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.

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.

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.

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.

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.

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.

Novel catheter design enables transurethral catheterization of male mice.

The male mouse is underrepresented in research of the urinary tract due to the difficulty of transurethral catheterization. As a result, there is a lack of analysis of sex differences in urinary tract research. Here, we present a novel catheter design and technique that enables urethral catheterization of male mice for bladder inoculation. Our catheterization technique uses the resistance met at the level of the external urinary sphincter and prostate to guide the retraction, positioning, and advancement of the catheter into the urinary bladder. We have shown that this method can be used to reproducibly catheterize 12 male mice with minimal urogenital trauma but cannot be used as a cystometric technique. This method will facilitate the expansion of research into sex differences in various genitourinary conditions that require transurethral catheterization of mice.

Symptom- and urinalysis-based approach to diagnosing urinary tract infections in children with neuropathic bladders.

BACKGROUND: Accurately diagnosing urinary tract infections (UTI) in children with neuropathic bladders can be difficult given the lack of specificity of both clinical symptoms and routine screening tests. We aimed to identify a priori unknown classes/groups of children with neuropathic bladder with respect to symptoms and UA results and examine their relationships with odds of UTI. METHODS: We used latent class analysis (LCA) to identify unobserved classes/groups of children with neuropathic bladder based on symptoms and urinalysis (UA) results, respectively. Demographic and clinical data were gathered by retrospective chart review of a cohort with neuropathic bladder. Symptoms and UA results were obtained by chart review of visits where urine culture was ordered. RESULTS: Around 193 patients were included in UA results analysis and 179 in symptom-based analysis. Two latent classes of patients were identified with respect to symptoms, labeled "pyelonephritis class" and "cystitis class," and two, with respect to UA results, were labeled "positive UA class" and "negative UA class." The pyelonephritis class had significantly higher odds of UTI compared to the asymptomatic class. While odds of UTI in cystitis class were higher than the asymptomatic class, this difference was not statistically significant. Positive UA class had significantly higher odds of UTI compared to negative UA class. CONCLUSION: Two unobserved classes/groups exist in children with neuropathic bladder with respect to symptoms, corresponding to cystitis and pyelonephritis, and two classes of UA results that correspond with either a positive or negative UA. Our results suggest a differential approach to treatments may be considered.

Urine neutrophil gelatinase-associated lipocalin in girls with recurrent urinary tract infections.

BACKGROUND: Children who experience more than one urinary tract infection (UTI) are at increased risk of kidney scarring due to their UTIs. Girls are at especially high risk for developing kidney scarring as a result of recurrent UTIs. Prior work suggested that neutrophil gelatinase-associated lipocalin (NGAL) may be lower in children with recurrent UTI compared with those without. The objective of this work was to compare urine NGAL concentrations in matched urine samples in girls with single and recurrent UTIs. METHODS: Girls less than 6 years of age who presented with signs and symptoms of a UTI were eligible for enrollment. Both acute, obtained from residual urine collected as part of their clinical evaluation, and follow-up urine samples, obtained after the completion of antibiotics when the patient was in their usual state of health, were collected from patients. Acute and follow-up urine NGAL concentrations were compared between girls with single and recurrent UTIs, as well as those with negative cultures who served as controls. RESULTS: Seventy girls were included in this study, 6 controls, 43 single UTIs, and 20 girls with recurrent UTIs. Patients in the control group had lower median acute NGAL concentrations than either those with single or recurrent UTI. There were no differences in either acute or follow-up urine NGAL concentrations between those with single and recurrent UTIs. CONCLUSION: In this cohort of girls less than 6 years of age, there is no difference in urine NGAL concentrations between those with single and recurrent UTIs.

Utility of DNA Next-Generation Sequencing and Expanded Quantitative Urine Culture in Diagnosis and Management of Chronic or Persistent Lower Urinary Tract Symptoms.

Many patients suffer from chronic, irritative lower urinary tract symptoms (LUTS). The evaluation and management of these patients have proven difficult with the use of standard diagnostic tools, including urinalysis and urine culture. The growing body of literature on the urinary microbiome has looked at the possible implications of the bladder microbiome and dysbiosis, or perturbations in the microbiome, in conditions associated with chronic LUTS. Disorders such as recurrent urinary tract infections (UTIs) and interstitial cystitis have been studied utilizing 16S rRNA rapid next-generation gene sequencing (NGS) and expanded quantitative urine culture (EQUC). In this article, we first present a brief review of the literature describing the current understanding of the urinary microbiome and the features and applications of NGS and EQUC. Next, we discuss the conditions most commonly associated with chronic, persistent LUTS and present the limitations of current diagnostic practices utilized in this patient population. We then review the limited data available surrounding treatment efficacy and clinical outcomes in patients who have been managed based on results provided by these two recently established diagnostic tools (DNA NGS and/or EQUC). Finally, we propose a variety of clinical scenarios in which the use of these two techniques may affect patients' clinical outcomes.

Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders.

BACKGROUND: Distinguishing between urinary tract infection (UTI) and colonization (UTC) in patients with neurogenic bladders who require clean intermittent catheterization (CIC) is difficult. Urinary neutrophil gelatinase-associated lipocalin concentrations (uNGAL) are increased in UTIs. Our objective was to determine the predictive accuracy of uNGAL for UTI in CIC-dependent children. METHODS: Cross-sectional study of CIC-dependent patients from August, 2015 to November, 2016. UTI was defined as (1) growth of ≥ 50,000 cfu/mL of a uropathogen, (2) > 10 urinary white blood cells/hpf, and (3) ≥ 2 of the following: temperature > 38 °C, abdominal pain, back pain, worsened incontinence, pain with catheterization, or malodorous/cloudy urine. Positive urine cultures that did not meet these criteria were grouped as UTC, and negative cultures were grouped as no growth. RESULTS: Two hundred one patients were included (no growth = 100, UTC = 77, UTI = 24). Median (interquartile range) uNGAL was higher in the UTI group (UTI 1361 (931, 2516) µg/g creatinine, UTC 246 (106, 548) µg/g creatinine, no growth 36 (11, 179) µg/g creatinine, p < 0.01 for all comparisons). The area under the ROC curve for uNGAL for UTI versus no UTI was 0.89, 95% CI (0.80-0.98). CONCLUSION: uNGAL is elevated in CIC-dependent children with UTI compared to those with negative cultures and those with UTC.

The Role of the Genitourinary Microbiome in Pediatric Urology: a Review.

PURPOSE OF REVIEW: In this review, we highlight the effects of the microbiome on urologic diseases that affect the pediatric patient. RECENT FINDINGS: Perturbations in the urinary microbiome have been shown to be associated with a number of urologic diseases affecting children, namely urinary tract infection, overactive bladder/urge urinary incontinence, and urolithiasis. Recently, improved cultivation and sequencing technologies have allowed for the discovery of a significant and diverse microbiome in the bladder, previously assumed to be sterile. Early studies aimed to identify the resident bacterial species and demonstrate the efficacy of sequencing and enhanced quantitative urine culture. More recently, research has sought to elucidate the association between the microbiome and urologic disease, as well as to demonstrate effects of manipulation of the microbiome on various urologic pathologies. With an improved appreciation for the impact of the urinary microbiome on urologic disease, researchers have begun to explore the impact of these resident bacteria in pediatric urology.

Neutrophil gelatinase-associated lipocalin: utility in urologic conditions.

Neutrophil gelatinase-associated lipocalin (NGAL) is best known as a non-invasive early marker of acute kidney injury (AKI). However, recent published reports have described additional utility of both plasma NGAL (pNGAL) and urine NGAL (uNGAL) in various pathologic conditions within the pediatric urinary tract, including urinary tract infection, vesicoureteral reflux (VUR), renal scarring, and obstructive uropathy. These two forms of NGAL have different applications related to their mechanisms of upregulation: pNGAL can serve as a marker of systemic inflammatory conditions, whereas uNGAL is specific for insults to the renal epithelium. Therefore, pNGAL has good predictive accuracy in systemic inflammation associated with pyelonephritis and renal damage, while uNGAL is an effective marker for identifying infection within the genitourinary environment as well as subclinical renal damage as a result of scarring or obstruction. Continued work should focus on the effect of trending NGAL values in patients with pyelonephritis, VUR, and hydronephrosis, to determine if longitudinal NGAL patterns have value in predicting adverse outcomes.

Urinary NGAL deficiency in recurrent urinary tract infections.

INTRODUCTION: Children with recurrent urinary tract infections (rUTI) often show no identifiable cause of their infections. Neutrophil gelatinase-associated lipocalin (NGAL) is known to be upregulated within the uroepithelium and kidney of patients with UTI and exhibits a localized bacteriostatic effect through iron chelation. We hypothesize that some patients with rUTI without an identifiable cause of their recurrent infections have locally deficient NGAL production. We therefore explored whether a lack of NGAL production may be a factor in the pathogenesis of rUTI. MATERIALS AND METHODS: Patients seen in the urology clinic for rUTI who were <21 years of age were enrolled. Patients were excluded if they had UTI at the time of enrollment, evidence of renal disease, decreased renal function, known anatomic abnormality of the genitourinary tract, or other reasons that predispose to UTI, such as neurogenic bladder, the need for intermittent catheterization, or unrepaired posterior urethral valves. Control patients were healthy children enrolled from the emergency department with no history of UTI or renal dysfunction, normal urinalysis at the time of enrollment, and presenting no diagnosis associated with increased NGAL levels, such as acute kidney injury or infection. NGAL was measured by immunoblot. RESULTS: Fifteen cases and controls were enrolled. Median urinary NGAL levels were significantly decreased in rUTI patients compared with controls [15 (14-29) ng/ml vs 30 (27-61) ng/ml; p = 0.002)] Although comparatively diminished, measurable NGAL levels were present in all patients with rUTI. CONCLUSIONS: Urinary NGAL is significantly decreased in patients with compared with patients without rUTI. These data suggest that some patients with rUTI may be predisposed to UTI because of a relative local deficiency in urinary NGAL production.

A Validated Method for Identifying Unplanned Pediatric Readmission.

OBJECTIVE: To validate the accuracy of pre-encounter hospital designation as a novel way to identify unplanned pediatric readmissions and describe the most common diagnoses for unplanned readmissions among children. STUDY DESIGN: We examined all hospital discharges from 2 tertiary care children's hospitals excluding deaths, normal newborn discharges, transfers to other institutions, and discharges to hospice. We performed blinded medical record review on 641 randomly selected readmissions to validate the pre-encounter planned/unplanned hospital designation. We identified the most common discharge diagnoses associated with subsequent 30-day unplanned readmissions. RESULTS: Among 166,994 discharges (hospital A: n = 55,383; hospital B: n = 111,611), the 30-day unplanned readmission rate was 10.3% (hospital A) and 8.7% (hospital B). The hospital designation of "unplanned" was correct in 98% (hospital A) and 96% (hospital B) of readmissions; the designation of "planned" was correct in 86% (hospital A) and 85% (hospital B) of readmissions. The most common discharge diagnoses for which unplanned 30-day readmissions occurred were oncologic conditions (up to 38%) and nonhypertensive congestive heart failure (about 25%), across both institutions. CONCLUSIONS: Unplanned readmission rates for pediatrics, using a validated, accurate, pre-encounter designation of "unplanned," are higher than previously estimated. For some pediatric conditions, unplanned readmission rates are as high as readmission rates reported for adult conditions. Anticipating unplanned readmissions for high-frequency diagnostic groups may help focus efforts to reduce the burden of readmission for families and facilities. Using timing of hospital registration in administrative records is an accurate, widely available, real-time way to distinguish unplanned vs planned pediatric readmissions.

Accuracy of Urinalysis for UTI in Spina Bifida.

OBJECTIVES: Urinary tract infections (UTIs) are common, but overdiagnosed, in children with spina bifida. We sought to evaluate the diagnostic test characteristics of urinalysis (UA) findings for symptomatic UTI in children with spina bifida. METHODS: Retrospective cross-sectional study using data from 2 centers from January 1, 2016, to December 31, 2021. Children with myelomeningocele aged <19 years who had paired UA (and microscopy, when available) and urine culture were included. The primary outcome was symptomatic UTI. We used generalized estimating equations to control for multiple encounters per child and calculated area under the receiver operating characteristics curve, sensitivity, and specificity for positive nitrites, pyuria (≥10 white blood cells/high-powered field), and leukocyte esterase (more than trace) for a symptomatic UTI. RESULTS: We included 974 encounters from 319 unique children, of which 120 (12.3%) met our criteria for UTI. Pyuria had the highest sensitivity while nitrites were the most specific. Comparatively, nitrites were the least sensitive and pyuria was the least specific. When the cohort was limited to children with symptoms of a UTI, pyuria remained the most sensitive parameter, whereas nitrites remained the least sensitive. Nitrites continued to be the most specific, whereas pyuria was the least specific. Among all encounters, the overall area under the receiver operating characteristics curve for all components of the UA was lower in children who use clean intermittent catheterizations compared with all others. CONCLUSIONS: Individual UA findings have moderate sensitivity (leukocyte esterase or pyuria) or specificity (nitrites) but overall poor diagnostic accuracy for symptomatic UTIs in children with spina bifida.

Gender and work-life balance: Results of a national survey of pediatric hospitalists.

In medicine, difficulty integrating work and home can lead to decreased job satisfaction, diminished well-being, and increased turnover. Understanding the experience of pediatric hospitalists can provide insights into building a stable, long-term workforce. We aim to examine gender differences in work-life balance and parental leave for physicians practicing Pediatric Hospital Medicine. METHODS: This was a cross-sectional survey study of 1096 pediatric hospitalists. Responses were collected via an online survey platform and summarized using descriptive statistics, including frequency distributions and measures of central tendency. A multivariable logistic regression was used to examine associated variables and work-life balance satisfaction. We analyzed free responses on parental leave to provide nuance to quantitative survey data. RESULTS: Five hundred and sixty-five respondents (52% response rate) completed the survey with 71% women. 343 (62%) prioritize work-life balance in career decision-making. Women report taking on more household responsibilities than their partners (41.4% vs. 8.4%; p < .001) including a larger percentage of caregiving and domestic tasks. Female gender and performing <50% caregiving were associated with decreased work-life balance satisfaction; performing <50% domestic tasks increased satisfaction. Median parental leaves were 4 weeks, with men taking significantly shorter leaves (3.5 vs. 6 weeks; p < .001) and more "paid back" time off. CONCLUSION: Work-life balance is an important factor in career decisions for men and women. Women perceive carrying a larger load at home. Qualitative results suggest that parental leave may be inadequate in length and salary support for men and women. This study adds insights into work-life integration in PHM.