Diagnosis of Pediatric Non-Esophageal Eosinophilic Gastrointestinal Disorders by Eosinophil Peroxidase Immunohistochemistry.

BACKGROUND: Diagnosis of non-esophageal eosinophilic gastrointestinal disorders requires quantification of tissue eosinophils. Our objective was to evaluate eosinophil peroxidase (EPX) immunohistochemistry (IHC) as a method for histologic diagnosis of eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD). METHODS: We performed a retrospective analysis of biopsies from pediatric EG/EoD cases and controls. Subjects with EG or EoD had ≥30 eosinophils per high power field (eos/hpf) in ≥5 hpf in the stomach and/or ≥3 hpf in the duodenum, respectively. Controls had no histopathologic diagnosis recorded. Tissue eosinophil counts were assessed by hematoxylin & eosin stains. EPX stains were assessed using a unique histopathologic scoring system. Slides were digitized and EPX+ staining area/mm2 was quantified by image analysis. RESULTS: Twenty-six EG/EoD cases and 40 controls were analyzed. EPX scores and EPX/mm2 levels were markedly elevated in EG/EoD (p ≤ 0.0001). Eosinophil density (eos/mm2) correlated strongly with EPX scores and EPX/mm2 levels in the stomach (r ≥ 0.77) and moderately with EPX scores and EPX/mm2 levels in the duodenum (r ≥ 0.52); (p < 0.0001). EPX quantification identified EG/EoD subjects with high diagnostic accuracy (EPX score: AUC = 1 for EG and EoD; EPX/mm2: AUC = 0.98 (95%CI 0.96-1) for EG, AUC = 0.91 (95%CI 0.81-1) for EoD). CONCLUSION: EPX-based assessment of eosinophilic inflammation may facilitate automated histologic diagnosis.

Infliximab-Associated Immunomediated Hepatitis in Children With Inflammatory Bowel Disease.

Infliximab (IFX) is commonly used to induce and maintain remission in inflammatory bowel disease (IBD). We report the first 2 cases of children with ulcerative colitis who had normal liver transaminases before IFX and were diagnosed with immunomediated hepatitis after IFX induction. Both the cases had negative antibodies for antinuclear, smooth muscle, and liver kidney microsome, with 1 patient having positive autoimmune serology (dsDNA) and overlap primary sclerosing cholangitis. IFX was discontinued and transaminases normalized without steroid administration. Clinicians treating pediatric patients with IBD with IFX should be aware of IFX immunomediated hepatitis. This phenomenon is previously reported in adult patients with IBD. To our knowledge, these are the first cases reported in pediatric patients with IBD.

The oesophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic oesophagitis.

OBJECTIVE: Eosinophil predominant inflammation characterises histological features of eosinophilic oesophagitis (EoE). Endoscopy with biopsy is currently the only method to assess oesophageal mucosal inflammation in EoE. We hypothesised that measurements of luminal eosinophil-derived proteins would correlate with oesophageal mucosal inflammation in children with EoE. DESIGN: The Enterotest diagnostic device was used to develop an oesophageal string test (EST) as a minimally invasive clinical device. EST samples and oesophageal mucosal biopsies were obtained from children undergoing upper endoscopy for clinically defined indications. Eosinophil-derived proteins including eosinophil secondary granule proteins (major basic protein-1, eosinophil-derived neurotoxin, eosinophil cationic protein, eosinophil peroxidase) and Charcot-Leyden crystal protein/galectin-10 were measured by ELISA in luminal effluents eluted from ESTs and extracts of mucosal biopsies. RESULTS: ESTs were performed in 41 children with active EoE (n=14), EoE in remission (n=8), gastro-oesophageal reflux disease (n=4) and controls with normal oesophagus (n=15). EST measurement of eosinophil-derived protein biomarkers significantly distinguished between children with active EoE, treated EoE in remission, gastro-oesophageal reflux disease and normal oesophagus. Levels of luminal eosinophil-derived proteins in EST samples significantly correlated with peak and mean oesophageal eosinophils/high power field (HPF), eosinophil peroxidase indices and levels of the same eosinophil-derived proteins in extracts of oesophageal biopsies. CONCLUSIONS: The presence of eosinophil-derived proteins in luminal secretions is reflective of mucosal inflammation in children with EoE. The EST is a novel, minimally invasive device for measuring oesophageal eosinophilic inflammation in children with EoE.

Assessing the Effect of Infant Peanut Exposure Guidelines on Peanut Aspiration Using Google Trends Search Analysis.

Background The American Academy of Pediatrics (AAP) changed guidelines in 2017 to recommend introducing infants to peanuts as early as four months. Peanuts are also one of the most commonly aspirated food-related foreign bodies. Google Trends search pattern analysis has been validated in epidemiologic research as being reflective of healthcare events. Methodology Google Trends measures the popularity of a search term in a given week compared to the popularity of all search terms in that week, calculated as relative search volume (RSV), yielding a value between 0 and 100. We compiled peanut aspiration-related search data from January 2012 to January 2022 and compared the relative popularity of these searches before the change in guidelines to after. Results All queried search terms significantly increased in RSV when comparing the five years before and following January 2017. When pooling all terms, the median RSV increase was 13.8% (p < 0.001). "Choke on peanut" and the combination of peanut and cough had the highest median RSV increases from 9.6 to 17 and 50.8 to 63.1, respectively. Conclusions The change in 2017 of the AAP guidelines on early childhood peanut exposure was associated with an increase in online searches for peanut aspiration. This may be reflective of increased aspiration events, or possibly increased concern for aspiration. Current results support the need to closely counsel families on infant-safe peanut products to prevent dangerous aspiration events.

Esophageal human ß-defensin expression in eosinophilic esophagitis.

BACKGROUND: Defensins are antimicrobial peptides expressed on mucosal surfaces that contribute to maintaining intestinal homeostasis by providing innate defense mechanisms for the epithelia. Defensin expression is altered in a number of diseases that affect mucosal surfaces, such as atopic dermatitis, allergic rhinitis, and inflammatory bowel disease. Similar to atopic dermatitis, eosinophilic esophagitis (EoE) is a chronic disease in which the squamous epithelial surface is affected by a similar TH2 microenvironment and eosinophil-predominant inflammation. Therefore, we hypothesized that defensin expression would be decreased in EoE. METHODS: To address this, we measured defensin expression in vitro in cell lines derived from patients with EoE (EoE1-T) or gastroesophageal reflux disease (GERD) (NES-G4T cells) and ex vivo in esophageal mucosal biopsy samples from children with EoE or GERD and control children without esophageal disease. RESULTS: Interleukin-5 induced a decrease in human ß-defensin (hBD) -1 and hBD3 expression in EoE1-T but not in NES-G4T cells. Compared with esophageal biopsy specimens from GERD and control children, specimens from EoE pediatric patients revealed a significant decrease in mRNA and protein expression for hBD1 and hBD3. CONCLUSION: Diminished expression of hBD1 and hBD3 may make the esophageal epithelium more susceptible to the development and/or perpetuation of EoE.

Effect of proton pump inhibitor on esophageal eosinophilia.

OBJECTIVE: Differentiation between the common etiologies of dense esophageal eosinophilia such as gastroesophageal reflux disease (GERD) and eosinophilic esophagitis can be difficult. We hypothesized that histologic features may provide diagnostic clues concerning the etiology of esophageal eosinophilia. METHODS: : We performed a retrospective chart review of 204 children with the diagnosis of esophagitis characterized by ≥ 15 eosinophils (eos) per high-power field (HPF) in at least 1 biopsy. We then restricted our analysis to subjects who had received at least 8 weeks of only proton pump inhibitors (PPIs) followed by endoscopy and who had a clinicopathologic response to this treatment. Symptoms, endoscopic findings, and pathologic descriptions were reviewed and an eosinophil peroxidase (EPX) index was determined to assess for degranulation/eosinophil activation. RESULTS: Of the 204 identified charts, 7 subjects identified met the inclusion criteria. Five of these 7 patients showed a clinicopathologic response to PPIs after their follow-up endoscopy, (mean peak eosinophil count: 92 vs 5 eos/HPF, and EPX index: 39.2 vs 14.6, pre- and posttreatment, respectively). Two patients experienced initial resolution of symptoms and esophageal eosinophilia with PPI therapy; however, within 17-23 months they redeveloped symptoms and esophageal eosinophilia while receiving PPI therapy at the time of a third endoscopy (mean peak eosinophil count: 40 vs 11 vs 36 eos/HPF, and EPX index: 44 vs 21 vs 36.5, pre-, post- and posttreatment, respectively). No clinicopathologic features or degranulation patterns differentiated subjects with GERD/PPI responsive esophageal eosinophilia from those who had transient response to PPI treatment. CONCLUSIONS: No clinicopathologic features differentiated subjects who responded to PPI treatment. PPI treatment can be helpful to exclude GERD and PPI responsive esophageal eosinophilia but long-term follow-up is critical in the management of esophagitis.

CT imaging features of eosinophilic colitis in children.

BACKGROUND: Eosinophilic colitis (EC) is a gastrointestinal disease of undetermined etiology whose clinical features overlap with those of the inflammatory bowel diseases. To the best of our knowledge, the CT imaging features of EC have not been described in children. OBJECTIVE: To report and analyze the clinical, imaging and histological findings in seven children with EC. MATERIALS AND METHODS: Children with EC were identified in a pediatric pathology database, and those with CT imaging within 2 months of diagnosis were included, totaling seven children. Clinical, imaging and pathological features were reviewed and analyzed. RESULTS: The most common presenting symptoms were abdominal pain, bloody diarrhea and rectal bleeding. EC was characterized as a dense and predominantly eosinophilic inflammatory infiltrate in the lamina propria or epithelium without granulomas. CT scans were abnormal in six children (86%), demonstrating colonic wall thickening, predominantly cecal, in five (71%), mild to moderate terminal ileal thickening in two (29%), and pneumatosis in one (14%). Right colonic involvement was greater than terminal ileal involvement. CONCLUSION: CT imaging findings in children with EC include right colonic wall thickening of variable extent downstream and absent or mild involvement of the terminal ileum. EC should be considered in the differential diagnosis in children presenting with abdominal pain and bloody diarrhea.

Learning early about peanut-triggered food protein-induced enterocolitis syndrome.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E mediated food allergy that typically presents with repetitive emesis and may be associated with lethargy, marked pallor, hypotension, hypothermia, and/or diarrhea. Although many foods are known to cause FPIES, peanut-triggered FPIES is emerging due to changes in the feeding practice guidelines, which recommends early peanut introduction in infants. Objective: We aimed to characterize peanut-triggered acute FPIES cases in our pediatric population and to describe their attributes, treatment, and outcomes. We hypothesized that increases in the incidence of peanut-triggered FPIES coincided with implementation of the guidelines for early peanut introduction. Methods: A retrospective chart review was conducted of pediatric patients who presented to Phoenix Children's Hospital Emergency Department and subspecialty clinics during a 6-year period (January 2013 to September 2019). Results: Thirty-three cases of patients with acute FPIES were identified, five of which were peanut triggered. In those patients with peanut-triggered FPIES, the median age for peanut introduction was 7 months (range, 5-24 months). Two patients had positive peanut skin-prick test results. All five cases were identified in the past 2 years (2018 to 2019). No peanut-triggered reactions were documented in the preceding 4-year period (2013 to 2017). Conclusion: Peanut may be an emerging trigger of acute FPIES, coinciding with an earlier introduction of peanut in the infant diet after implementation of the new addendum guidelines for the prevention of peanut allergy. Oats and rice were the most common triggers of acute FPIES in our cohort. Further study will help clarify the significance and reproducibility of these findings.

Deep interarytenoid notch in young children managed with systematic thickener wean and injection laryngoplasty.

OBJECTIVES: Deep interarytenoid notch (DIN) is a congenital variation of the larynx often associated with dysphagia and aspiration (DA) in young children. Feeding therapy with thickeners and surgical management with injection larygoplasty (IL) are used with various efficacies. Thickeners address the functional domain and IL addresses the anatomical domain of treatment. Our objective was to evaluate DIN patients managed with both interventions. METHODS: We conducted a retrospective pilot descriptive study of DIN patients with DA aged 1-3 years receiving thickeners and IL. Patients received a systematic weekly reduction of thickeners, referred to as the Thickener Weaning Protocol (TWP), based on clinical signs and symptoms of DA. The outcomes were assessed by the rate of thickener level reduction and DA-related sign/symptom frequency achieved at 6 months post-treatment. RESULTS: Thirteen patients with DIN associated DA were analyzed. The TWP was initiated within 2 months in 77% of patients, and within 4 months in 100% of patients. Thickener scores improved from an average of 5.76 (3/4 honey) to 2.15 (thin) (p = 0.001). DA-related signs/symptoms frequency improved from an average of 3.3 to 0.84 (p = 0.05). CONCLUSIONS: These findings suggest that treatment of DIN associated DA with a combination of thickeners and IL results in significant clinical improvements in young children.

Esophageal microbiome in eosinophilic esophagitis.

OBJECTIVE: The microbiome has been implicated in the pathogenesis of a number of allergic and inflammatory diseases. The mucosa affected by eosinophilic esophagitis (EoE) is composed of a stratified squamous epithelia and contains intraepithelial eosinophils. To date, no studies have identified the esophageal microbiome in patients with EoE or the impact of treatment on these organisms. The aim of this study was to identify the esophageal microbiome in EoE and determine whether treatments change this profile. We hypothesized that clinically relevant alterations in bacterial populations are present in different forms of esophagitis. DESIGN: In this prospective study, secretions from the esophageal mucosa were collected from children and adults with EoE, Gastroesophageal Reflux Disease (GERD) and normal mucosa using the Esophageal String Test (EST). Bacterial load was determined using quantitative PCR. Bacterial communities, determined by 16S rRNA gene amplification and 454 pyrosequencing, were compared between health and disease. RESULTS: Samples from a total of 70 children and adult subjects were examined. Bacterial load was increased in both EoE and GERD relative to normal subjects. In subjects with EoE, load was increased regardless of treatment status or degree of mucosal eosinophilia compared with normal. Haemophilus was significantly increased in untreated EoE subjects as compared with normal subjects. Streptococcus was decreased in GERD subjects on proton pump inhibition as compared with normal subjects. CONCLUSIONS: Diseases associated with mucosal eosinophilia are characterized by a different microbiome from that found in the normal mucosa. Microbiota may contribute to esophageal inflammation in EoE and GERD.

Novel device to sample the esophageal microbiome--the esophageal string test.

A growing number of studies implicate the microbiome in the pathogenesis of intestinal inflammation. Previous work has shown that adults with esophagitis related to gastroesophageal reflux disease have altered esophageal microbiota compared to those who do not have esophagitis. In these studies, sampling of the esophageal microbiome was accomplished by isolating DNA from esophageal biopsies obtained at the time of upper endoscopy. The aim of the current study was to identify the esophageal microbiome in pediatric individuals with normal esophageal mucosa using a minimally invasive, capsule-based string technology, the Enterotest™. We used the proximal segment of the Enterotest string to sample the esophagus, and term this the "Esophageal String Test" (EST). We hypothesized that the less invasive EST would capture mucosal adherent bacteria present in the esophagus in a similar fashion as mucosal biopsy. EST samples and mucosal biopsies were collected from children with no esophageal inflammation (n = 15) and their microbiome composition determined by 16S rRNA gene sequencing. Microbiota from esophageal biopsies and ESTs produced nearly identical profiles of bacterial genera and were different from the bacterial contents of samples collected from the nasal and oral cavity. We conclude that the minimally invasive EST can serve as a useful device for study of the esophageal microbiome.

Recent advances in the treatment of eosinophilic esophagitis.

First described nearly 20 years ago, eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus characterized by eosinophilic infiltration of the esophageal epithelium. Over 50% of the current literature on EoE has been published in the last 3 years, signaling both a rising incidence and increased recognition of this disorder. Treatment options available for patients with EoE include dietary management and/or pharmacologic therapy. An individualized approach to treatment is preferred, with an emphasis on patient-parental preference. The objective of this article is to discuss the current and future treatment options for EoE.