case-control pilot study at a single large, academic children's hospital. Cases included toilet trained prepubertal females over 2 years of age with BBD established through a validated scoring system and controls included asymptomatic, presumably healthy, children. Children were excluded if they had symptoms or lab work consistent with a concurrent UTI or antibiotic course for any reason within the prior 14 days. We performed 16 S ribosomal RNA gene sequencing and expanded quantitative urine culture on clean catch urine samples. To compare within sample (alpha) diversity, we used the Kruskal-Wallis test. To compare between sample (beta) diversity, we calculated the Bray-Curtis distance and performed the PERMANOVA test. RESULTS: Data from 25 children with BBD and 8 asymptomatic controls were analyzed. The demographic and clinical characteristics of the two comparison groups were similar, though a higher proportion of Black children were included in the asymptomatic control group. Neither alpha diversity nor beta diversity was significantly different between the two groups. The core microbiome of the BBD group included all the genera in the core urogenital urobiome of the controls, plus additional genera associated with opportunistic infection and/or UTI, including Escherichia, Campylobacter and Streptococcus. DISCUSSION: The results of both the 16 S sequencing and expanded quantitative urine culture in this small study suggest that the urogenital urobiomes of children with BBD do not differ significantly from those of asymptomatic children. However, the core urogenital urobiome of children with BBD included genera associated with opportunistic infection and/or UTI. This study was limited by the sample collection method ("clean catch" midstream voided urine samples, which introduce the possibility of vulvovaginal contamination), small sample size, and unequal balance of patient characteristics between the two study groups. CONCLUSION: The urogenital urobiomes of children with and without BBD do not appear to significantly differ. Larger studies are needed to confirm these findings.

Accuracy of NGAL as a Biomarker for Urinary Tract Infection in Young Febrile Children: An Individual Patient Data Meta-Analysis.

OBJECTIVE: To compare the accuracy of urine neutrophil gelatinase-associated lipocalin (NGAL) and leukocyte esterase (LE) for the diagnosis of urinary tract infection (UTI) in children. STUDY DESIGN: We performed a systematic review and individual patient data meta-analysis of studies that examined urine NGAL as a marker of UTI in children <18 years of age. We created a standardized definition of UTI and applied it to all included children. We compared sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC) of NGAL with LE. RESULTS: We included individual patient data from 3 studies for a total of 845 children. Included children had a mean age of 0.9 years (SD, 0.6 years). Using a cutoff of 32.7 ng/mL, NGAL had a sensitivity of 90.3% (95% CI: 83.2%-95.0%) and specificity of 93.7% (95% CI: 91.7%-95.4%) for the diagnosis of UTI. LE, using a cutoff of ≧ trace had a sensitivity of 81.1% (95% CI: 72.5%-87.9%) and specificity of 97.0% (95% CI: 95.4%-98.1%). The AUC for NGAL was 0.95 (95% CI: 0.92-0.98). The AUC for LE was 0.90 (95% CI: 0.86-0.93). CONCLUSION: In young, febrile children, urinary NGAL is more sensitive for the diagnosis of UTI than LE but is slightly less specific.

Equity in Receipt of a Lumbar Puncture for Febrile Infants at an Academic Center.

BACKGROUND: The evaluation of febrile infants ≤60 days of age is often guided by established protocols. However, structural racism and physicians' implicit bias may affect how such clinical guidelines are applied. OBJECTIVE: To determine the association between self-identified race, insurance type, ZIP code-based median household income (MHI) and receiving a guideline-concordant lumbar puncture (GCLP) in febrile infants. METHODS: This was a 3-year retrospective cross-sectional study of all febrile infants ≤60 days old presenting to a children's hospital from 2015 to 2017. GCLP was defined as obtaining or appropriately not obtaining a lumbar puncture as defined by the hospital's clinical practice guideline, which recommended performing a lumbar puncture for all febrile infants ≤60 days of age unless an infant was >28 days of age and had respiratory syncytial virus-positive bronchiolitis. Univariate analyses were used to identify variables associated with receiving a GCLP. Variables with a P < .1 were included in a multivariate logistic regression with race, MHI, and insurance type. RESULTS: We included 965 infants. Age (adjusted odds ratio, 0.95; 95% confidence interval, 0.94-0.97) and temperature on arrival (adjusted odds ratio, 1.36; 95% confidence interval, 1.04-1.78) were significantly associated with receipt of a GCLP. Self-identified race, insurance type, and MHI were not associated with receiving a GCLP. CONCLUSION: Receipt of a GCLP was not associated with race, MHI, or insurance type. As recent national guidelines change to increase shared decision-making, physician awareness and ongoing assessment of the role of factors such as race and socioeconomic status in the clinical evaluation and outcomes of febrile infants will be critical.

Predictors of Empiric Antibiotic Use in the Emergency Department in Children Without Urinary Tract Infections.

OBJECTIVES: Urinary tract infections (UTIs) are a common diagnosis within the pediatric emergency department (ED). Because of the necessary delay in obtaining urine culture results, clinicians must decide whether to prescribe antibiotics for a suspected UTI before urine culture results. The primary objective of this study was to identify the proportion of children given empiric antibiotics who subsequently did not meet consensus definition of an UTI. The secondary objective was to identify factors associated with return visits to the ED after an index visit for UTI. We also attempted to identify predictors of prescription of empiric antibiotics for children who did not have a UTI. METHODS: This was a retrospective chart review of all patients between the ages of 2 months and 18 years diagnosed with a UTI between July 2016 and June 2017 in the ED of a single urban quaternary care center. Patients were excluded for the following reasons: use of bag for urine collection, subsequent admission to the hospital, receipt of antibiotics within the previous 3 days, use of antibiotics for an indication other than a UTI, and urine culture obtained at an outside facility. RESULTS: Of 404 included patients, 389 (96.2%) were discharged on antibiotics and 243 (62.4%) did not have a UTI. On the multivariate analysis, age ≧ 36 months was associated with increased odds of receiving antibiotics and not having a UTI while both ≥1+ leukocyte esterase and ≥1+ nitrites on urinalysis were associated with decreased odds of receiving antibiotics and not meeting UTI criteria. Sixty-two patients revisited the ED within 30 days of the initial visit, 24 (38.7%) of which met criteria for UTI during the index visit. Prescription of antibiotics at the time of the index visit was associated with decreased odds of reutilization, whereas an extended-spectrum ß-lactamase producing organism cultured from urine at the index visit was associated with increased odds of reutilization. CONCLUSIONS: A high number of patients discharged on empiric antibiotics did not meet criteria for a UTI. We did not identify clinically useful factors that predicted prescription of empiric antibiotics for children who do not have a UTI. We believe that unnecessary antibiotic prescriptions could be substantially decreased by decreasing empiric use of antibiotics coupled with reliable follow-up for positive urine cultures.

Gender Distribution of Scholarship and Measures of National Recognition in Hospital Medicine.

OBJECTIVE: Our specific aim was to assess the gender distribution of aspects of scholarly productivity and professional standing for pediatric hospital medicine over a 5-year period. We also evaluated for correlation between the makeup of editorial boards, conference planning committees, and chosen content. METHODS: We reviewed scholarly publications, presentations, editorial boards, planning committees, awardees, and society leadership in pediatric hospital medicine from 2015 to 2019 and determined gender using published methods to assess for differences between observed proportions of women authors and presenters and the proportion of women in the field. RESULTS: The field of pediatric hospital medicine at large is 69% women (95% confidence internal [CI] 68%-71%), and an estimated 57% of senior members are women (95% CI 54%-60%). We evaluated 570 original science manuscripts and found 67% (95% CI 63%-71%) women first authors and 49% (95% CI 44%-53%) women senior authors. We evaluated 1093 presentations at national conferences and found 69% (95% CI 65%-72%) women presenters of submitted content and 44% (95% CI 37%-51%) women presenters of invited content. Senior authorship and invited speaking engagements demonstrated disproportionately low representation of women when compared with senior members of the field (senior authorship, P = .002; invited presenters, P < .001). Strong positive correlation between gender composition of conference planning committees and selected content was also noted (r = 0.94). CONCLUSION: Our study demonstrated representative gender distribution for some aspects of scholarly productivity in pediatric hospital medicine; however, a lack of gender parity exists in senior roles.

The pediatric urobiome in genitourinary conditions: a narrative review.

The microbial ecosystem within the bladder that can be measured within the urine, or urobiome, is an emerging field of study with little published data regarding children. However, investigations into urobiome research have the potential to significantly impact the understanding of the pathophysiology of genitourinary conditions, as well as potentially identify novel therapeutics. Therefore, both researchers and clinicians should be aware of pediatric urobiome research. The purpose of this review is to highlight the literature around urobiome research in urinary tract infections, nephrolithiasis, and neurogenic bladder; comment on pediatric-specific considerations when reading and interpreting the urobiome literature; and to identify new potential areas of research.

Biomarkers for febrile urinary tract infection in children.

BACKGROUND: The sensitivity and specificity of the leukocyte esterase test for the diagnosis of urinary tract infection (UTI) are suboptimal. Recent studies have identified markers that appear to more accurately differentiate children with and without UTI. The objective of this study was to determine the accuracy of these markers, which included CCL3, IL-8, CXCL1, TNF-alpha, IL-6, IFN-gamma, IL-17, IL-9, IL-2, and NGAL, in the diagnosis of UTI. METHODS: This was a prospective cross-sectional study to compare inflammatory proteins between urine samples from febrile children with a UTI, matched febrile controls without a UTI, and asymptomatic healthy controls. RESULTS: We included 192 children (75 with febrile UTI, 69 febrile controls, and 48 asymptomatic healthy controls). Urinary proteins that best discriminated between febrile children with and without UTI were NGAL, a protein that exerts a local bacteriostatic role in the urinary tract through iron chelation; CCL3, a chemokine involved in leukocyte recruitment; and IL-8, a cytokine involved in neutrophil recruitment. Levels of these proteins were generally undetectable in asymptomatic healthy children. CONCLUSIONS: NGAL, CCL3, and IL-8 may be useful in the early diagnosis of UTI. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01391793) A higher resolution version of the Graphical abstract is available as Supplementary information.

Collection, Processing, and Storage Consideration for Urinary Biomarker Research.

There are several urinary proteins that show promise as novel markers of urinary tract infections. The identification of a novel biomarker that has greater predictive accuracy compared to current diagnostic methods has the potential to greatly improve the ability to manage patients with urinary tract infections. However, sample collection, processing, and storage can all potentially impact the results of biomarker research. Understanding the effects of each of these stages on biomarker studies is necessary to inform future, high-quality research in this area, as well as to critically review other studies in this area. Here, the study reviews the literature regarding the effects of each stage of urine sample processing and reports the effects of various conditions on urinary proteins. The protocol will focus on collection techniques, time and temperature of storage, processing techniques, use of reagents, and long-term freezing on biomarker stability. It will focus on proteins but will briefly discuss other materials that may be utilized in biomarker research. In doing so, this protocol will provide a guide to future researchers to assist in the design of urinary biomarkers studies.

Defining Urinary Tract Infections in Children With Spina Bifida: A Systematic Review.

CONTEXT: Children with spina bifida are at high risk for urinary tract infections (UTI). However, there is no standardized definition of UTI in this population, leading to variability in both clinical management and research. This was highlighted in the 2013 systematic review on the same topic. OBJECTIVE: Evaluate the frequency with which researchers are defining UTI in their studies of children with spina bifida and to determine what parameters are used. DATA SOURCES: We searched Medline and Scopus databases for articles that included pediatric patients with spina bifida and used UTI as an outcome. STUDY SELECTION: Exclusion criteria included publication before October 1, 2012, non-English language, and nonprimary research articles. DATA EXTRACTION: Two independent reviewers each extracted data. RESULTS: A total of 39 studies were included; 74% of these analyzed included an explicit definition of UTI. The most commonly used definition included a combination of symptoms and culture results (34.5%), whereas 31% used a combination of symptoms, culture results, and urinalysis data. Only 3.4% of articles used a urine culture alone to define UTI. CONCLUSIONS: More articles that focus on children with spina bifida included a definition of UTI. However, significant variability persists in the definition of UTI in this patient population.

Forming Consensus To Advance Urobiome Research.

Urobiome research has the potential to advance the understanding of a wide range of diseases, including lower urinary tract symptoms and kidney disease. Many scientific areas have benefited from early research method consensus to facilitate the greater, common good. This consensus document, developed by a group of expert investigators currently engaged in urobiome research (UROBIOME 2020 conference participants), aims to promote standardization and advances in this field by the adoption of common core research practices. We propose a standardized nomenclature as well as considerations for specimen collection, preservation, storage, and processing. Best practices for urobiome study design include our proposal for standard metadata elements as part of core metadata collection. Although it is impractical to follow fixed analytical procedures when analyzing urobiome data, we propose guidelines to document and report data originating from urobiome studies. We offer this first consensus document with every expectation of subsequent revision as our field progresses.

Perspectives from the Society for Pediatric Research: advice on sustaining science and mentoring during COVID-19.

The COVID-19 pandemic will leave an indelible mark on the careers of current medical trainees. Given the disruptions to medical education, economic impact on institutions, and the uncertainties around future job prospects, trainees are facing unprecedented challenges. This situation is especially concerning for futures of pediatric physician-scientist trainees, where concerns regarding maintaining the pipeline were well documented prior to the emergence of COVID-19. In this Perspectives article, we leverage the unique expertise of our workgroup to address concerns of physician-scientist trainees and to provide suggestions on how to navigate career trajectories in the post-COVID-19 era. We identified and addressed four major areas of concern: lack of in-person conferences and the associated decrease access to mentors and networking activities, decreased academic productivity, diminished job prospects, and mental health challenges. We also suggest actions for trainees, mentors and educational leaders, and institutions to help support trainees during the pandemic, with a goal of maintaining the pediatric physician-scientist pipeline.

A single intravesical instillation of Lactobacillus rhamnosus GG is safe in children and adults with neuropathic bladder: A phase Ia clinical trial.

Context/objective: Manipulation of the microbiome is an emerging approach to promote health. We conducted a Phase Ia safety study of a single bladder instillation of probiotics in asymptomatic patients with neuropathic bladder to determine the tolerability and safety of a single Lactobacillus instillation.Design: Phase Ia safety study.Setting: Outpatient rehabilitation clinic at a rehabilitation hospital (adults) and urology clinic at a free-standing children's hospital (children).Participants: Ten patients with neuropathic bladder were included: five children with spina bifida and five adults with spinal cord injury.Interventions: A single Lactobacillus rhamnosus GG (Culturelle, 20 billion live organisms) instillation.Outcome measures: After the instillation, participants self-monitored symptoms using the Urinary Symptoms Questionnaire for People with Neuropathic Bladder using Intermittent Catheterization daily for one week. Repeat urinalysis, urine culture, and 16S bacterial rRNA-based microbiome analyses were performed 7-10 days after instillation.Results: Probiotic instillation was well-tolerated. One child had upper respiratory tract symptoms during the trial, and two had transient cloudy urine. No adults reported any symptoms following instillation. Lactobacillus did not grow on culture post-instillation. There were differences in beta diversity of the urine microbiome in children vs. adults with neuropathic bladder (P < 0.0156). Lactobacillus was present in the pre-instillation urinary microbiomes all of the adults and 4 out of 5 of the pediatric subjects, and identified in 4 out of 5 of both the adult and pediatric subjects' post-instillation urinary microbiomes.Conclusion: Intravesical instillation of Culturelle probiotic may be safe and well-tolerated in patients with neuropathic bladder.

The association between urine neutrophil gelatinase-associated lipocalin and UTI in people with neurogenic lower urinary tract dysfunction.

STUDY DESIGN: Secondary analysis of urine samples collected from a prospective within-subject clinical trial. OBJECTIVES: Describe the baseline variation in urine neutrophil gelatinase-associated lipocalin (uNGAL) levels in adults with neurogenic lower urinary tract dysfunction (NLUTD) and determine if uNGAL levels vary according to likelihood of having a UTI. SETTING: Greater Washington D.C. region. METHODS: Urine samples were collected from a cohort of adults with NLUTD from a clinical trial. Samples were divided into groups of "Not UTI", "Unlikely UTI", and "Likely UTI" based on symptoms and urine culture results. uNGAL was compared between groups using Kruskal-Wallis and post hoc Dunn's test. Mixed effects logistic model was used to assess the association of uNGAL and Likely UTI. RESULTS: Twenty-seven participants provided a total of 104 samples. uNGAL levels were lowest for the No UTI group (n = 29; 37 ng/ml interquartile range (IQR) (15, 71)), intermediate for the Unlikely UTI group (n = 67; 95 ng/ml IQR (37, 161)) and highest for the Likely UTI group (n = 8; 187 ng/ml IQR(146, 224)). uNGAL levels were higher in those with Likely UTI compared to both Unlikely UTI (p < 0.05) and No UTI (p < 0.01). uNGAL had an association with Likely UTI (OR 1.01, 95% CI (1.00-1.02), p = 0.049). CONCLUSIONS: Adults with NLUTD have notable variation in uNGAL levels in the absence of symptoms potentially due to UTI. uNGAL levels are higher in those who are likely to have UTI have higher uNGAL levels compared to those with non-specific symptoms and/or less growth on urine culture. uNGAL may have utility as a marker of UTI in people with NLUTD. SPONSORSHIP: Patient-Centered Outcomes Research Institute (PCORI) funded this work. Bioporto provided partial salary support for SLG, IL, and OKL. NGAL ELISAs were provided by Bioporto in kind.

Recurrent UTIs in Girls: What Is the Role of the Microbiome?

Urinary tract infections (UTIs) are one of the most common childhood bacterial infections. Recurrent UTIs can lead to renal scarring. Compared to boys, girls are more likely to develop scars as a result of recurrent UTIs. Therefore, there is a need to identify girls at high risk for recurrent UTIs and develop interventions to decrease the risk of recurrent UTIs. In this commentary, we will review the hypothesized pathophysiology of recurrent UTIs, explore the literature on the role of the microbiome in recurrent UTIs, focusing on female pediatric patients when able, and highlight the need for future research in this area.

Perspectives from the Society for Pediatric Research: Probiotic use in urinary tract infections, atopic dermatitis, and antibiotic-associated diarrhea: an overview.

Probiotics have received significant attention within both the scientific and lay communities for their potential health-promoting properties, including the treatment or prevention of various conditions in children. In this article, we review the published data on use of specific probiotic strains for three common pediatric conditions: the prevention of urinary tract infections and antibiotic-associated diarrhea and the treatment of atopic dermatitis. Research into the utility of specific probiotic strains is of varying quality, and data are often derived from small studies and case series. We discuss the scientific merit of these studies, their overall findings regarding the utility of probiotics for these indications, issues in reporting of methods, and results from these clinical trials, as well as future areas of investigation.