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BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven esophageal disorder. Connective tissue disorders (CTDs) and esophageal connective tissue alterations are associated with EoE. Therefore, angiotensin II type 1 receptor blockade with losartan, an accepted CTD treatment, is a potential EoE treatment. OBJECTIVE: We evaluated losartan's effects on esophageal pathology, symptoms, and safety in patients with EoE with and without a CTD in an open-label, non-placebo controlled multisite study. METHODS: Fifteen participants with EoE, aged 5 to 23 years, underwent treatment with per-protocol titrated doses of losartan in an open-label, 16-week pilot trial. Losartan was added to standard of care therapy and 14 patients completed the study. Eosinophil counts served as the primary end point, whereas we also assessed the EoE Histology Scoring System, Endoscopic Reference Scores, EoE Diagnostic Panel, and patient-reported outcomes. RESULTS: Esophageal eosinophilia was not reduced after losartan. The peak eosinophil count was not reduced for the proximal (median [interquartile range]: -3 [-22 to 3]; P = .49) and distal esophagus (median [interquartile range]: -18 [-39 to -1]; P = .23). There were no differences in losartan response in EoE with or without CTD (n = 7 and 8, respectively). Regardless, in a small subset of four participants esophageal eosinophilia was resolved with a concomitant reduction in EoE Histology Scoring System score and Endoscopic Reference Score. Across all subjects, the Pediatric EoE Symptom Score, Pediatric Quality of Life Inventory EoE Module, and EoE Diagnostic Panel improved after losartan (P < .05). CONCLUSIONS: Losartan treatment was associated with improved patient-reported outcome scores and EoE Diagnostic Panel biomarkers although without a reduction in esophageal eosinophilia overall. A subset of patients demonstrated improved histopathologic and endoscopic features that could not be tied to a specific feature predicting response to treatment.
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BACKGROUND: Empirical elimination diets are effective for achieving histological remission in eosinophilic oesophagitis, but randomised trials comparing diet therapies are lacking. We aimed to compare a six-food elimination diet (6FED) with a one-food elimination diet (1FED) for the treatment of adults with eosinophilic oesophagitis. METHODS: We conducted a multicentre, randomised, open-label trial across ten sites of the Consortium of Eosinophilic Gastrointestinal Disease Researchers in the USA. Adults aged 18-60 years with active, symptomatic eosinophilic oesophagitis were centrally randomly allocated (1:1; block size of four) to 1FED (animal milk) or 6FED (animal milk, wheat, egg, soy, fish and shellfish, and peanut and tree nuts) for 6 weeks. Randomisation was stratified by age, enrolling site, and gender. The primary endpoint was the proportion of patients with histological remission (peak oesophageal count <15 eosinophils per high-power field [eos/hpf]). Key secondary endpoints were the proportions with complete histological remission (peak count ≤1 eos/hpf) and partial remission (peak counts ≤10 and ≤6 eos/hpf) and changes from baseline in peak eosinophil count and scores on the Eosinophilic Esophagitis Histology Scoring System (EoEHSS), Eosinophilic Esophagitis Endoscopic Reference Score (EREFS), Eosinophilic Esophagitis Activity Index (EEsAI), and quality of life (Adult Eosinophilic Esophagitis Quality-of-Life and Patient Reported Outcome Measurement Information System Global Health questionnaires). Individuals without histological response to 1FED could proceed to 6FED, and those without histological response to 6FED could proceed to swallowed topical fluticasone propionate 880 µg twice per day (with unrestricted diet), for 6 weeks. Histological remission after switching therapy was assessed as a secondary endpoint. Efficacy and safety analyses were done in the intention-to-treat (ITT) population. This trial is registered on ClinicalTrials.gov, NCT02778867, and is completed. FINDINGS: Between May 23, 2016, and March 6, 2019, 129 patients (70 [54%] men and 59 [46%] women; mean age 37·0 years [SD 10·3]) were enrolled, randomly assigned to 1FED (n=67) or 6FED (n=62), and included in the ITT population. At 6 weeks, 25 (40%) of 62 patients in the 6FED group had histological remission compared with 23 (34%) of 67 in the 1FED group (difference 6% [95% CI -11 to 23]; p=0·58). We found no significant difference between the groups at stricter thresholds for partial remission (≤10 eos/hpf, difference 7% [-9 to 24], p=0·46; ≤6 eos/hpf, 14% [-0 to 29], p=0·069); the proportion with complete remission was significantly higher in the 6FED group than in the 1FED group (difference 13% [2 to 25]; p=0·031). Peak eosinophil counts decreased in both groups (geometric mean ratio 0·72 [0·43 to 1·20]; p=0·21). For 6FED versus 1FED, mean changes from baseline in EoEHSS (-0·23 vs -0·15; difference -0·08 [-0·21 to 0·05]; p=0·23), EREFS (-1·0 vs -0·6; difference -0·4 [-1·1 to 0·3]; p=0·28), and EEsAI (-8·2 vs -3·0; difference -5·2 [-11·2 to 0·8]; p=0·091) were not significantly different. Changes in quality-of-life scores were small and similar between the groups. No adverse event was observed in more than 5% of patients in either diet group. For patients without histological response to 1FED who proceeded to 6FED, nine (43%) of 21 reached histological remission; for patients without histological response to 6FED who proceeded to fluticasone propionate, nine (82%) of 11 reached histological remission. INTERPRETATION: Histological remission rates and improvements in histological and endoscopic features were similar after 1FED and 6FED in adults with eosinophilic oesophagitis. 6FED had efficacy in just less than half of 1FED non-responders and steroids had efficacy in most 6FED non-responders. Our findings indicate that eliminating animal milk alone is an acceptable initial dietary therapy for eosinophilic oesophagitis. FUNDING: US National Institutes of Health.
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Esofagitis Eosinofílica , Estados Unidos , Animales , Humanos , Femenino , Masculino , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/patología , Dieta de Eliminación , Calidad de Vida , FluticasonaRESUMEN
BACKGROUND & AIMS: The nature of the involvement of esophageal tissue in eosinophilic esophagitis (EoE) is unclear. We estimated the intrabiopsy site agreements of the EoE Histologic Scoring System (EoEHSS) scores for the grade (degree) and stage (extent) of involvement of the esophageal epithelial and lamina propria and examined if the EoE activity status influenced the intrabiopsy site agreement. METHODS: Demographic, clinical, and EoEHSS scores collected as part of the prospective Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages study were analyzed. A weighted Cohen's kappa agreement coefficient (k) was used to calculate the pairwise agreements for proximal:distal, proximal:middle, and middle:distal esophageal biopsy sites, separately for grade and stage scores, for each of the 8 components of EoEHSS. A k > 0.75 was considered uniform involvement. Inactive EoE was defined as fewer than 15 eosinophils per high-powered field. RESULTS: EoEHSS scores from 1263 esophageal biopsy specimens were analyzed. The k for the stage of involvement of the dilated intercellular spaces across all 3 sites in inactive EoE was consistently greater than 0.75 (range, 0.87-0.99). The k for lamina propria fibrosis was greater than 0.75 across some of the biopsy sites but not across all 3. Otherwise, the k for all other features, for both grade and stage, irrespective of the disease activity status, was 0.75 or less (range, 0.00-0.74). CONCLUSIONS: Except for the extent of involvement of dilated intercellular spaces in inactive EoE, the remaining epithelial features and lamina propria are involved unevenly across biopsy sites in EoE, irrespective of the disease activity status. This study enhances our understanding of the effects of EoE on esophageal tissue pathology.
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Esofagitis Eosinofílica , Humanos , Esofagitis Eosinofílica/patología , Estudios Prospectivos , Membrana Mucosa/patología , Eosinófilos/patología , Biopsia , Epitelio/patologíaRESUMEN
Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus associated with elevated numbers of eosinophils. Disease diagnosis and monitoring require determining the concentration of eosinophils in esophageal biopsies, a time-consuming, tedious and somewhat subjective task currently performed by pathologists. Here, we developed a machine learning pipeline to identify, quantitate and diagnose EoE patients' at the whole slide image level. We propose a platform that combines multi-label segmentation deep network decision support system with dynamics convolution that is able to process whole biopsy slide. Our network is able to segment both intact and not-intact eosinophils with a mean intersection over union (mIoU) of 0.93. This segmentation enables the local quantification of intact eosinophils with a mean absolute error of 0.611 eosinophils. We examined a cohort of 1066 whole slide images from 400 patients derived from multiple institutions. Using this set, our model achieved a global accuracy of 94.75%, sensitivity of 94.13%, and specificity of 95.25% in reporting EoE disease activity. Our work provides state-of-the-art performances on the largest EoE cohort to date, and successfully addresses two of the main challenges in EoE diagnostics and digital pathology, the need to detect several types of small features simultaneously, and the ability to analyze whole slides efficiently. Our results pave the way for an automated diagnosis of EoE and can be utilized for other conditions with similar challenges.
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Esofagitis Eosinofílica , Biopsia , Esofagitis Eosinofílica/diagnóstico , Humanos , Recuento de Leucocitos , RegistrosRESUMEN
BACKGROUND & AIMS: Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) is undetermined. METHODS: Subjects with EoC (n = 27) and controls (normal [NL, n = 20], Crohn's disease [CD, n = 14]) were enrolled across sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. EoC was diagnosed as colonic eosinophilia (ascending ≥100, descending ≥85, sigmoid ≥65 eosinophils/high-power field) with related symptoms. Colon biopsies were subjected to RNA sequencing. Associations between gene expression and histologic features were analyzed with Spearman correlation; operational pathways and cellular constituents were computationally derived. RESULTS: We identified 987 differentially expressed genes (EoC transcriptome) between EoC and NL (>1.5-fold change, P < .05). Colonic eosinophil count correlated with 31% of EoC transcriptome, most notably with CCL11 and CLC (r = 0.78 and 0.77, P < .0001). Among EoC and other EGIDs, there was minimal transcriptomic overlap and minimal evidence of a strong allergic type 2 immune response in EoC compared with other EGIDs. Decreased cell cycle and increased apoptosis in EoC compared with NL were identified by functional enrichment analysis and immunostaining using Ki-67 and cleaved caspase-3. Pericryptal circumferential eosinophil collars were associated with the EoC transcriptome (P < .001). EoC transcriptome-based scores were reversible with disease remission and differentiated EoC from IBD, even after controlling for colonic eosinophil levels (P < .0001). CONCLUSIONS: We established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment.
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Colitis Microscópica , Eosinofilia , Enfermedades Inflamatorias del Intestino , Enteritis , Eosinofilia/diagnóstico , Eosinofilia/genética , Gastritis , HumanosRESUMEN
INTRODUCTION: Approximately half of esophageal biopsies from patients with eosinophilic esophagitis (EoE) contain inadequate lamina propria, making it impossible to determine the lamina propria fibrosis (LPF). This study aimed to develop and validate a web-based tool to predict LPF in esophageal biopsies with inadequate lamina propria. METHODS: Prospectively collected demographic and clinical data and scores for 7 relevant EoE histology scoring system epithelial features from patients with EoE participating in the Consortium of Eosinophilic Gastrointestinal Disease Researchers observational study were used to build the models. Using the least absolute shrinkage and selection operator method, variables strongly associated with LPF were identified. Logistic regression was used to develop models to predict grade and stage of LPF. The grade model was validated using an independent data set. RESULTS: Of 284 patients in the discovery data set, median age (quartiles) was 16 (8-31) years, 68.7% were male patients, and 93.4% were White. Age of the patient, basal zone hyperplasia, dyskeratotic epithelial cells, and surface epithelial alteration were associated with presence of LPF. The area under the receiver operating characteristic curve for the grade model was 0.84 (95% confidence interval: 0.80-0.89) and for stage model was 0.79 (95% confidence interval: 0.74-0.84). Our grade model had 82% accuracy in predicting the presence of LPF in an external validation data set. DISCUSSION: We developed parsimonious models (grade and stage) to predict presence of LPF in esophageal biopsies with inadequate lamina propria and validated our grade model. Our predictive models can be easily used in the clinical setting to include LPF in clinical decisions and determine its effect on treatment outcomes.
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Esofagitis Eosinofílica/diagnóstico , Esófago/patología , Internet , Membrana Mucosa/patología , Adolescente , Adulto , Biopsia/métodos , Niño , Preescolar , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences. METHODS: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro. RESULTS: TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling. CONCLUSIONS: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
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Células Endoteliales/metabolismo , Esofagitis Eosinofílica/genética , Estenosis Esofágica/genética , Esófago/irrigación sanguínea , Fibroblastos/metabolismo , Interleucina-13/metabolismo , Tetraspaninas/genética , Adolescente , Adulto , Niño , Preescolar , Esofagitis Eosinofílica/complicaciones , Esofagitis Eosinofílica/patología , Estenosis Esofágica/etiología , Estenosis Esofágica/patología , Femenino , Regulación de la Expresión Génica , Silenciador del Gen , Humanos , Masculino , Persona de Mediana Edad , ARN Interferente Pequeño , Tetraspaninas/metabolismo , Adulto JovenRESUMEN
BACKGROUND & AIMS: Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and peak esophageal eosinophils per high-power field (eos/hpf). METHODS: Adults enrolled in a multisite prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsy specimens. Patients were stratified based on dilation status as absent, performed 1 year or less before endoscopy, and performed more than 1 year before endoscopy. Assessments included Spearman correlations of the relationship between symptoms and eos/hpf and linear regression with EEsAI as the outcome, eos/hpf as predictor, and interaction for dilation and eos/hpf. RESULTS: Among 100 patients (n = 61 males; median age, 37 y), 15 and 40 patients underwent dilation 1 year or less and more than 1 year before index endoscopy, respectively. In nondilated patients, the association between eos/hpf and symptoms was moderate (ρ = 0.49; P < .001); for a 10-eos/hpf increase, the predicted EEsAI increased by 2.69 (P = .002). In patients dilated 1 or less and more than 1 year before index endoscopy, this association was abolished (ρ = -0.38; P = .157 for ≤1 y and ρ = 0.02; P = .883 >1 y); for a 10-eos/hpf increase, the predicted EEsAI changed by -1.64 (P = .183) and 0.78 (P = .494), respectively. Dilation modified the association between symptoms and eos/hpf (P = .005 and P = .187 for interaction terms of eos/hpf and dilation 1 or less years before and more than 1 year before index endoscopy, respectively). CONCLUSIONS: In nondilated EoE adults, eos/hpf correlate modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than 1 year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up evaluation.
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Esofagitis Eosinofílica , Adulto , Dilatación , Endoscopía Gastrointestinal , Esofagitis Eosinofílica/tratamiento farmacológico , Humanos , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Eosinophilic gastritis (EG) is a clinicopathologic disorder with marked gastric eosinophilia and clinical symptoms. There is an unmet need among patients with EG for more precise diagnostic tools. OBJECTIVE: We aimed to develop tissue- and blood-based diagnostic platforms for EG. METHODS: Patients with EG and control subjects without EG were enrolled across 9 Consortium of Eosinophilic Gastrointestinal Disease Researchers-associated sites. An EG Diagnostic Panel (EGDP; gastric transcript subset) and EG blood biomarker panel (protein multiplex array) were analyzed. EGDP18 scores were derived from the expression of 18 highly dysregulated genes, and blood EG scores were derived from dysregulated cytokine/chemokine levels. RESULTS: Gastric biopsy specimens and blood samples from 185 subjects (patients with EG, n = 74; control subjects without EG, n = 111) were analyzed. The EGDP (1) identified patients with active EG (P < .0001, area under the curve ≥ 0.95), (2) effectively monitored disease activity in longitudinal samples (P = .0078), (3) highly correlated in same-patient samples (antrum vs body, r = 0.85, P < .0001), and (4) inversely correlated with gastric peak eosinophil levels (r = -0.83, P < .0001), periglandular circumferential collars (r = -0.73, P < .0001), and endoscopic nodularity (r = -0.45, P < .0001). For blood-based platforms, eotaxin-3, thymus and activation-regulated chemokine, IL-5, and thymic stromal lymphopoietin levels were significantly increased. Blood EG scores (1) distinguished patients with EG from control subjects without EG (P < .0001, area under the curve ≥ 0.91), (2) correlated with gastric eosinophil levels (plasma: r = 0.72, P = .0002; serum: r = 0.54, P = .0015), and (3) inversely correlated with EGDP18 scores (plasma: r = -0.64, P = .0015; serum: r = -0.46, P = .0084). Plasma eotaxin-3 levels strongly associated with gastric CCL26 expression (r = 0.81, P < .0001). CONCLUSION: We developed tissue- and blood-based platforms for assessment of EG and uncovered robust associations between specific gastric molecular profiles and histologic and endoscopic features, providing insight and clinical readiness tools for this emerging rare disease.
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Citocinas , Endoscopía Gastrointestinal , Enteritis , Eosinofilia , Gastritis , Adolescente , Adulto , Biomarcadores/sangre , Niño , Citocinas/sangre , Citocinas/inmunología , Enteritis/sangre , Enteritis/diagnóstico , Enteritis/inmunología , Enteritis/patología , Eosinofilia/sangre , Eosinofilia/diagnóstico , Eosinofilia/inmunología , Eosinofilia/patología , Femenino , Gastritis/sangre , Gastritis/diagnóstico , Gastritis/inmunología , Gastritis/patología , Humanos , MasculinoRESUMEN
OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus. METHODS: In a prospective, multisite study, children and adults (ages 7-55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation. RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n = 62), inactive EoE (n = 37), and patient controls with a normal esophagus (n = 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eighty-seven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information. DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.
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Esofagitis Eosinofílica/diagnóstico , Eosinófilos , Mucosa Esofágica/citología , Esófago/citología , Adolescente , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Biopsia , Quimiocina CCL24/análisis , Quimiocina CCL24/metabolismo , Quimiocina CCL26/análisis , Quimiocina CCL26/metabolismo , Niño , Endoscopía del Sistema Digestivo , Esofagitis Eosinofílica/patología , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Esófago/diagnóstico por imagen , Esófago/patología , Estudios de Factibilidad , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Chronic intermittent hypoxia and hedgehog (Hh) pathway dysregulation are associated with nonalcoholic fatty liver disease (NAFLD) progression. In this study, we determined the relationship between obstructive sleep apnea (OSA)/nocturnal hypoxia and Hh signaling in pediatric NAFLD. Adolescents with histologic NAFLD (n = 31) underwent polysomnogram testing, laboratory testing, and Sonic Hh (SHh), Indian hedgehog (IHh), glioblastoma-associated oncogene 2 (Gli2), keratin 7 (K7), α-smooth muscle actin (α-SMA), and hypoxia-inducible factor 1α (HIF-1α) immunohistochemistry. Aspartate aminotransferase (AST) correlated with SHh, r = 0.64; Gli2, r = 0.4; α-SMA, r = 0.55; and K7, r = 0.45 (P < 0.01), as did alanine aminotransferase (ALT) (SHh, r = 0.51; Gli2, r = 0.43; α-SMA, r = 0.51; P < 0.02). SHh correlated with NAFLD activity score (r = 0.39), whereas IHh correlated with inflammation (r = -0.478) and histologic grade (r = -0.43); P < 0.03. Subjects with OSA/hypoxia had higher SHh (4.0 ± 2.9 versus 2.0 ± 1.5), Gli2 (74.2 ± 28.0 versus 55.8 ± 11.8), and α-SMA (6.2 ± 3.3 versus 4.3 ± 1.2); compared to those without (P < 0.03). OSA severity correlated with SHh (r = 0.31; P = 0.09) and Gli2 (r = 0.37; P = 0.04) as did hypoxia severity, which was associated with increasing SHh (r = -0.53), Gli2 (r = -0.52), α-SMA (r = -0.61), and K7 (r = -0.42); P < 0.02. Prolonged O2 desaturations <90% also correlated with SHh (r = 0.55) and Gli2 (r = 0.61); P < 0.05. Conclusion: The Hh pathway is activated in pediatric patients with NAFLD with nocturnal hypoxia and relates to disease severity. Tissue hypoxia may allow for functional activation of HIF-1α, with induction of genes important in epithelial-mesenchymal transition, including SHh, and NAFLD progression.
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Epithelial barrier dysfunction is a significant factor in many allergic diseases, including eosinophilic esophagitis (EoE). Infiltrating leukocytes and tissue adaptations increase metabolic demands and decrease oxygen availability at barrier surfaces. Understanding of how these processes impact barrier is limited, particularly in allergy. Here, we identified a regulatory axis whereby the oxygen-sensing transcription factor HIF-1α orchestrated epithelial barrier integrity, selectively controlling tight junction CLDN1 (claudin-1). Prolonged experimental hypoxia or HIF1A knockdown suppressed HIF-1α-dependent claudin-1 expression and epithelial barrier function, as documented in 3D organotypic epithelial cultures. L2-IL5OXA mice with EoE-relevant allergic inflammation displayed localized eosinophil oxygen metabolism, tissue hypoxia, and impaired claudin-1 barrier via repression of HIF-1α/claudin-1 signaling, which was restored by transgenic expression of esophageal epithelial-targeted stabilized HIF-1α. EoE patient biopsy analysis identified a repressed HIF-1α/claudin-1 axis, which was restored via pharmacologic HIF-1α stabilization ex vivo. Collectively, these studies reveal HIF-1α's critical role in maintaining barrier and highlight the HIF-1α/claudin-1 axis as a potential therapeutic target for EoE.
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Claudina-1/metabolismo , Esofagitis Eosinofílica/metabolismo , Células Epiteliales/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Transducción de Señal , Uniones Estrechas/metabolismo , Adolescente , Adulto , Animales , Línea Celular Transformada , Niño , Preescolar , Claudina-1/genética , Esofagitis Eosinofílica/genética , Esofagitis Eosinofílica/patología , Células Epiteliales/patología , Femenino , Regulación de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Ratones , Ratones Transgénicos , Estabilidad Proteica , Uniones Estrechas/genética , Uniones Estrechas/patologíaRESUMEN
BACKGROUND & AIMS: Evaluation and treatment of children with eosinophilic esophagitis (EoE) requires serial endoscopic, visual, and histologic assessment by sedated esophagogastroduodenoscopy (EGD). Unsedated transnasal endoscopy (TNE) was reported to be successful in a pilot study of children. We evaluated video goggle and virtual reality-based unsedated TNE in children with EoE, collecting data on rates of completion, adverse events, and adequacy of visual and histologic findings. METHODS: We performed a retrospective study of 190 children and young adults (age, 3-22 y) who underwent video goggle or virtual reality-based unsedated TNE from January 2015 through February 2018. We analyzed data on patient demographics, procedure completion, endoscope type, adverse events, visual and histologic findings, estimated costs, and duration in the facility. Esophageal biopsies from the first 173 subjects who underwent TNE were compared with those from previous EGD evaluations. RESULTS: During 300 attempts, 294 TNEs were performed (98% rate of success). Fifty-four patients (age, 6-18 y) underwent multiple TNEs for dietary or medical management of EoE. There were no significant adverse events. Visual and histologic findings were adequate for assessment of EoE. TNE reduced costs by 53.4% compared with EGD (TNE $4393.00 vs EGD $9444.33). TNE was used increasingly from 2015 through 2017, comprising 31.8% of endoscopies performed for EoE. The total time spent in the clinic (front desk check-in to check-out) in 2018 was 71 minutes. CONCLUSIONS: In a retrospective study of 190 children and young adults (age, 3-22 y) who underwent video goggle or virtual reality-based unsedated TNE, TNE was safe and effective and reduced costs of EoE monitoring. Advantages of TNE include reduced risk and cost associated with anesthesia as well as decreased in-office time, which is of particular relevance for patients with EoE, who require serial EGDs.
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Esofagitis Eosinofílica/patología , Esofagoscopía/métodos , Gafas Inteligentes , Realidad Virtual , Adolescente , Biopsia , Niño , Preescolar , Manejo de la Enfermedad , Endoscopía del Sistema Digestivo/economía , Esofagoscopía/economía , Esófago/patología , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenAsunto(s)
Peroxidasa del Eosinófilo/inmunología , Eosinofilia/diagnóstico , Esofagitis/diagnóstico , Reflujo Gastroesofágico/diagnóstico , Adolescente , Niño , Preescolar , Eosinofilia/tratamiento farmacológico , Eosinofilia/enzimología , Eosinofilia/inmunología , Esofagitis/enzimología , Esofagitis/inmunología , Esófago/enzimología , Esófago/inmunología , Femenino , Reflujo Gastroesofágico/enzimología , Reflujo Gastroesofágico/inmunología , Humanos , Lactante , Recuento de Leucocitos , Masculino , Inhibidores de la Bomba de Protones/uso terapéuticoRESUMEN
BACKGROUND: A prior practice survey revealed variations in the management of patients with sickle cell disease (SCD) and stressed the need for comprehensive guidelines. Here we discuss: 1) common indications for red blood cell exchange (RCE), 2) options for access, 3) how to prepare the red blood cells (RBCs) to be used for RCE, 4) target hemoglobin (Hb) and/or hematocrit (Hct) and HbS level, 5) RBC depletion/RCE, and 6) some complications that may ensue. STUDY DESIGN AND METHODS: Fifteen physicians actively practicing apheresis from 14 institutions representing different areas within the United States discussed how they manage RCE for patients with SCD. RESULTS: Simple transfusion is recommended to treat symptomatic anemia with Hb level of less than 9 g/dL. RCE is indicated to prevent or treat complications arising from the presence of HbS. The most important goals are reduction of HbS while also preventing hyperviscosity. The usual goals are a target HbS level of not more than 30% and Hct level of less than 30%. CONCLUSION: Although a consensus as to protocol details may not be possible, there are areas of agreement in the management of these patients, for example, that it is optimal to avoid hyperviscosity and iron overload, that a target Hb S level in the range of 30% is generally desirable, and that RCE as an acute treatment for pain crisis in the absence of other acute or chronic conditions is ordinarily discouraged.
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Anemia de Células Falciformes/terapia , Transfusión de Eritrocitos/métodos , Viscosidad Sanguínea , Manejo de la Enfermedad , Hemoglobina Falciforme/análisis , Humanos , Sobrecarga de Hierro/prevención & control , Estados UnidosRESUMEN
BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm2) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.
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Técnicas de Diagnóstico del Sistema Digestivo/normas , Esofagitis Eosinofílica/diagnóstico , Gastroenterología/normas , Inhibidores de la Bomba de Protones/administración & dosificación , Algoritmos , Consenso , Esofagitis Eosinofílica/tratamiento farmacológico , Humanos , Valor Predictivo de las Pruebas , Pronóstico , Inhibidores de la Bomba de Protones/efectos adversosRESUMEN
BACKGROUND: Patient-reported outcome metrics for eosinophilic esophagitis (EoE) have been developed and validated but not used in a multicenter pediatric population or systematically aligned with histology. OBJECTIVE: We sought to understand (1) the potential of caregiver report to predict patient self-reported symptoms and (2) the correlation of patient-reported outcome domains with histology. METHODS: Patients with EoE (n = 310) and their parents participating in the Consortium of Gastrointestinal Eosinophilic Disease Researchers (CEGIR) observational clinical trial were queried for baseline patient symptoms and quality of life (QOL) by using the Pediatric Eosinophilic Esophagitis Symptom Score, version 2 (PEESSv2.0), and the Pediatric QOL EoE module (PedsQL-EoE), and biopsy specimens were analyzed by using the EoE Histology Scoring System. RESULTS: PEESSv2.0 parental and child reports aligned across all domains (r = 0.68-0.73, P < .001). PedsQL-EoE reports correlated between parents and children across ages and multiple domains (r = 0.48-0.79, P < .001). There was a tight correlation between symptoms on PEESSv2.0 and their effects on QOL both on self-report and parental report (P < .001). Self-reported symptoms on PEESSv2.0 (positively) and PedsQL-EoE (inversely) showed a weak correlation with proximal, but not distal, peak eosinophil counts and features and architectural tissue changes on the EoE Histology Scoring System (P < .05). CONCLUSIONS: Parents of children with EoE aged 3 to 18 years accurately reflected their children's disease symptoms and QOL. Self- and parent-reported symptoms correlate with proximal esophageal histology. Our data suggest that parental report in young children can function as an adequate marker for self-reported symptoms and that self-reported symptoms can reflect changes in tissue histology in the proximal esophagus. These findings should be considered during clinical trials for drug development.
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Esofagitis Eosinofílica/patología , Padres , Medición de Resultados Informados por el Paciente , Autoinforme , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Calidad de Vida , Encuestas y CuestionariosRESUMEN
BACKGROUND: Eosinophilic oesophagitis is understood in terms of quantifiable histological, endoscopic, and molecular features. Data are scant for inter-relations of these features and their potential to identify distinct disease endotypes. We aimed to identify clinical-pathological correlations between endoscopic and histological disease variables by transcription profiling of the oesophagus of patients with eosinophilic oesophagitis of varying severity and disease activity states. METHODS: We did a cross-sectional study across ten hospital sites in the USA associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. We analysed oesophageal biopsy specimens taken from paediatric and adult patients with eosinophilic oesophagitis (discovery cohort), using the eosinophilic oesophagitis diagnostic panel (EDP), a set of 96 informative transcripts. Histological and endoscopic features were assessed by quantification of oesophageal eosinophils and use of the eosinophilic oesophagitis histology scoring system (HSS) and the eosinophilic oesophagitis endoscopic reference score (EREFS). Associations among the various histological, endoscopic, and molecular features were analysed by Spearman correlation. Results were replicated in a biologically independent, single-centre, validation cohort of patients with active eosinophilic oesophagitis. FINDINGS: The discovery cohort contained 185 samples and the validation cohort comprised 100 specimens. In the discovery cohort, EDP showed intersite consistency, significant correlation with oesophageal eosinophils (p<0·0001), and similar findings between paediatric and adult patients. Of eight HSS domains, basal zone hyperplasia correlated with the EDP (median Spearman ρ 0·47 [IQR 0·36-0·60]). Of five EREFS features, distal furrows correlated with the EDP (median Spearman ρ 0·42 [0·32-0·50]). By analysing active eosinophilic oesophagitis in the discovery cohort, the EDP identified three clusters associated with distinct endotypes (termed EoEe1-3) despite similar eosinophil levels. EoEe1 was associated with a normal-appearing oesophagus (risk ratio [RR] 3·27, 95% CI 1·04-10·27; p=0·0443), an inverse association with a history of oesophageal dilation (0·27, 0·09-0·82; p=0·0105) and showed relatively mild histological, endoscopic, and molecular changes. EoEe2 showed an inflammatory and steroid-refractory phenotype (RR 2·77, 95% CI 1·11-6·95; p=0·0376) and had the highest expression of inflammatory cytokines and steroid-responding genes. EoEe3 was associated with a narrow-calibre oesophagus (RR 7·98, 95% CI 1·84-34·64; p=0·0013) and adult onset (2·22, 1·19-4·12; p=0·0155), and showed the highest degree of endoscopic and histological severity and the lowest expression of epithelial differentiation genes. These endotypes were replicated in the validation cohort by clustering and with an eosinophilic oesophagitis endotype-prediction algorithm. INTERPRETATION: Our new disease classification stratifies patients with eosinophilic oesophagitis into subgroups with potential clinical and therapeutic significance and provides a framework for a precision medicine approach to eosinophilic oesophagitis. FUNDING: National Institutes of Health.
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Esofagitis Eosinofílica/clasificación , Esofagitis Eosinofílica/patología , Adolescente , Adulto , Anciano , Biopsia , Niño , Preescolar , Estudios Transversales , Esofagitis Eosinofílica/genética , Esofagoscopía , Femenino , Perfilación de la Expresión Génica , Humanos , Hiperplasia , Recuento de Leucocitos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: To determine the effects of treating obstructive sleep apnea/nocturnal hypoxia on pediatric nonalcoholic fatty liver disease (NAFLD) severity and oxidative stress. STUDY DESIGN: Biopsy proven participants (n = 9) with NAFLD and obstructive sleep apnea/hypoxia were studied before and after treatment with continuous positive airway pressure (CPAP) for sleep disordered breathing, including laboratory testing and markers of oxidative stress, urine F(2)-isoprostanes. RESULTS: Adolescents (age 11.5 ± 1.2 years; body mass index, 29.5 ± 3.8 kg/m2) with significant NAFLD (mean histologic necroinflammation grade, 2.3 ± 0.9; fibrosis stage, 1.4 ± 1.3; NAFLD Activity Score summary, 4.8 ± 1.6) had obstructive sleep apnea/hypoxia by polysomnography. At baseline, they had severe obstructive sleep apnea/hypoxia, elevated aminotransferases, the metabolic syndrome, and significant oxidative stress (high F(2)-isoprostanes). Obstructive sleep apnea/hypoxia was treated with home CPAP for a mean 89 ± 62 days. Although body mass index increased, obstructive sleep apnea/hypoxia severity improved on CPAP and was accompanied by reduced alanine aminotransferase, metabolic syndrome markers, and F(2)-isoprostanes. CONCLUSIONS: This study provides strong evidence that treatment of obstructive sleep apnea/nocturnal hypoxia with CPAP in children with NAFLD may reverse parameters of liver injury and reduce oxidative stress. These data also suggest CPAP as a new therapy to prevent progression of NAFLD in those children with obesity found to have obstructive sleep apnea/nocturnal hypoxia.
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Presión de las Vías Aéreas Positiva Contínua , Hipoxia/terapia , Enfermedad del Hígado Graso no Alcohólico/terapia , Apnea Obstructiva del Sueño/terapia , Adolescente , Biomarcadores/metabolismo , Índice de Masa Corporal , Niño , Enfermedad Crónica , Estudios de Cohortes , F2-Isoprostanos/orina , Femenino , Humanos , Hipoxia/complicaciones , Masculino , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Estrés Oxidativo , Proyectos Piloto , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/complicacionesRESUMEN
BACKGROUND: The current management paradigm for children with single ventricle heart disease involves a series of palliative surgeries, culminating in the Fontan operation. This physiology results in a high central venous pressure, and in the setting of single ventricle heart disease, results in hepatic injury and fibrosis over time. Fontan-associated liver disease (FALD) is universally present in this cohort, and the current gold standard for diagnosis remains biopsy. Noninvasive assessments of liver fibrosis, such as ultrasound with elastography or acoustic radiation force impulse (ARFI), has been utilized in this cohort. The effect of poor cardiovascular efficiency, as measured by cardiopulmonary exercise test (CPET), on assessments of liver fibrosis remains poorly understood. METHODS: Retrospective, cross-sectional study. Subjects were evaluated in a multidisciplinary clinic setting for patients who have undergone Fontan operation. CPETs, liver ultrasound with elastography (ARFI), and standard laboratory tests were performed as part of routine clinical care pathway. Statistical analysis included linear correlation. RESULTS: There was a poor correlation between mean ARFI velocity and peak oxygen consumption (VO2max ) in this cohort (r = .20, P = NS). Similarly, there was poor correlation between ARFI and biomarkers of liver injury, time since Fontan operation and Fontan pressure. DISCUSSION: ARFI had poor correlation with functional capacity after Fontan, as measured by VO2max obtained during CPET. While a single measurement of liver elastography was not associated with cardiopulmonary efficiency, longitudinal data may reveal an association.