Urinary tract infections in children

Abstract

Bacterial urinary tract infections (UTIs) are prevalent in childhood and adolescence. Paediatric UTIs present unique challenges with respect to diagnosis, prevention and management, and the potential for adverse sequelae. Uropathogenic Escherichia coli (UPEC) accounts for the majority of UTIs and is the best studied uropathogen. Novel discoveries have advanced our understanding of host–pathogen interactions, cellular and molecular mechanisms of host defence, and risk factors for UTI recurrence. Emerging evidence also highlights an association of the gut, vaginal and urinary microbiota in influencing UTI risk and recurrence. Yet, key knowledge gaps persist regarding UTI pathogenesis, host susceptibility, optimal diagnostic and management strategies and prevention of UTI recurrence and sequelae, especially in paediatric populations. The development of standardized clinical pathways offers an opportunity to improve care consistency and outcomes by integrating evidence-based practices into routine management. As technologies evolve and understanding deepens, future efforts must integrate host, microbial and clinical insights to optimize UTI prevention and treatment in paediatric populations.

Introduction

Urinary tract infections (UTIs) are the second most common bacterial infection in childhood, afflicting 8% of girls and 2% of boys by the age of 7 years^1–4. Up to 30% of children with a history of UTI develop one or more subsequent UTI⁴. In the USA alone, UTIs account for an estimated $630 million annually in health care costs as well as > 500,000 emergency department visits and one million clinic visits^5–7. Certain paediatric populations are especially prone to UTIs, including children with structural and functional urinary tract abnormalities³. Children with febrile UTIs are acutely at risk of morbidity and mortality owing to urosepsis, renal abscess formation and/or acute kidney injury⁸. Chronically, 10–40% of children with febrile UTI develop renal scars^8–10, which can lead to long-term impairment in estimated glomerular filtration rate (GFR), proteinuria and hypertension. With the growing threat of antibiotic resistance, investigation of alternative UTI preventive measures and treatment modalities is urgently needed. Advances have increased our understanding of microbial properties, host defences and risk factors, as well as treatment strategies for UTI.

In this Review, we discuss these developments while considering paediatric-specific risk factors and address current strategies for the diagnosis and clinical management of UTI.

Microbial determinants and epidemiology

Uropathogenic Escherichia coli (UPEC) accounts for 80% of initial UTI episodes in children and is the best studied bacterial uropathogen^11–14. Other common uropathogens include Gram-negative bacteria such as Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa, as well as Gram-positive bacteria such as Enterococcus faecalis, Streptococcus agalactiae, Staphylococcus aureus and Staphylococcus saprophyticus. Non-UPEC UTIs are most common in hosts with structural or functional abnormalities of the kidney and urinary tract and those with immunocompromised status^15,16. Numerous virulence mechanisms have been well-characterized for UPEC, but comparatively little is known about other uropathogens.

UTIs are initiated when uropathogenic bacteria breech host defences and seed infections in the bladder (cystitis)¹⁷. If uncontrolled, bacteria can ascend via the ureters to infect kidneys (pyelonephritis)¹⁷. Uropathogenic bacteria colonizing the periurethral area, gut or vaginal tracts can serve as the reservoir for infections^18,19 and the urinary tract is frequently challenged by bacteria, for example, in children during toilet training²⁰, bowel and bladder dysfunction²¹, after catheter insertion and sexual activity in adolescents¹⁸. Bladder colonization is generally prevented by host immune defences and bladder physiology, including the limited availability of micronutrients such as iron and zinc that are essential for uropathogen proliferation, urine flow, urothelial cell exfoliation and soluble factors blocking bacterial attachment to the urothelium^22,23.

The bladder is a challenging niche to colonize, so uropathogens tend to be adept at scavenging host metals, regulating motility and adhesins and evading host defences (Fig. 1). To overcome host nutritional immunity, uropathogens encode numerous metal-scavenging systems²⁴. The most common are the siderophores, which are high-affinity iron-chelating metallophores that strip iron from host reservoirs and deliver the metal intracellularly. Pathogens typically produce ‘stealth’ siderophores that are not recognized by the innate immune protein, lipocalin 2 (LCN2)^25,26. Notably, UPEC pathogenic potential can be predicted by phenotypic assays that combine the ability of UPEC to grow in nutrient-limiting conditions, siderophore production and type 1 fimbrial expression²⁷. Metal acquisition systems are also crucial for the full virulence potential of other uropathogens.

Fig. 1 |. Overview of major uropathogenic Escherichia coli virulence factors.

Uropathogenic E. coli (UPEC) uses an array of metal-scavenging systems to establish infection, most notably stealth siderophores that evade immune detection. Motility systems propel bacteria through urine and mucus layers to ascend and colonize the urinary tract. Type 1 pili (T1P; Fim system) bind to uroplakin Ia (UPIa) in the bladder and desmoglein 2 (DSG2) in the kidney, and P pili (Pap) bind to sphingolipids in the kidney. Urothelial exfoliation can provide access for extracellular or intracellular biofilm-like colonies in underlying bladder cells, which can contribute to recurrent urinary tract infections.

Bacterial adherence has been closely scrutinized in the field of uropathogenesis. Motility can propel bacteria through urine and mucus layers, but adherence is crucial for anchoring bacteria to surfaces of host cells or catheters against the shear force of urine²⁸. The best-described adhesins are the type 1 pili (T1P, Fim) and P pili (Pap). The T1P FimH tip adhesin binds to urothelial cell uroplakin Ia (UPIa) in the bladder and desmoglein 2 in the kidney, whereas the P pili PapG tip adhesin binds sphingolipids in the kidney^29–32. Bacterial adhesins also support uropathogen gut colonization, motility, biofilm formation, cellular invasion and formation of intracellular bacterial communities along with urothelial exfoliation and immune evasion²⁸.

Growing evidence challenges the long-standing axiom that the urinary tract is a sterile environment. Evidence has shown the presence of resident microbiota across pelvic organ systems, including the urinary tract, gastrointestinal tract and the vagina^33–35. These microbial communities seem to have interdependent and cumulative roles in maintaining host health by crosstalk with mucosa-associated lymphoid tissue, macrophages and maintaining the microbial community³⁶. Disruptions in the gut or vaginal microbiota, as well as alterations in the urobiome itself, have been linked to increased UTI risk³⁷.

Women with recurrent UTI often exhibit reduced gut microbial diversity, particularly among butyrate-producing bacteria that help to regulate host immune defences. Similarly, a decrease in protective Lactobacillus species in the vaginal microbiota has been associated with increased vaginal colonization by Escherichia coli and UTI risk³⁸. The paediatric urobiome has been shown to be variable and complex. For example, girls exhibit greater microbial diversity than boys and reduced diversity is linked to increased recurrent UTI risk³⁹. Bladder and bowel dysfunction and dysbiosis have also been implicated in increased paediatric UTI incidence, with altered abundance of Actinobacteria and Proteobacteria species⁴⁰. An observational study investigating the alterations in the gut microbiome of children with febrile UTI demonstrated increased representation of gut E. coli and reduced probiogenic bacteria, resembling the microbiomes of adult populations with recurrent UTI^41,42. These findings highlight the important role of microbial communities in urinary tract health and suggest new directions for UTI prevention strategies.

Host defence against urinary tract infection

Hosts employ many mechanisms of defence against UTI, including the urothelial barrier, immune phagocytes, spatial zonation of the immune response and kidney intercalated cells.

Urothelial mechanisms of host defence

The bladder urothelium forms an active barrier against bacterial infection and has been best studied in the context of UPEC UTI⁴³. UPEC uses intracellular pathways to persist within the urothelium (Fig. 2). After binding to urothelial cells via fimbriae, UPEC-derived lipopolysaccharide (LPS) triggers Toll-like receptor 4 (TLR4) signalling that promotes UPEC internalization into RAB27B% cytoplasmic compartments called fusiform vesicles (FVs)^44,45. UPEC increases expression of PIT1, a major phosphate transporter in the FVs. The reduced phosphate levels activate UPEC phospholipase (pdlA), which disrupts the FVs and enables UPEC to escape into cytoplasm⁴⁶ and form intracellular bacterial communities, facilitated by oxygen scavenging and metabolic reprogramming⁴⁴. Alternatively, UPEC can establish long-term quiescent intracellular reservoirs (QIRs) within autophagosomes⁴⁷, enabling evasion of host defences and contributing to recurrent infections.

Fig. 2 |. Antimicrobial properties of urothelium.

The urothelium uses mechanosensory and barrier properties, exfoliation, uropathogenic Escherichia coli (UPEC) expulsion and exocytosis, as well as the production of antimicrobial peptides (AMPs) and cytokines to defend the urinary tract from invading uropathogens, which can thwart urothelial defences and establish intracellular reservoirs in the form of intracellular bacterial communities or quiescent intracellular reservoirs. NRF2, nuclear factor erythroid 2-related factor 2; TLR4, Toll-like receptor 4.

The urothelium employs multiple integrated pathways to prevent UPEC invasion and limit UPEC persistence (Fig. 2). These pathways encompass mechanosensory signalling, barrier properties, antimicrobial peptide (AMP) production, exfoliation, UPEC expulsion and exocytosis, and regulation of protein homeostasis (proteostasis). These cell-intrinsic pathways are increasingly well-characterized in adult models; however, their developmental regulation in children remains incompletely defined. In mechanosensory signalling, UPEC-derived LPS induces ATP release by the urothelium, triggering P2X2 and P2X3 receptors to trigger enhanced micturition reflexes crucial for bladder contraction to promote UPEC clearance⁴⁸. UPEC encounters bladder host defences including the urothelial barrier with apical plaques and tight junctions to prevent pathogen entry^49,50. In addition, urothelial cells secrete AMPs, including lipocalins, cathelicidins, defensins and ribonucleases, to shield the urothelium from UPEC invasion⁵¹. Insulin receptor signalling supports both barrier integrity and NF-κB-driven AMP expression and its loss increases UPEC susceptibility⁵². UPEC also activates the NLRP3 inflammasome in urothelial cells, which triggers cytolysis and exfoliation⁵³ and can be expelled from the urothelium via RAB27B + FVs⁵⁴. NUR77 is a transcription factor and cytosolic LPS sensor that promotes UPEC clearance by triggering expulsion⁵⁵. Another urothelial transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), is activated by reactive oxygen species and promotes UPEC expulsion by increasing RAB27B transcription⁵⁶. Alternatively, internalized UPEC can be directed towards urothelial lysosomes and subjected to exocytosis via TRPML3 (ref. 57). Finally, the urothelial transcriptional regulator, interferon-related developmental regulator 1 (IFRD1), maintains ribosomal function and proteostasis. Ifrd1-deficient bladders exhibit endoplasmic reticulum stress, oxidative damage, increased permeability and UTI susceptibility⁵⁸.

Urothelial defence responses are influenced by sex hormones, which could explain some of the variation in UTI susceptibility; however, studies of their roles in paediatric populations are limited. In adult mice and human urothelial cells, oestrogen promotes urothelial barrier properties, AMP production and proteostasis, and oestrogen deficiency worsens UTI severity^59,60. Conversely, androgens exacerbate chronic infection⁶¹, although their influence on innate immune properties of urothelium is unclear. Future work should examine how sex hormones influence the maturation of urothelial immune pathways across childhood and adolescence and affect UTI risk.

Insights into the underlying mechanisms of host–pathogen interactions inform new therapeutic interventions that go beyond the use and overuse of antibiotics to eliminate UPEC from the urothelium. Potential therapeutic strategies include use of FimH-based antagonists, monoclonal antibodies, or vaccination strategies to prevent UPEC binding to the urothelium^62–65, intravesical administration of AMPs⁶⁶, PIT1 inhibition to block UPEC escape from the FVs⁴⁶ and NRF2 activation using FDA-approved dimethyl fumarate to enhance UPEC expulsion⁵⁶.

These observations underscore how dissecting urothelial–pathogen interactions can yield novel, evidence-based approaches to reducing UTI recurrence and antibiotic reliance. Paediatric UTI presents distinct challenges shaped by developmental differences in urothelial immunity, repair and host–pathogen interactions. These challenges can arise owing to congenital anomalies of the kidney and urinary tract (CAKUT), genetic variations that alter host immunity and a developing microbiome^67–69. Increased understanding of paediatric-specific responses is needed to inform tailored prevention and treatment strategies.

The role of immune phagocytes

The innate immune system has a crucial role in the initial defence against uropathogens, with phagocytic cells such as neutrophils, macrophages and dendritic cells serving as key effectors⁷⁰. These immune phagocytes coordinate pathogen recognition, clearance, and the initiation of inflammatory responses essential for infection control⁷⁰. However, the dynamics of phagocyte recruitment, activation, and function within the urinary tract remain incompletely understood, particularly in the paediatric population. Additionally, certain uropathogens, particularly UPEC, have evolved strategies to evade or subvert phagocytic responses, contributing to chronic and recurrent UTI. Immune phagocytes have multifaceted roles during UTI, contributing to both protective immunity and disease pathogenesis (Fig. 3).

Fig. 3 |. Roles of immune phagocytes during urinary tract infection.

Sentinel resident macrophages (Res-MΦs) detect bacterial antigens during urinary tract infection and secrete chemotactic factors, primarily C-C motif chemokine 2 (CCL2) and C-X-C motif chemokine 2 (CXCL2), to recruit monocytes and neutrophils. Monocyte-derived macrophages (Mo-MΦs) release TNF, which enhances neutrophil recruitment by stimulating additional CXCL2 production in Res-MΦs. Suburothelial perivascular macrophages (suPVMs) limit systemic bacterial spread by releasing macrophage extracellular traps (METs). Phagocyte release of matrix metalloproteinase 9 (MMP9) and MMP13 increases urothelial permeability, facilitating neutrophil transurothelial migration. Neutrophils deploy robust bactericidal responses, including antimicrobial peptide (AMP) release, NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) production and NETosis. PMN, polymorphonuclear leukocyte.

Recognition that urinary tract organs maintain a network of resident immune cells that is supplemented by recruitment of circulating immune cells during UTI is growing. Resident dendritic cells (Res-DCs) and macrophages (Res-MΦs) form a dynamic cell network that continuously samples self-antigens and pathogen-associated molecular patterns (PAMPs) in the urinary tract^71,72. Upon recognition of bacterial antigens, primarily LPS, via TLR4 (ref. 73), these sentinel phagocytes orchestrate rapid pro-inflammatory and antimicrobial responses.

TLR4 activation of Res-MΦs and Res-DCs triggers secretion of C-X-C motif chemokine 2 (CXCL2), a chemokine that recruits neutrophils to the infection site to promote bacterial clearance^73,74. Additionally, bladder and kidney Res-MΦs secrete chemokines such as the C-C motif chemokine 2 (CCL2) and CXCL2 to recruit monocyte-derived macrophages (Mo-MΦs) and neutrophils, respectively^75,76. Suburothelial perivascular macrophages (suPVMs), a specialized subset of Res-MΦs, have a key role in preventing bacterial dissemination and urosepsis during cystitis, via the release of macrophage extracellular traps (METs). METs not only restrict the bacterial access to blood vessels but also facilitate neutrophil transurothelial migration in a matrix metalloproteinase 13 (MMP13)-dependent manner⁷⁷.

In the infected bladder, Mo-MΦs release TNF, which amplifies CXCL2 secretion by Res-MΦs. CXCL2 induces MMP9 release by neutrophils, which degrades extracellular matrix and enables neutrophils to cross the urothelium to combat and clear the bacteria⁷⁵. These findings highlight a crucial interplay between Res-MΦs and Mo-MΦs in orchestrating effective host defence during cystitis. However, dysregulated recruitment or activation of MΦs, particularly in the infected kidney (pyelonephritis), can result in bystander tissue damage. For instance, neutrophil depletion leads to an accumulation of activated Mo-MΦs that promote tubulo-interstitial nephritis, renal scarring and kidney dysfunction⁷⁸. Hence, an effective balance between macrophages and neutrophils is essential not only for bacterial elimination but to prevent collateral tissue damage during ascending UTI. MΦs exert potent bactericidal mechanisms during UTI: MΦs employ AMPs, such as RNase 6 (refs. 79,80), iron retention mechanisms⁸¹ and METs for bacterial elimination⁷⁷.

Neutrophils have the primary role in UPEC elimination among immune phagocytes^78,82 and deploying AMPs including defensins⁸³, reactive oxygen species⁸⁴ and neutrophil extracellular traps (NETs)^84–87. NETs form when neutrophils unravel and eject their DNA coated with cytotoxic effector proteins. This process requires post-translational citrullination of histones by enzyme peptidyl arginine deiminase type 4 (PADI4), causing the charge to change, enabling DNA de-condensation and ejection from the cell⁸⁸. The extruded NETs entrap pathogens within the DNA webs and enable their killing by neutrophil cytotoxic proteins⁸⁹. A highly abundant protein in urine, Tamm–Horsfall glycoprotein (THP or uromodulin) has been shown to inhibit excessive pro-inflammatory neutrophil response to UPEC by binding to Siglec-9 receptor on neutrophils but it also enhances NET formation during UTI^86,90. Another key factor in neutrophil-mediated UPEC elimination is NADPH oxidase 2 (NOX2), which drives superoxide production during UTI⁸⁴. Beyond its bactericidal function, NOX2-derived reactive oxygen species also have a crucial role in a negative-feedback loop to dampen neutrophil-mediated inflammation by inducing NRF2 signalling. Mice deficient in NOX2 (Cybb^−/−) exhibit increased bacterial loads and augmented bladder oedema during cystitis, underscoring the dual role of neutrophil NOX2 in bacterial clearance and immune regulation⁸⁴. The protective role of neutrophils is further supported by clinical evidence in children. CXCR1 encodes a receptor for IL8, a key chemokine for neutrophil transurothelial migration during UTI^91–93. Genetic polymorphisms in CXCR1 and reduced CXCR1 expression have been associated with heightened susceptibility to acute pyelonephritis in children^94,95. Moreover, paediatric patients with chronic neutropenia display an increased incidence of UTIs, highlighting the importance of intact neutrophil responses in the host defence⁹⁶.

Altogether, this body of evidence indicates that a crucial interplay between immune phagocytes mediates effective antibacterial responses while limiting immunopathology during UTI. Disruption of this balance could result in chronic inflammation, tissue damage and increased UTI susceptibility.

Spatial zonation of the immune response

Appreciation that all organs contain a network of tissue immune cells in homeostasis is increasing. These resident immune populations can be complemented by circulating cells recruited in response to organ perturbations. Historically, the study of tissue immunity has largely focused on mouse organs, with inherent differences in genetic and environmental factors from humans. However, the development of technologies that enable high-dimensional profiling of transcripts within single cells has transformed our ability to understand the immune cell landscape of human organs, including the kidney^97,98. Early single-cell RNA sequencing ‘atlases’ of human kidney revealed not only mononuclear phagocytes, such as macrophages and dendritic cells, but also heterogeneity in adaptive immune-cell populations, including CD4⁺ T cells, tissue-resident memory CD8⁺ T cells, B cells and NK cells^99–101. These kidney immune cells are in a unique and anatomically heterogenous environment (Fig. 4). To achieve its homeostatic functions of blood filtration and fluid balance, blood passes through glomeruli, located in the cortex, generating a filtrate that flows through a series of epithelium-lined tubules, reaching the medulla, where urine is concentrated owing to the high interstitial sodium concentration generated^102,103. This hypersaline environment promotes epithelial-cell production of the monocyte-recruiting chemokine CCL2 and augments the antibacterial function of local macrophages⁷⁶. Pelvic epithelial cells also have immune functionality, producing IL8 (a neutrophil-recruiting chemokine) and AMPs such as LCN2, together creating a zone of defence that counters the threat of ascending bacteria¹⁰¹. This expression of chemokines and AMPs was not present in human fetal kidneys¹⁰¹, suggesting postnatal acquisition, potentially in response to microbial colonization.

Fig. 4 |. Immune defences of the kidney.

Kidney defence mechanisms include sodium-enhanced macrophage antibacterial function within the medulla (panel a), production of antimicrobial peptides (AMPs) such as lipocalin 2 (LCN2) by pelvic epithelial cells (panel b) as well as urinary neutrophils and neutrophil extracellular traps (NETs) (panel c) — working together to prevent and eradicate ascending urinary tract infection. CCL2, C-C motif chemokine 2; CXCL8, C-X-C motif chemokine 8; PADI4, peptidyl arginine deiminase 4; UPEC, uropathogenic Escherichia coli.

The discovery of the transcript and protein of neutrophil-recruiting chemokines within pelvic epithelial cells from uninfected human kidneys was surprising, suggesting the potential for tonic recruitment of neutrophils into the urinary space, contradicting the dogma that urine is devoid of neutrophils in the absence of infection. Exploring this observation further using microscopy and proteomics, neutrophils were identified in urine from healthy individuals, including those forming NETs⁸⁷. Using human urine ex vivo, and in vivo mouse models of UTI, NETs have been shown to interact with THP, forming large webs to entrap UPEC⁸⁶. PADI4 inhibition in vivo blocked NET formation and converted a simple bladder infection into severe pyelonephritis⁸⁷, suggesting that urine neutrophil NET formation is a crucial mechanism for preventing ascending UTI. Furthermore, the leucocyte esterase dipstick test used in clinics globally does not detect neutrophils per se, as previously assumed, but rather NETosing neutrophils⁸⁷, redefining the interpretation of this point-of-care test. Additional insight into how kidney-unique environmental features contribute to immunity will no doubt continue to emerge as the field harnesses ever-improving genomic and spatial technologies.

Intercalated cells as immune effectors

Intercalated cells (ICs), interspersed among principal cells in the kidney collecting duct, regulate systemic pH through proton and bicarbonate transport¹⁰⁴. Beyond their traditional role in acid–base homeostasis, ICs are increasingly appreciated as active participants in host–pathogen interactions and host defence against ascending UTI¹⁰⁵ (Fig. 5). Proton secretion by type A ICs requires carbonic anhydrase II (CAII)¹⁰⁶, and CAII-deficient mice exhibit increased susceptibility to experimental UTI¹⁰⁷. Moreover, UPEC preferentially attaches to and invades ICs rather than principal cells^108,109. Subsequently, ICs were shown to actively internalize UPEC and acidify intracellular compartments in a process resembling non-professional phagocytosis¹¹⁰. This work further supported the notion that ICs internalize LPS-coated beads introduced into the collecting duct lumen, supporting their endocytic capacity in vivo¹¹⁰. Results of other studies suggest that UPEC exploits desmoglein 2, an epithelial junctional protein that is highly enriched in the mouse and human distal nephron and collecting duct, for entry into ICs^30,111. These findings complicate efforts to clearly delineate host-mediated phagocytosis from bacterial invasion strategies, but the possibility exists that these two processes are inextricably linked.

Fig. 5 |. Innate immune properties of kidney intercalated cells during urinary tract infection.

During ascending urinary tract infection, intercalated cells (ICs) mount an innate immune response. Uropathogenic Escherichia coli (UPEC) are detected by Toll-like receptor 4 (TLR4), triggering the release of antimicrobial peptides (AMPs) and pro-inflammatory cytokines. ICs acidify the collecting duct lumen through apical H⁺-ATPases and promote bacterial clearance through phagocytosis, facilitated by the desmosomal protein desmoglein 2 (DSG2).

ICs also contribute to antimicrobial defence by secreting AMPs such as defensins, cathelicidin, hepcidin, LCN2 and ribonucleases^51,109. AMPs have been localized to the distal nephron and collecting system, further underscoring their ideal positioning for protection against ascending infection¹⁰¹. ICs express cytokines and chemokines, including IL6, IL18, CXCL1 and CXCL10 (refs. 112,113). These secreted factors shape both the luminal antimicrobial milieu and recruit immune cells to sites of infection. Notably, ICs demonstrate transcriptional plasticity under inflammatory stimuli, with upregulation of pattern recognition receptors (PRRs) including TLR4, and induction of NLRP3 inflammasome signalling in response to UPEC or LPS¹⁰⁸.

Advances in experimental models provide new opportunities to interrogate IC-specific immune functions. A newly developed Atp6v1g3-Cre mouse enables selective genetic manipulation of ICs, enabling functional dissection of immune pathways in vivo without affecting other organs¹¹⁴. Complementary to in vivo approaches, human collecting duct organoid models have been established that retain IC identity and can be used to study epithelial–pathogen interactions in a controlled, tractable system¹¹⁵.

Immature collecting ducts might lack the full complement of defence mechanisms needed to protect against infection, which could contribute to the increased risk of UTI-associated sequelae in neonates¹¹⁶. Much of the current understanding of the neonatal collecting duct is derived from early studies in rabbit models. In these models, the neonatal collecting duct contains fewer ICs than the adult collecting duct, and many of these cells exhibit an immature phenotype^117–120. This immaturity might also increase susceptibility to infection, as reduced IC number has been shown to correlate with increased UTI risk¹⁰⁹.

Congenital anomalies affecting paediatric patients, including urinary tract obstruction, vesicoureteral reflux (VUR) and renal dysplasia, confer a heightened risk of UTI and pyelonephritis^121–123. In addition to infection risk, these anomalies are also linked to collecting duct maldevelopment¹¹⁷. In mouse models of urinary tract obstruction, expression of markers of mature intercalated cells were reduced^124,125. Altogether, these findings suggest that delayed or disrupted maturation of the collecting duct owing to developmental stage or congenital anomaly could contribute to increased UTI susceptibility in early childhood.

Together, these findings position ICs as hybrid epithelial–immune cells, capable of sensing, responding to and clearing urinary pathogens. This immunoregulatory role complements their classical functions and underscores their importance in maintaining urinary tract health.

Risk factors for urinary tract infection and renal injury

Host defences recognize and combat invading uropathogens, but intrinsic factors related to patient anatomy, age and underlying conditions substantially influence susceptibility to UTI and renal injury. Understanding these risk factors is crucial for identifying individuals at a high risk, guiding timely diagnosis and implementing targeted preventive measures. Anatomical, developmental and genetic factors can modulate UTI risk; in paediatric populations, these vulnerabilities intersect with immune defences to shape clinical outcomes. Elements of UTI risk are still being explored, but certain clinical factors clearly confer risk of UTI.

Inherent elements of UTI risk exist that vary based on patient age and sex. In the initial 6 months of life, boys are more commonly affected by UTI than girls (5.3% versus 2%)^126,127. However, the risk of UTI in girls increases with age, surpassing boys at between 3 and 6 months of age and persisting at an incidence of 3% in prepubertal girls compared with 1% in prepubertal boys^126,128. One of the most recognized associations between UTI and genital anatomy relates to male circumcision status, with neonatal circumcision decreasing the risk of UTI between 3-fold and 10-fold in boys <2 years of age and being particularly beneficial in the setting of other urinary tract anomalies^129,130. Other data suggest that UTI risk in uncircumcised boys can be reduced simply by retracting the foreskin^131,132, supporting overall awareness of preputial management. Perhaps most importantly, UTI can be a sign of underlying CAKUT. These congenital anomalies result in urinary obstruction, stasis and/or VUR. VUR refers to the retrograde flow of urine from the bladder into the kidney, increasing the risk of developing pyelonephritis and subsequent renal scarring¹³³.

Recurrent and febrile urinary tract infection

Approximately 30% of children with CAKUT present with UTI¹³⁴, leading to some clinical guidelines recommending obtaining initial renal and bladder ultrasonography to evaluate a febrile UTI in children^135,136 while also acknowledging the utility of ultrasonography after the first febrile UTI is questioned¹³⁷. There is an increased likelihood of CAKUT, particularly VUR, being found after first-time UTI in children who are relatively young, male, have a family history of CAKUT and present with fever ≥38 °C, bacteraemia, non-E. coli infection and an abnormal renal ultrasonography^138–140. Contemporary studies demonstrate a prevalence of ~20–25% of VUR in children after the first febrile UTI^141,142. Given some concerns regarding the clinical importance of identifying low-grade VUR owing to spontaneous resolution over time and a limited effect on the risk of further UTI and/or renal scarring^9,143, the retired American Academy of Paediatrics (AAP) guidelines recommended a voiding cystourethrogram only in the presence of abnormal renal ultrasonography and/or after subsequent febrile UTI¹⁴⁴. However, the European Association of Urology–European Society for Paediatric Urology guidelines recommend voiding cystourethrogram regardless of ultrasonography findings after febrile UTI in all children <1 year old but more restricted uses in older children, similar to the retired AAP guidelines (for example, recurrent febrile UTI, abnormal imaging)¹⁴⁵.

After toilet training, dysfunctional bowel and bladder habits, such as infrequent urination and constipation, become important UTI risk factors. Bladder and bowel habits are often intertwined with disturbances of one affecting the other, called bowel and bladder dysfunction (BBD)¹⁴⁶. Importantly, BBD occurs in the absence of underlying neurological aetiology and is considered a functional disorder, largely attributed to learned behavioural patterns potentially owing to delayed toilet training, voluntary contraction of the pelvic floor during voiding triggered by adverse toilet training experiences, painful urination and/or environmental aversion^147,148. Additionally, poor bladder emptying, whether from infrequent urination or partial mechanical obstruction owing to a large rectal volume of stool, can lead to failure to expunge any bacterial inoculum that enters the urinary tract. BBD is associated with an increased susceptibility to pyelonephritis and resulting renal scarring and can even affect the natural history of VUR, limiting spontaneous resolution and the surgical success of VUR correction when intervention is required^{3,145,146,149}. BBD has been implicated in risk of UTI recurrence, particularly in the setting of VUR^3,148. Thus, clinical guidelines recommend screening and aggressively managing BBD in relevant toilet-trained patient populations¹⁴⁵.

An obvious direct effect on bladder function that leads to an increased risk of UTI occurs in the setting of a neurological abnormality, such as spina bifida, or injury that results in a neurogenic bladder. Neurological damage to the bladder often leads to poor emptying of the bladder and might require regular assisted drainage with either an indwelling catheter or intermittent catheterization¹⁵⁰. Foreign bodies used to manipulate the urinary tract are themselves a risk for colonizing the urinary tract with bacteria, but the use of a catheter in this situation is often to try and decrease infection by trading improved bladder drainage with any potential introduction of microbes to the bladder. Interestingly, beyond abnormal bladder function, some data suggest altered immune function in the setting of neurological lesions, particularly spinal cord injury, that requires further clinical investigation^151–154.

Renal scarring

Approximately 15% of children with initial febrile UTI had evidence of renal scarring measured by technetium-99m dimercaptosuccinic acid scan (DMSA scan), best detected 6 months after UTI^121,155,156. The proposed mechanism of renal scarring is that bacterial infection provokes an excessive inflammatory response, in which macrophage activation results in collateral injury accompanied by hypoxia, triggering myofibroblast activation and extracellular matrix deposition that replaces the functional renal parenchyma^78,157–159. The proposed role of excessive inflammation as a driver of renal scarring underlies efforts to administer systemic corticosteroids to suppress the inflammatory response and prevent renal scarring. Results of a meta-analysis of randomized controlled trials of adjuvant corticosteroids in children with pyelonephritis showed that moderate-quality evidence supports their use, but more research on their effectiveness and harm is needed before widespread adoption in the clinical setting to prevent renal scarring¹⁶⁰. VUR is associated with a substantially increased risk of renal scarring following initial UTI, especially in children with grade III VUR or higher^156,161. Longitudinal studies have supported the association of high VUR grade with renal scarring and identified additional risk factors for new scars including delayed initiation of antibiotic treatment, recurrent UTI, increased age, Hispanic ethnicity and the presence of BBD^3,162,163.

Genetic determinants of urinary tract infection susceptibility

Mounting evidence supports a role for genetics in paediatric UTI susceptibility. Construction of multi-generation pedigrees has provided evidence in support of genetic determinants of pyelonephritis with dominant and recessive modes of inheritance¹⁶⁴. This finding is further substantiated by the identification of promoter polymorphisms in IRF3 and CXCR1 that result in reduced protein expression and increased UTI susceptibility^94,165. Conversely, polymorphisms in the IRF7 promoter that attenuate IRF7 expression are associated with reduced susceptibility to recurrent pyelonephritis in children¹⁶⁶. TLR4 promoter polymorphisms that dampen TLR4 expression are associated with increased rates of asymptomatic bacteriuria and might protect against severe bacterial infection¹⁶⁷. A common non-synonymous SNP in RNASE7 that results in reduced antimicrobial activity has been associated with increased frequency of UTI in girls independent of VUR status⁶⁸. In addition to these polymorphisms, evidence points towards a role for gene copy number variation in DEFA1A3, DMBT1 and DCHS1 in conferring UTI susceptibility in children^168–170. In aggregate, the observations from these studies indicate that genetic variation contributes to UTI risk. A drawback is that the vast majority have been performed in white girls and have not been independently validated. Further studies are required to establish their validity in independent cohorts and generalizability across the human population. By contrast, relatively less information is available regarding genetic determinants of renal scarring, partly owing to the variable frequency of renal scarring among paediatric UTI cohorts. Exome sequencing was used to uncover an association between renal scarring and polymorphisms in mitochondrial genes known to be involved in renal disease¹⁷¹.

Thus, paediatric UTI and renal injury risk is shaped by age, sex, anatomy and genetics, with functional and neurological bladder disorders increasing susceptibility by impairing bladder emptying and promoting recurrent infection. Renal scarring results from inflammation following febrile UTI and is influenced by reflux severity, UTI recurrence and genetic factors.

Urinary tract infection diagnosis and management

Understanding the host immune response to UTI provides crucial insights into disease progression and pathogen clearance, but effective clinical management requires timely and accurate diagnosis. Alongside diagnostic precision, selecting appropriate antimicrobial therapy and determining optimal treatment duration are essential components of patient care.

Urinary tract infection diagnosis

In preverbal children, signs and symptoms of UTI are non-specific; fever might be the only finding¹⁷². Moreover, obtaining urine samples in this age group is particularly challenging. Thus, many children are tested in order to diagnose a single child with UTI. To limit the number of children undergoing testing without missing those with a UTI, a prediction tool (UTICalc) was developed (https://uticalc.pitt.edu)¹⁷². The user inputs five findings (age, maximum temperature, duration of fever, history of UTI, sex and circumcision status, presence of another source of fever on examination) and the calculator outputs the probability of UTI and provides recommendations regarding testing^172,173. This tool has been externally validated¹⁷⁴. The probability of UTI based on results of the leukocyte esterase test can also be calculated by UTICalc¹⁷². Urine culture is the gold standard for the diagnosis of UTI, but empirical treatment with antimicrobials is often initiated based on results of screening tests, especially in febrile children. Owing to the limitations of current screening tests (such as leukocyte esterase level and white blood cell count)^175,176, overtreatment and undertreatment both occur frequently in this age group¹⁷⁷. Thus, sending a urine culture for these children remains important so that informed decisions can be made regarding empirical treatment. New evidence supports using a threshold of 10,000 colony-forming units per millilitre for the diagnosis of UTI in this age group¹³. In verbal children, findings include urinary symptoms (for example, dysuria, frequency, urgency, new onset of incontinence) and abdominal pain¹⁷⁸. On examination children might have suprapubic tenderness. As signs and symptoms of UTI are more specific than in preverbal children, diagnosis and empirical treatment are often more straightforward. The accuracy of screening tests, utility of routine urine culture and the colony-count threshold to use for UTI diagnosis have not been extensively studied in verbal children, highlighting an important knowledge gap in diagnostic test validation.

Choice of antimicrobials

Currently, cephalexin is the preferred agent for the treatment of UTI because of its narrow spectrum, high bioavailability and efficacy against most frequently isolated pathogens^179–185. Trimethoprim-sulfamethoxazole and amoxicillin-clavulanate might be acceptable options in some communities in which resistance to these agents is still infrequent.

Duration of antimicrobial treatment

The duration of antibiotic treatment has been examined in three studies^186–188. Results of a meta-analysis of these studies suggested that a 5-day course of treatment is sufficient for children without any fever¹⁸⁹. However, the largest randomized controlled trial assessing treatment duration in acute pyelonephritis reported a higher treatment failure rate (4.2%) in the group receiving a 5-day course of antibiotics than in the group receiving a standard 10-day course (0.6%)¹⁸⁶. Thus, more studies are needed before reduced-duration courses can be recommended for febrile or complicated UTI.

Accurate diagnosis and judicious use of antibiotics are crucial for effective UTI management, guiding evidence-based clinical decisions that balance infection eradication with minimizing antibiotic resistance.

Antibiotic prophylaxis in at-risk children

Some patients with a history of prenatal hydronephrosis or VUR are at an increased risk of ascending UTI. These children can be treated with continuous antibiotic prophylaxis (CAP), which is a low-dose daily antibiotic treatment given to prevent UTI. The efficacy of CAP is controversial and the mechanism of CAP in preventing UTIs has not been elucidated, but an accepted assumption is that CAP leads to sufficient urine antimicrobial concentrations to either prevent uropathogens from establishing an infection or to quickly clear pathogens early in the infectious phase, before they can establish an invasive or entrenched infection^190–192.

Continuous antibiotic prophylaxis for prenatal hydronephrosis

CAP is widely used to prevent UTI in infants diagnosed with prenatal hydronephrosis. Despite its common application, the supporting evidence is limited, contributing to variations in clinical guidelines and provider practices¹⁹². Current evidence does not support a clear benefit of CAP in infants with prenatal hydronephrosis; moreover, such use might contribute to the development of antimicrobial resistance¹⁹³. General paediatricians frequently prescribe CAP¹⁹⁴, paediatric nephrologists and urologists often reserve its use for infants with bilateral or high-grade isolated hydronephrosis¹⁹⁵.

Results of a 2013 systematic review of nearly 4000 patients across 21 studies showed that infants with high-grade hydronephrosis exhibited a four-fold increase in UTI risk compared with those with low-grade hydronephrosis. The number needed to treat (NNT) to prevent one UTI was calculated at 7 for high-grade hydronephrosis. CAP had minimal influence on UTI incidence in low-grade hydronephrosis (2.2% with versus 2.8% without CAP), but it substantially reduced UTI rates in high-grade hydronephrosis (14.6% with CAP versus 28.9% without). These findings support CAP in high-grade hydronephrosis, although study heterogeneity remains a limitation¹⁹⁶. By contrast, the Society for Fetal Urology (SFU) hydronephrosis registry showed a 4% UTI rate in children with isolated hydronephrosis, suggesting reduced overall baseline risk in some cohorts¹⁹¹.

The European Association of Urology–European Society for Paediatric Urology maintains that the benefits of CAP across heterogeneous hydronephrosis populations remain unproven¹²³. However, they acknowledge evidence indicating that CAP might reduce febrile UTI in high-risk groups, such as girls, uncircumcised boys and those with hydroureteronephrosis¹⁹². The AAP guidelines on prenatal hydronephrosis recommend CAP for patients with ureteral dilation ≥7 mm or severe urinary tract dilation¹⁹⁷. The Indian Society of Paediatric Nephrology (ISPN) guidelines recommend avoiding routine CAP in infants with hydronephrosis until more robust data are available¹⁹⁸.

In primary non-refluxing megaureters, or hydroureteronephrosis, the risk of febrile UTI seems to be substantially elevated¹⁹⁹. In one study involving 80 infants, a 34% incidence of febrile UTI within the first 6 months was reported, prompting recommendations for early CAP in this group²⁰⁰. However, reduced infection rates (~15%) with delayed onset have been observed, complicating the consensus²⁰¹. The British Association of Paediatric Urologists supports CAP use during the first 6–12 months²⁰². Notably, circumcision and CAP use are the most consistent factors linked to reduced UTI risk²⁰³. A multicentre study from the SFU hydronephrosis registry showed that hydroureters ≥7 mm in diameter can be used to identify a high-risk cohort who benefit from CAP, whereas infants with non-refluxing hydroureters of ≥7 mm might not²⁰⁴.

CAP is commonly believed to reduce UTI in infants with prenatal hydronephrosis, but conclusive evidence from randomized controlled trials is lacking. An ongoing randomized controlled trial evaluating trimethoprim versus placebo in infants with SFU grade III–IV hydronephrosis has been concluded and is aimed at addressing this gap²⁰⁵. Consequently, some clinicians advocate initiating CAP at birth for selected patients, but others prefer vigilant monitoring and prompt management of suspected UTI.

Continuous antibiotic prophylaxis in children with vesicoureteral reflux

VUR is common, affecting 1–2% of children^206,207. VUR increases the risk of kidney infection, and many children with VUR have recurrent kidney infections^162,208. In some children, recurrent infection leads to kidney scarring and dysfunction, termed reflux nephropathy²⁰⁹. In the early 2000s, the research community began interrogating the efficacy of CAP in preventing UTI and renal scarring in children with VUR. Results of the RIVUR trial demonstrated that CAP with the trimethoprim–sulfamethoxazole combination effectively decreased UTI recurrence by 50% compared with placebo in children with VUR enrolled after the first or second febrile or symptomatic UTI²¹⁰. Results of the PREDICT trial showed that CAP is also effective in preventing first UTI in children with grade 3 or higher VUR²¹¹.

The results of these trials demonstrated that CAP prevents UTI, but equal incidence of new renal scarring on DMSA scans was reported between the CAP and placebo groups in both trials^162,211. However, notably, new renal scars in the PREDICT trial were not associated with UTI occurrence in the study period²¹¹, raising concern over the specificity of this scarring for reflux nephropathy. In the RIVUR trial, a secondary analysis demonstrated that CAP was protective against recurrent UTI-associated kidney function deterioration versus placebo²¹².

Changes in kidney function by estimated GFR have also been assessed using the RIVUR data. GFR was not initially found to correlate with scarring, but reanalysis revealed differences in GFR associated with the frequency of recurrent UTI¹⁶². When GFR data were stratified by number of lifetime UTI, a dose–response emerged in the placebo group, demonstrating a trend towards decreased GFR with each subsequent UTI episode. This trend in kidney functional decline was not observed in the CAP group²¹².

Current evidence shows that CAP prevents UTIs and could mitigate GFR changes associated with recurrent UTI. Limiting UTI frequency and severity also limits child suffering and decreases emotional and financial stress on the family that could result from avoidable hospital admissions to treat UTI. Conversely, CAP is not a benign treatment and increases the likelihood of antimicrobial-resistant UTI infection as well as non-E. coli UTI¹⁹³. Additionally, CAP can alter the composition of the gut microbiome, although to our knowledge the long-term effect of this in children with VUR has not been studied^{211,213–215}. Further prospective studies are needed to fully elucidate the link between CAP, renal scarring and kidney function in children with VUR and UTI, as well as to identify the children who will gain the most benefit from this therapy.

Non-antibiotic approaches

Given the association of CAP and microbial resistance, considerable attention has been directed towards strategies to leverage non-antibiotic therapies towards UTI prevention. Most of the evidence in support of non-antibiotic measures has been generated in adult women with cystitis, making extrapolation to the paediatric UTI population challenging. The performance of cranberry extract and Lactobacillus probiotics in randomized controlled trials in children has been examined in a systematic review and meta-analysis²¹⁶. Other candidate interventions, such as methenamine hippurate and D-mannose, were not adequately tested in the paediatric population to qualify for inclusion. Cranberry extract was associated with a substantial reduction in UTI recurrence and Lactobacillus did not seem to influence UTI recurrence, with the strong caveat that reporter bias, inconsistencies in study design and UTI definition made it very challenging to draw a confident conclusion from these studies²¹⁶. More rigorous studies are needed to investigate candidate non-antibiotic therapies to prevent UTI in children.

Clinical pathway development and implementation

A clinical pathway (CPW) is a multidisciplinary, standardized care plan for a particular problem or procedure that details steps for evaluation and management²¹⁷. CPWs are aimed at reducing variation, improving quality and optimizing clinical outcomes for a specific group of patients by translating evidence or guidelines into practice within a local context. A Cochrane Review concluded that CPWs probably reduce in-hospital complications and reduce length of stay, and could increase adherence to recommended practices²¹⁸. In one large paediatric health system, the implementation of 15 clinical pathways resulted in decreased resource use (that is, a halt in rising costs and decreased length of hospital stay) while maintaining good clinical outcomes²¹⁹. For paediatric UTI specifically, CPW implementation in an Emergency Department and three Urgent Care centres led to a substantial increase in first-line, narrow-spectrum antibiotic prescriptions²²⁰. Similarly, a CPW improved adherence to recommended use and duration of a first-line antibiotic in a large primary care network through a multi-faceted approach including a local clinical guideline, education and a UTI order set from which clinicians could select a first-line antibiotic with defaulted dose and duration²²¹.

Several paediatric centres provide CPWs for UTI that are publicly available. For example, at Nationwide Children’s Hospital in Columbus, Ohio (USA) (https://www.nationwidechildrens.org/for-medical-professionals/tools-for-your-practice/clinical-pathways), a multidisciplinary pathway team was assembled and included physicians in primary care, emergency medicine, urgent care, hospital medicine, infectious diseases, nephrology and urology, as well as nurses and a pharmacist. The team developed two UTI pathways, one for Emergency Department and Urgent Care management and one for inpatient management. These pathways include algorithms in the form of flow charts with links to additional detailed information to guide clinicians through the clinical course from initial presentation to disposition in the Emergency Department or Urgent Care, and from hospital admission to discharge. They provide information about UTI signs and symptoms, differential diagnoses and recommendations for laboratory tests, imaging studies, treatments and consultations. After completion of the pathway document, clinical informaticists developed order sets in the electronic health record with decision-support text and defaulted order options to encourage adherence to pathway recommendations.

Once developed, CPWs and associated decision-support tools must be disseminated and adopted by the end users. Ideally, the pathway team will identify key quality metrics and track performance over time. Implementing a CPW requires time, personnel and support from leadership. In a multicentre study that evaluated implementation strategies for CPWs, engagement of a multidisciplinary team and alignment with institutional values and goals were identified as facilitators of CPW implementation, whereas information technology challenges such as limited staff and competing priorities were barriers to implementation²²².

Conclusions

As we look towards the future, bacterial UTI will continue to be highly prevalent in children and adolescents. Although new discoveries have advanced our understanding of host–pathogen interactions, cellular and molecular mechanisms of host defence and the importance of local microbiomes, further studies are needed to apply these discoveries to the paediatric population and translate them into UTI prevention and treatment strategies. Longitudinal studies over the past decade have enabled identification of clinical and genetic risk factors for UTI recurrence in children and investigated renal scarring and renal dysfunction as chronic UTI sequelae. Randomized clinical trials in children have advanced our understanding of the appropriate duration of antibiotics for UTI treatment and the value of CAP in children with VUR and hydronephrosis. Standardized CPWs provide opportunities to improve care consistency and outcomes by local implementation of evidence-based best practices. Ultimately, the best outcomes for children with UTI will be achieved through ongoing preclinical, translational and clinical studies propelled by an engaged community of stakeholders.

Key points.

• The bladder presents a challenging niche for colonization; consequently, bacterial uropathogens have evolved strategies to establish infection and evade host immune defences.

• Kidney immune cells operate within a complex environment in which urothelial cells produce antimicrobial peptides and chemokines, leading to neutrophil recruitment and formation of neutrophil extracellular traps.

• The risk factors that contribute to urinary tract infection (UTIs) and renal scarring include congenital abnormalities, such as vesicoureteral reflux, along with bowel and bladder dysfunction and genetic polymorphisms.

• Current strategies for UTI management include accurate diagnosis and judicious use of antibiotics for effective treatment as well as prophylaxis.

• With increasing prevalence of paediatric UTIs, development and implementation of robust clinical pathways will be vital for improving patient care and outcomes.

Glossary

Acute kidney injury

Rapid deterioration of renal excretory function

Carbonic anhydrase II

(CAII). Enzyme that is essential for acid–base regulation

Congenital anomalies of the kidney and urinary tract

(CAKUT). Group of developmental abnormalities that affect the kidneys, bladder, ureters and urethra

Cystitis

Bladder inflammation commonly caused by bacterial infection. Symptoms include urinary urgency, frequency and lower abdominal pain

Dimercaptosuccinic acid scan

(DMSA scan). Nuclear medicine test used to image kidneys to assess renal structure and function

Dysbiosis

Imbalance of the microbiome potentially caused by infections, antibiotics, stress or poor diet

Fusiform vesicles

(FVs). Intracellular compartments that transport urothelial plaques to the bladder epithelial surface

Macrophage extracellular traps

(METS). Net-like structures produced by macrophages that are composed of DNA strands, histones and proteins, which entrap and kill pathogens

Neutrophil extracellular traps

(NETs). Net-like structures composed of DNA strands, histones and proteins, produced by neutrophils, that entrap and kill pathogens

Principal cells

Cell type in the kidney’s collecting duct that regulates electrolyte and water balance

Promoter polymorphisms

Variation in a gene’s promotor region that may alter the expression of the gene

Pyelonephritis

Kidney inflammation caused by bacterial infection with symptoms such as fever and flank pain

Quiescent intracellular reservoirs

(QIRs). Persistent reservoirs of Escherichia coli in the bladder mucosa following initial invasion of bladder epithelial cells and infection of the bladder

Renal scarring

Fibrosis of the kidney parenchyma caused by inflammation, infection and injury resulting in kidney disease

Tamm–Horsfall glycoprotein

(THP or uromodulin). Major urinary protein that prevents Escherichia coli from binding to urothelium

Tubulo-interstitial nephritis

Inflammation of the renal interstitium and tubules owing to autoimmune diseases, infections or drugs

UTICalc

Paediatric UTI probability calculator based on clinical variables

Related links

Nationwide Children’s: https://www.nationwidechildrens.org/for-medical-professionals/tools-for-your-practice/clinical-pathways

UTICalc: https://uticalc.pitt.edu