Primary Septic Arthritis in Children Demonstrates Presumed and Confirmed Varieties Which Require Age-specific Evaluation and Treatment Strategies.

BACKGROUND: There is uncertainty involved in the evaluation and treatment of children suspected to have septic arthritis particularly when no causative pathogen is confirmed. This study evaluates children with primary septic arthritis to refine the processes of evaluation and treatment and improve the rate of pathogen confirmation. METHODS: Children suspected to have septic arthritis from 2009 to 2019 were retrospectively studied. Diagnosis of primary septic arthritis, defined as hematogenous joint infection without associated osteomyelitis, was established by clinical evaluation, radiology and laboratory results, including joint fluid analysis. Excluded cases were categorized by etiology. Children with primary septic arthritis were divided into confirmed and presumed cohorts for statistical comparison. RESULTS: A total of 355 children (average age 4.4 y, range 0.05 to 18 y) were initially treated as septic arthritis. Eighty-seven (24.5%) were excluded due to other conditions, including 34 (9.6%) with noninfectious conditions. Among 268 children with primary septic arthritis, 134 were confirmed and 134 were presumed. A higher rate of 16S polymerase chain reaction (PCR) acquisition (71.6% vs. 45.5%) occurred in the confirmed cohort. Overall yield for various methods of pathogen identification were 27 of 239 (11.3%) by blood culture, 83 of 268 (31.0%) by joint fluid culture and 85 of 157 (54.1%) by PCR. PCR identified a pathogen in 87.5% of children with confirmed septic arthritis. Antibiotic pretreatment was associated with a lower rate of joint fluid culture positivity. Pathogens aggregated within specific age groups. The 4 to 9-year-old age group displayed the widest spectrum of pathogens with limited predictability. CONCLUSIONS: This study emphasizes the need for systematic processes of evaluation and treatment for children suspected to have primary septic arthritis, including minimization of antibiotic pretreatment, age-based empiric antibiotic selection, and sufficient follow-up to ensure noninfectious conditions are distinguished in culture-negative cases. Extended observation, before intervention, may be appropriate for some children. LEVEL OF EVIDENCE: Level III-retrospective control study.

Primary Septic Arthritis Among Children 6 to 48 Months of Age: Implications for PCR Acquisition and Empiric Antimicrobial Selection.

INTRODUCTION: Primary septic arthritis requires unique evaluation and treatment considerations for children in the 6- to 48-month age range because of the spectrum of identified pathogens and high rate of negative cultures. The purpose of this study is to evaluate primary septic arthritis in this age group in order to differentiate children with infection caused by Kingella kingae from those with other confirmed pathogens and those with no identified pathogen. METHODS: Preschool children who underwent multidisciplinary evaluation and treatment for septic arthritis between 2009 and 2019 were retrospectively studied. Three cohorts were established for comparison of clinical and laboratory features of primary septic arthritis: (1) confirmed K. kingae, (2) confirmed other pathogen, and (3) presumed (without identified pathogen). RESULTS: Among 139 children with septic arthritis, 40 (29%) were confirmed K. kingae, 29 (21%) other pathogen, and 70 (50%) presumed. Children with Kingella and those with presumed septic arthritis had significantly lower initial C-reactive protein (4.8 and 4.5 vs. 9.3 mg/dL) and fewer febrile hospital days (0.2 and 0.4 vs. 1.3 d) than children with other confirmed pathogens. Children with other pathogens had higher rates of bacteremia (38% vs. 0%) and positive joint fluid cultures (86% vs. 15%) than that of children with Kingella. The rate of polymerase chain reaction (PCR) acquisition was 38 of 40 (95.0%) Kingella cases, 18 of 29 (62.1%) other pathogen cases, and 33 of 70 (47.1%) presumed cases. CONCLUSIONS: K. kingae was the most commonly identified pathogen among 6-month to 4-year-old children. The Kingella and other identified pathogens in this study serve to guide empiric antimicrobial recommendations for this age range. Because of similarities between children with septic arthritis because of K. kingae and those with no identified pathogen, it is likely that an unrecognized burden of Kingella resides in culture negative cases, particularly if no PCR is sent. Systematic evaluation, including PCR acquisition, and a high index of suspicion for K. kingae are recommended to thoroughly evaluate septic arthritis in preschool children. LEVEL OF EVIDENCE: Level III-Retrospective cohort comparison.

Association of in-line digestive enzyme cartridge with enteral feeds on improvement in anthropometrics among pediatric patients with cystic fibrosis.

BACKGROUND: Approximately 85% of patients with cystic fibrosis (CF) have exocrine pancreatic insufficiency (EPI) with 10% requiring supplemental nighttime enteral tube feedings. Administration of pancreatic enzyme replacement therapy (PERT) with nighttime feedings is fraught with challenges. RELiZORB (Alcresta Therapeutics, Inc), an in-line lipase cartridge, delivers PERT continuously with enteral feedings. Outcomes related to the use of this in-line lipase cartridge are lesser known. This project evaluated anthropometrics related to in-line lipase cartridge use among pediatric patients with CF already receiving oral PERT therapy prior to nighttime enteral feedings. METHODS: Retrospective chart review was performed on 29 patients with CF and EPI receiving supplemental tube feedings and utilizing in-line lipase cartridge for a continuous 12 month period between 2015 and 2019. Anthropometrics were evaluated 12 months before and after initiation of in-line lipase cartridge. RESULTS: Compared with mean height z score at 6-months pre-in-line lipase cartridge, mean height z score at 6-months post-in-line-lipase cartridge (adjusted mean difference [AMD] = 0.2540; 95% CI = [0.0487, 0.4592]; P = 0.0153) and mean height z score at 12-months post-in-line lipase cartridge (AMD = 0.2684; 95% CI = [0.0203, 0.5166]; P = 0.0340) were significantly higher. Mean weight z score at 12-months post-in-line-lipase-cartridge neared statistical significance compared with 6-months pre-in-line lipase cartridge (AMD = 0.2816; 95% CI = [-0.0003, 0.5634]; P = 0.0502) when excluding seven patients with advanced lung disease (forced expiratory volume in the first second of expiration of 40%). Weight-for-length or body mass index did not significantly differ compared with pre-in-line lipase cartridge. CONCLUSION: Use of in-line lipase cartridge with enteral feeds improved anthropometrics, especially height, in pediatric patients with CF.

Children with Primary Septic Arthritis Have a Markedly Lower Risk of Adverse Outcomes Than Those with Contiguous Osteomyelitis.

BACKGROUND: It is widely believed that septic arthritis poses a risk of joint destruction and long-term adverse outcomes for children if not treated emergently. In the present study, children who had primary confirmed septic arthritis were compared with those who had septic arthritis and adjacent osteomyelitis to evaluate differences that affect the relative risk of adverse outcomes. METHODS: Children who underwent multidisciplinary treatment for septic arthritis with or without contiguous osteomyelitis between 2009 and 2019 were retrospectively studied. Clinical, laboratory, treatment, and outcome data were compared between cohorts of children with primary confirmed septic arthritis and children with septic arthritis and contiguous osteomyelitis. RESULTS: One hundred and thirty-four children had primary confirmed septic arthritis, and 105 children had septic arthritis with contiguous osteomyelitis. Children with osteomyelitis were older (median, 7.4 versus 2.4 years), had higher initial C-reactive protein (median, 15.7 versus 6.4 mg/dL), and had a higher rate of thrombocytopenia (21.0% versus 1.5%). They also had a higher rate of bacteremia (69.5% versus 20.2%) for a longer duration (median, 2.0 versus 1.0 days). Detected pathogens in children with osteomyelitis as compared with those with primary septic arthritis were more likely to be Staphylococcus aureus (77.1% versus 32.1%) and less likely to be Kingella kingae (2.9% versus 32.1%). Children with contiguous osteomyelitis had longer hospitalizations (median, 8.0 versus 4.0 days), a higher rate of intensive care (21.0% versus 1.5%), a higher readmission rate (17.1% versus 5.2%), and a higher complication rate (38.1% versus 0.7%). CONCLUSIONS: Primary septic arthritis in children is dissimilar to septic arthritis associated with osteomyelitis. The present study demonstrates that long-term adverse outcomes in children with septic arthritis are likely due to the contiguous osteomyelitis. Children with primary septic arthritis are sufficiently distinguishable from those who have contiguous osteomyelitis to guide decisions for magnetic resonance imaging acquisition, duration of antibiotic therapy, and length of outpatient follow-up in order to recognize and address adverse outcomes. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

T-Cell Deletion of MyD88 Connects IL17 and IκBζ to RAS Oncogenesis.

Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IκBζ signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-κB and IκBζ signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates IκBζ in normal and RAS-transformed keratinocytes. Activation of IκBζ signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IκBζ-deficient RAS-initiated keratinocytes indicate that IκBζ signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of IκBζ signaling during cancer progression associates with poor prognosis in RAS-driven human cancers. IMPLICATIONS: The paradox that elevation of IκBζ and stimulation of IκBζ signaling through tumor extrinsic factors is required for RAS-mediated benign tumor formation while relative IκBζ expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell-autonomous pathways during cancer progression.

MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis.

The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance in tumorigenesis is not clear. We found that the incidence of carcinogen-induced skin squamous tumors was substantially increased in transgenic MT-HGF (mouse metallothionein-hepatocyte growth factor) mice, which have increased abundance of the MET ligand HGF. Squamous tumors also erupted spontaneously on the skin of MT-HGF mice that were promoted by wounding or the application of 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C. Carcinogen-initiated tumors had Ras mutations, but spontaneous tumors did not. Cultured keratinocytes from MT-HGF mice and oncogenic RAS-transduced keratinocytes shared phenotypic and biochemical features of initiation that were dependent on autocrine activation of epidermal growth factor receptor (EGFR) through increased synthesis and release of EGFR ligands, which was mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological inhibition of EGFR caused the regression of MT-HGF squamous tumors that developed spontaneously in orthografts of MT-HGF keratinocytes combined with dermal fibroblasts and implanted onto syngeneic mice. The global gene expression profile in MET-transformed keratinocytes was highly concordant with that in RAS-transformed keratinocytes, and a core RAS/MET coexpression network was activated in precancerous and cancerous human skin lesions. Tissue arrays revealed that many human skin SCCs have abundant HGF at both the transcript and protein levels. Thus, through the activation of EGFR, MET activation parallels a RAS pathway to contribute to human and mouse cutaneous cancers.