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The pathophysiology of mast cell (MC)-driven disorders is diverse, ranging from localized reactions to systemic disorders caused by abnormal accumulation and activation in multiorgan systems. Prompt and accurate diagnosis is critically important, both for informing treatment and objective assessment of treatment outcomes. As new therapeutics are being developed to deplete MCs or silence them (eg, by engaging inhibitory receptors that block activation), new biomarkers are needed that can distinguish between MC activation versus burden. Serum tryptase is the gold standard for assessing both MC burden and activation; however, commercial tryptase assays have limitations related to timing of release, lack of discernment between inactive (α) and active (β) forms of tryptase, and interpatient variability of baseline levels. Alternative approaches to measuring MC activation include urinary MC mediators, flow cytometry–based assays or gene expression profiling. Additional markers of MC activation are needed for use in clinical diagnostics, to help selection of treatment of MC diseases, and for assessing outcomes of therapy. We review the spectrum of disorders with known or suspected MC contribution, describe the utility and limitations of current MC markers and assays, and discuss the need for new markers that can differentiate between MC activation and burden.

We investigated reproducibility and generalizability of the recently developed web-based model to predict lamina propria fibrosis (LPF) in esophageal biopsies with inadequate lamina propria (LP) from patients with eosinophilic esophagitis (EoE) using an independent dataset (N = 183). For grade and stage scores of LPF, the area under the curve for predictive model was 0.77 (0.69–0.84) and 0.75 (0.67–0.82), and its accuracy was 78% and 72%, respectively. These model performance metrics were similar to that of the original model. A significant positive correlation was noted between the models’ predictive probability and the grade and stage of LPF assessed by a pathologist (grade: r2= 0.48, P< 0.001; and stage: r2= 0.39, P< 0.001). These results support the reproducibility and generalizability of the web-based model to predict the presence of LPF in esophageal biopsies with inadequate LP in EoE. Additional studies are warranted to refine the web-based predictive models to provide predictive probability for sub-scores of LPF severity.

We investigated reproducibility and generalizability of the recently developed web-based model to predict lamina propria fibrosis (LPF) in esophageal biopsies with inadequate lamina propria (LP) from patients with eosinophilic esophagitis (EoE) using an independent dataset (N = 183). For grade and stage scores of LPF, the area under the curve for predictive model was 0.77 (0.69–0.84) and 0.75 (0.67–0.82), and its accuracy was 78% and 72%, respectively. These model performance metrics were similar to that of the original model. A significant positive correlation was noted between the models’ predictive probability and the grade and stage of LPF assessed by a pathologist (grade: r2= 0.48, P< 0.001; and stage: r2= 0.39, P< 0.001). These results support the reproducibility and generalizability of the web-based model to predict the presence of LPF in esophageal biopsies with inadequate LP in EoE. Additional studies are warranted to refine the web-based predictive models to provide predictive probability for sub-scores of LPF severity.

The aim of the study was to determine the mucosal microbiota associated with eosinophilic esophagitis (EoE) and eosinophilic gastritis (EoG) in a geographically diverse cohort of patients compared to controls. We conducted a prospective study of individuals with eosinophilic gastrointestinal disease (EGID) in the Consortium of Eosinophilic Gastrointestinal Disease Researchers, including pediatric and adult tertiary care centers. Eligible individuals had clinical data, mucosal biopsies, and stool collected. Total bacterial load was determined from mucosal biopsy samples by quantitative polymerase chain reaction (PCR). Community composition was determined by small subunit rRNA gene amplicons. One hundred thirty-nine mucosal biopsies were evaluated corresponding to 93 EoE, 17 EoG, and 29 control specimens (18 esophageal) from 10 sites across the United States. Dominant community members across disease activity differed significantly. When comparing EoE and EoG with controls, the dominant taxa in individuals with EGIDs was increased (Streptococcusin esophagus; Prevotellain stomach). Specific taxa were associated with active disease for both EoE (Streptococcus, Gemella) and EoG (Leptotrichia), although highly individualized communities likely impacted statistical testing. Alpha diversity metrics were similar across groups, but with high variability among individuals. Stool analyses did not correlate with bacterial communities found in mucosal biopsy samples and was similar in patients and controls. Dominant community members (Streptococcusfor EoE, Prevotellafor EoG) were different in the mucosal biopsies but not stool of individuals with EGIDs compared to controls; taxa associated with EGIDs were highly variable across individuals. Further study is needed to determine if therapeutic interventions contribute to the observed community differences.

Esophagogastroduodenoscopy (EGD) is a frequently utilized investigative tool in the management of gastrointestinal conditions in children. Biopsies obtained during EGD may pose risk for post-operative adverse events (AEs), and further understanding of risk is imperative to provide informed consent to families and safe patient care. In particular, the impact of biopsy number and location on the development of AEs has not been studied in pediatric patients. We prospectively assessed for AEs by telephone survey 3–7 days after 209 EGDs performed on patients ages 1–21 years over a 1-year period. Demographic, endoscopic, and histologic data were collected. The most common symptoms reported were throat pain (61%), chest pain (26%), and dysphagia (26%). Binary regression models identified age and pre-operative symptoms as factors that influenced the likelihood of post-operative morbidity. Multiple biopsies from 3 different locations of the esophagus did not impact the risk of post-operative AEs.

Esophagogastroduodenoscopy (EGD) is a frequently utilized investigative tool in the management of gastrointestinal conditions in children. Biopsies obtained during EGD may pose risk for post-operative adverse events (AEs), and further understanding of risk is imperative to provide informed consent to families and safe patient care. In particular, the impact of biopsy number and location on the development of AEs has not been studied in pediatric patients. We prospectively assessed for AEs by telephone survey 3–7 days after 209 EGDs performed on patients ages 1–21 years over a 1-year period. Demographic, endoscopic, and histologic data were collected. The most common symptoms reported were throat pain (61%), chest pain (26%), and dysphagia (26%). Binary regression models identified age and pre-operative symptoms as factors that influenced the likelihood of post-operative morbidity. Multiple biopsies from 3 different locations of the esophagus did not impact the risk of post-operative AEs.

A 20-year-old woman presented with dysphagia at 8 years of age. She underwent esophagogastroduodenoscopy with biopsies (EGD), which was diagnostic of eosinophilic esophagitis. Diet elimination resulted in improvement in symptoms, reduction in eosinophilia, and resolution of basal zone hyperplasia (BZH) on repeat EGD; however, food reintroduction resulted in recurrence of eosinophilia. Subsequently, her pulmonologist started benralizumab, a monoclonal antibody against the interleukin-5 receptor (IL5Ra) on eosinophils, for her asthma. Seven months after starting benralizumab, she underwent EGD for persistent dysphagia, which was notable for resolution of esophageal eosinophilia but demonstrated marked BZH in association with high numbers of CD3+T cells and tryptase+mast cells. She transitioned to dupilumab and had resolution of dysphagia. EGD was performed 10 months after starting dupilumab and demonstrated resolution of BZH and mast cell inflammation with significant reduction in T cells. Review of other patients at our center treated with biologics, most commonly dupliumab, reveals varying degrees of BZH in association with mostly CD3+ lymphocyte inflammation. Mast cells and T cells appear to be capable of coordinating mucosal inflammation and symptoms of EoE independent of eosinophilia in a subset of patients.

Introduction: Previously, we discovered similar esophageal gene expression patterns in patients with systemic sclerosis and eosinophilic esophagitis where eosinophil/mast cell–targeted therapies are beneficial. Because systemic sclerosis and eosinophilic esophagitis patients experience similar esophageal symptoms, we hypothesized that eosinophil/mast cell–directed therapy may potentially benefit systemic sclerosis patients. Herein, we determine the association between esophageal mast cell quantities, gene expression, and clinical parameters in order to identify systemic sclerosis patients who may benefit from eosinophil/mast cell–directed therapy.Methods: Esophageal biopsies from systemic sclerosis patients and healthy participants were stained for tryptase, a mast cell marker, and associations with relevant clinical parameters including 24-h esophageal pH testing were assessed. Intra-epithelial mast cell density was quantified by semi-automated microscopy. Microarray data were utilized for functional and gene set enrichment analyses and to identify intrinsic subset assignment, a systemic sclerosis molecular classification system that includes inflammatory, proliferative, limited, and normal-like subsets.Results: Esophageal biopsies from 40 systemic sclerosis patients (39 receiving proton pump inhibition) and eleven healthy participants were studied. Mast cell numbers in both the upper esophagus (rs= 0.638, p= 0.004) and the entire (upper + lower) esophagus (rs= 0.562, p= 0.019) significantly correlated with acid exposure time percentage. The inflammatory, fibroproliferative, and normal-like intrinsic subset originally defined in skin biopsies were identified in esophageal biopsies. Although esophageal mast cell numbers in systemic sclerosis patients and healthy participants were similar, gene expression for mast cell–related pathways showed significant upregulation in the inflammatory intrinsic subset of systemic sclerosis patients compared to patients classified as proliferative or normal-like.Discussion: Esophageal mast cell numbers are heterogeneous in systemic sclerosis patients and may correlate with acid exposure. Patients with inflammatory intrinsic subset profiles in the esophagus demonstrate more tryptase staining. Mast cell–targeted therapy may be a useful therapeutic approach in systemic sclerosis patients belonging to the inflammatory intrinsic subset, but additional studies are warranted.

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In many pediatric acute liver failure (PALF) cases, a diagnosis is not identified, and the etiology is indeterminate (IND-PALF). Our pilot study found dense CD8 T-cell infiltrates and increased T-cell clonality in liver specimens from IND-PALF patients. We aimed to validate these findings in a multicenter cohort with investigators blinded to diagnosis. PALF Study Group registry subjects with IND-PALF (n = 37) and known diagnoses (DX-PALF) (n?=?18), ages 1 to 17 years, with archived liver tissue were included. Liver tissue slides were stained for T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells (Trm, CD103), and scored as minimal, moderate, or dense. Lymphocytes were isolated from frozen liver tissue for T-cell receptor beta (TCRß) sequencing. Dense hepatic CD8 staining was found in significantly more IND-PALF (n?=?29, 78%) compared with DX-PALF subjects (n?=?5, 28%) (P?=?0.001). IND-PALF subjects were more likely to have dense or moderate perforin (88% vs 50%, P?=?0.03) and CD103 (82% vs 40%, P?=?0.02) staining compared with DX-PALF subjects. TCRß sequencing of 15 IND-PALF cases demonstrated increased clonal overlap compared with 6 DX-PALF cases (P?=?0.002). Dense infiltration of effector Trm CD8 T cells characterizes liver tissue from IND-PALF subjects. Increased clonality suggests the T-cell expansion is antigen(s)-driven as opposed to a nonspecific inflammatory response. These findings support CD8 staining as a new biomarker of the activated CD8 T-cell PALF phenotype. Future studies are needed to characterize potential antigens, host risk factors, and inflammatory pathways with the goal of developing targeted therapies.

The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood.

Mast cells play a central role in the pathogenesis of eosinophilic gastrointestinal disorders (EGIDs), including eosinophilic esophagitis. Their interactions with immune and structural cells, involvement in tissue remodeling, and contribution to symptoms make them attractive targets for therapeutic intervention. More is being discovered regarding the intricate interplay of mast cells and eosinophils. Recent studies demonstrating that depletion of eosinophils is insufficient to improve symptoms of EGIDs have raised the question of whether other cells may play a role in symptomatology and pathogenesis of EGIDs.

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Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disorder of the esophagus. Consensus guidelines recommend obtaining esophageal, gastric, and duodenal biopsies at diagnostic endoscopy when EoE is suspected. The utility of repeated gastric and duodenal biopsies during follow-up endoscopy in patients previously diagnosed with EoE is not established. The aim of the present study was to explore the role of gastric and duodenal biopsies in children with an established diagnosis of EoE undergoing repeat endoscopy to assess histological response to treatment. Retrospective chart review of children diagnosed with EoE at a tertiary care center was conducted. A total of 160 patients with EoE with demographic clinical, endoscopic, and histological data at diagnosis and follow-up endoscopy were included. The frequency of gastric and duodenal biopsies at follow-up endoscopy with abnormal histology and their correlation to endoscopic findings was determined. At follow-up endoscopy, 83% (132/160) of patients had gastric and 74% (118/160) had duodenal biopsies. Histology was normal in 81% of gastric and 92% of duodenal biopsies. The most frequent gastric abnormalities were chemical and inactive chronic gastritis. The most frequent duodenal abnormality was villous blunting with increased intraepithelial lymphocytes. Two patients with normal gastric and duodenal histology progressed to eosinophilic gastroenteritis at follow-up endoscopy. Gastric and duodenal biopsies obtained in EoE patients during follow-up endoscopy show pathology in a minority of patients, increase costs, and may add potential risk of adverse events. Large multicenter, prospective studies of endoscopic practice during follow-up of EoE are warranted to provide evidence supporting best practices.

Immunoglobulin E–mediated food allergy (FA) affects children and adults with variable age of onset. Phenotype and quality of life (QoL) differences between childhood-onset FA (COFA) and adult-onset FA (AOFA) are not known.