Immune Dysregulation in Human ITCH Deficiency Successfully Treated with Hematopoietic Cell Transplantation.

BACKGROUND: Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease. OBJECTIVE: We aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency. METHODS: Disease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry. RESULTS: A patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease. CONCLUSIONS: Here we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.

Eosinophilic esophagitis in esophageal atresia: Tertiary care experience of a "selective" approach for biopsy sampling.

BACKGROUND: A high prevalence (9.5-30%) of eosinophilic esophagitis (EoE) in patients with esophageal atresia (EA) has been reported. The application of the EoE criteria to EA patients might be problematic. To date, only studies using a "routine" biopsy approach, even in asymptomatic patients, have been performed. The aim of the study was to establish the prevalence of EoE among symptomatic EA patients (EA/EoE group) without anastomotic stricture (AS) and to compare their characteristics with those of EoE patients from general population (EoE group). METHODS: From 2005 to 2018, we reviewed charts of children with EA and EoE. "Selective" biopsy approach only in EA children without AS and/or endoscopic feature of EoE was performed. Characteristics of EA/EoE and EoE groups were compared. RESULTS: Among 370 EA and 118 EoE, 15 EA/EoE patients were detected (4.0% of EA patients). Male predominance and a high prevalence of allergy without differences between EA/EoE and EoE groups was observed. EA/EoE children were significantly younger (p < 0.0001). PPI-responder patients were significantly more prevalent in EA/EoE group (p = 0.045). CONCLUSION: Our data confirm that EA patients are at high risk for developing EoE. High incidence, early onset, and high prevalence of PPI-responders might suggest that esophageal motility disorders interact to increase propensity to EoE in EA patients. However, our study also suggests that overdiagnosis of EoE may occur in EA and that adapted criteria for EoE diagnosis should be developed for EA patients. TRIAL REGISTRATION: Not applicable for this retrospective study.

Longitudinal Growth Outcomes Following First-line Treatment for Pediatric Patients With Eosinophilic Esophagitis.

OBJECTIVES: No formal comparative effectiveness studies have been conducted to evaluate the effect of eosinophilic esophagitis (EoE) treatment choice on long-term growth in pediatric patients. Long-term studies of inhaled corticoid steroids in asthma, however, suggest possible effects on linear growth. The aim of this study was to compare longitudinal, anthropometric growth in children with EoE according to treatment approach. METHODS: We conducted a retrospective, multicenter cohort study of anthropometric growth (height and body mass index [BMI] z scores) in pediatric (<18 years of age) patients newly diagnosed with EoE across 5 clinical sites between 2005 and 2014. We compared differences in growth according to treatment approach over a 12-month period. Modification by sex and age was examined and sensitivity analyses were conducted to assess robustness of results given study assumptions. RESULTS: In the 409 patients identified, the mean age and proportion male differed by treatment (P =  < 0.01 and P = 0.04, respectively). Baseline growth measures were associated with slight impairment of height at diagnosis (median baseline height z score of -0.1 [interquartile range -0.9, 0.8]). In general, treatment approach was not associated with any significant increase or decrease in expected growth over a 12-month period. Subtle decrease in linear growth was observed with treatment using a combined elemental and topical steroid (Δ height z score [adjusted]: -0.04; 95% confidence interval [CI]: -0.08, -0.01). Differences in linear growth differed by sex (P for interaction <0.01). For elemental formula in combination with topical steroids, only girls exhibited a significant decline in linear growth (Δ height z score [adjusted]: -0.24; 95% CI: -0.32, -0.17). A slight reduction in BMI was observed for patients treated with a combination of elemental diet and dietary elimination (Δ BMI z score [adjusted]: -0.07; 95% CI: -0.13, -0.01). CONCLUSIONS: Treatment of EoE, in general, is not associated with major anthropometric growth changes in most pediatric patients. Slight linear growth impairment was observed for topical steroid treatment, and sex differences in growth by treatment approach were observed. Future prospective studies should evaluate the effect of treatment on optimal growth and development and over a longer period of follow-up.

Practice Pattern Variation in Pediatric Eosinophilic Esophagitis in the Carolinas EoE Collaborative: A Research Model in Community and Academic Practices.

OBJECTIVES: Differences in the initial management of pediatric eosinophilic esophagitis (EoE) by practice setting have not been well characterized. We aimed to characterize these differences for sites in the Carolinas EoE Collaborative (CEoEC), a multicenter network of academic and community practices. METHODS: We performed a retrospective cohort study of pediatric EoE patients at five CEoEC sites: University of North Carolina (UNC) Hospital, Charlotte Asthma and Allergy Specialists, Greenville Health Systems, Wake Forest Baptist Medical Center, and the Medical University of South Carolina Hospital. Cases of EoE were defined by consensus guidelines. Data were extracted from electronic medical records. We tested for differences among sites and used a multinomial model (polytomous regression) to assess associations between treatment and site, adjusting on patient factors. RESULTS: We identified 464 children with EoE across the CEoEC sites. The median age was highest at Wake Forest (11.4 years), the median eosinophil count was highest at UNC (69 eos/hpf), and UNC had the most male patients (82%). UNC used topical steroids for initial treatment in 86% of cases, compared with <1% in Greenville (P < 0.01). Greenville used dietary elimination more frequently than UNC (81% vs 2%, P < 0.01). Differences in treatment approach held after adjusting for potential baseline confounders. There was no significant association between patient factors and initial treatment approach. CONCLUSIONS: Significant differences in EoE patient factors and treatment approaches were identified across CEoEC sites and were not explained by patient or practice factors. This suggests that institutional or provider preferences drive initial treatment approaches, and that more data are needed to drive best practice decisions.

Eosinophilic Esophagitis in Children and Adults.

Adults and children with eosinophilic esophagitis (EoE) have distinct clinical and endoscopic presentations. Recognition of clinical signs, along with laboratory and endoscopic findings, is critical for the identification of patients with EoE because delay in diagnosis has been associated with esophageal remodeling and stricture formation. Clinical presentation varies considerably between adults and children. This is less due to differences in the disease and more due to patient differences. This article describes the similarities and differences in clinical presentation of children and adults with EoE, including areas of epidemiology, clinical and endoscopic presentation, pathophysiology, and treatment.

Safety and Efficacy of Reslizumab for Children and Adolescents With Eosinophilic Esophagitis Treated for 9 Years.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic disease characterized by infiltration of eosinophils in the esophageal epithelium. There are limited treatment options for EoE. The rationale of the study was to evaluate the long-term safety and efficacy of reslizumab (RSZ) in pediatric patients who received RSZ in a randomized controlled trial (RCT) and expanded access program. METHODS: Records of patients who received RSZ in our center were reviewed. Patients received RSZ 2 mg/kg (or placebo) every 4 weeks as part of the RCT, open-label extension (OLE), and compassionate use (CU). Data were analyzed as of their most recent evaluation in August 2017. Labwork, history, and examinations were conducted every 12 weeks. Biopsy results were compared from baseline (before RCT) and at the most recent evaluation. Adverse events (AE) were recorded. RESULTS: Twelve patients entered the RCT at our center; 6 patients completed the OLE and 4 received RSZ through CU. Between the RCT, OLE, and CU periods, patients received 549 doses of RSZ (median 37, range 2-116). No serious AE were attributed to RSZ. Symptoms improved on treatment: dysphagia (42% vs 0%), abdominal pain (58% vs 0%), heartburn (18% vs 0%), vomiting (67% vs. 17%), reflux (58% vs. 0%). Median esophageal eosinophil count improved (35 eosinophils per high-power field vs 3, P < 0.001). Patients receiving RSZ maintain a relatively unrestricted diet. CONCLUSIONS: RSZ appears to be safe in children with EoE over 9 years of treatment experience. Symptoms and eosinophil count improved considerably during treatment with RSZ despite a relatively unrestricted diet.

Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Eosinophilic esophagitis is a chronic allergic disease with insufficient treatment options. Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus. OBJECTIVE: We sought to evaluate the effect of reslizumab, a neutralizing antibody against IL-5, in children and adolescents with eosinophilic esophagitis. METHODS: Patients with symptom severity scores of moderate or worse and an esophageal biopsy specimen with 24 or more intraepithelial eosinophils per high-power field were randomly assigned to receive infusions of 1, 2, or 3 mg/kg reslizumab or placebo at weeks 0, 4, 8, and 12. The coprimary efficacy measures were changes in peak esophageal eosinophil count and the physician's global assessment score at week 15 (end of therapy). RESULTS: Two-hundred twenty-six patients received study medication. Median reductions from baseline to the end of therapy in peak esophageal eosinophil counts were 59%, 67%, 64%, and 24% in the 1, 2, and 3 mg/kg reslizumab (all P < .001) and placebo groups, respectively. All treatment groups, including the placebo group, showed improvements in physician's global assessment scores; the differences between the reslizumab and placebo groups were not statistically significant. The most common adverse events in the reslizumab groups were headache, cough, nasal congestion, and upper respiratory tract infection. One patient in each reslizumab group and 2 in the placebo group had serious adverse events; none were considered related to the study medication. CONCLUSION: Reslizumab significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with eosinophilic esophagitis. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts.

Eosinophilic esophagitis: updated consensus recommendations for children and adults.

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.

Non-surgical interventions for eosinophilic esophagitis.

BACKGROUND: People with eosinophilic esophagitis (EE) have clinical symptoms of esophageal disease, an elevated intraepithelial eosinophil count (15 in one or more high power field at endoscopy), consistent endoscopic findings and failure to respond to gastric acid suppressants. The cause of EE is unknown, however dietary, environmental and immunological factors may contribute. Current medical therapies include steroids, dietary manipulation, mast cell inhibitors, leukotriene receptor antagonists and immune modulators; however there is no universal approach to treatment. OBJECTIVES: To evaluate the benefits and harms of medical interventions for EE. SEARCH STRATEGY: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group trials register (The Cochrane Library Issue 1, 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2009), MEDLINE (1966 to February 2009) and EMBASE (1980 to February 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a medical or dietary intervention for EE with a placebo or with another medical intervention. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened the titles of abstracts. MAIN RESULTS: Three RCTs fulfilled inclusion criteria, two in children and one in adults. In one trial, topical fluticasone decreased vomiting more than placebo (67% versus (vs) 27%, P<0.05) but did not improve dysphagia. Histological remission was reported in fluticasone group compared with placebo group (50% vs 9%, P=0.05; RR 5.5, 95%CI 0.81 to 37.49). One recipient of fluticasone developed oral candidiasis. In trial comparing fluticasone with oral prednisone, symptom resolution and improvement of esophagitis were similar. Majority of participants were symptom free at four weeks with no difference between groups (RR 1.03, 95%CI 0.95 to 1.11). Symptom relapse usually occurred within six weeks of stopping therapy and 45% had symptom relapse at six month follow-up with no difference between groups. With prednisone, 40% suffered adverse effects and three withdrew early from treatment with severe adverse effects (hyperphagia, weight gain, cushingoid features). With fluticasone, 15% developed esophageal candidiasis and 45% had relapse in symptoms at week 24. Histological improvement occurred in majority at four weeks with no difference between groups. In the third trial comparing mepolizumab to placebo, there was no difference in symptom response with mepolizumab compared to placebo, but decrease in esophageal eosinophil count was greater with mepolizumab than placebo (67% vs 25%). AUTHORS' CONCLUSIONS: As only three relevant RCTs were identified, we have limited capacity to compare the benefits and harms of medical interventions currently used for treating EE. Further RCTs on therapies for EE are required.

Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease.

BACKGROUND & AIMS: The aim of this study was to compare response to inactivated influenza vaccine in healthy children and pediatric patients with inflammatory bowel disease (IBD). METHODS: A prospective, open-label, controlled clinical trial during influenza seasons of 2002-2004 was performed. Single-dose inactive trivalent influenza vaccine was administered. Immune response to vaccination was measured by pre-immunization and postimmunization hemagglutinin inhibition titers. A postimmunization hemagglutinin inhibition titer of 40 or higher was considered protective against influenza. IBD activity and adverse events were recorded. RESULTS: Eighty subjects were enrolled (29 healthy controls, 51 IBD patients). One patient did not complete the study. Patients were divided into 3 subgroups: infliximab and immunomodulatory (16), immunomodulatory (20), and anti-inflammatory therapy (14). Immunomodulatory therapy included corticosteroids, 6-mercaptopurine, or methotrexate. Overall, there was a statistically significant decrease in immune response in patients compared with healthy controls who received 1 influenza vaccine antigen (B/Hong Kong, P = .0125). Patients receiving infliximab and immunomodulatory therapy were less likely to respond to 2 influenza vaccine antigens (A/New Caledonia/20/99 and B/Hong Kong/330/2001, P = .018 and .0002, respectively). Fifteen subjects (19%) reported 19 mild adverse events: 11 (14%) reported soreness at the site, 4 (5%) reported having a cold, 3 (4%) reported flu-like symptoms, and 1 (1%) reported a headache. The clinical activity of IBD was not affected by vaccination. CONCLUSIONS: The serologic conversion rate to influenza vaccine in patients with IBD ranged from 33% to 85%. Patients on concomitant infliximab and immunomodulatory therapy are at risk of inadequate response to vaccination. The vaccine was safe and did not affect IBD activity.

Safety of intravenous midazolam and fentanyl for pediatric GI endoscopy: prospective study of 1578 endoscopies.

BACKGROUND: Data on safety of intravenous sedation in pediatric GI endoscopy are sparse. OBJECTIVE: To evaluate safety of intravenous sedation for GI endoscopy. DESIGN/SETTING: Single-center prospective series of outpatient GI endoscopies performed from February 2003 to February 2004 at The Children's Hospital of Philadelphia. The recorded information included demographic, medication, and adverse event data. PATIENTS: A total of 1226 patients were studied. MAIN OUTCOME MEASUREMENTS: Description of adverse events relating to intravenous sedation. RESULTS: A total of 2635 endoscopies were performed, of which 1717 were outpatient procedures with the patient under intravenous sedation. Sedation data were available on 1578 procedures (92%, M/F 674/552): 758 esophagogastroduodenoscopies (EGD) alone, 116 colonoscopies (COL) alone, and 352 combined EGD and COL. The median dose of fentanyl was 2.77 microg/kg (SD 0.97, range 0-6.73), and of midazolam was 0.11 mg/kg (SD 0.06, range 0-0.39). The mean recovery time was 118 minutes (SD 47.3, range 31-375). Ten patients (0.8%) failed intravenous sedation. Serious adverse events (apnea) were noted in 2 patients (0.2%). Mild or moderate adverse events included desaturation below 92% for less than 20 seconds (100 patients, 9%), vomiting (64 patients, 5%), agitation (15 patients, 1%), desaturation below 92% for greater than 20 seconds (12 patients, 0.7%), and rash (8 patients, 0.7%). No cardiopulmonary resuscitation or sedation reversal was necessary. No patients required hospitalization. Patients younger than 6 years were more likely to develop respiratory adverse event (P < .01). CONCLUSIONS: Intravenous sedation with midazolam and fentanyl is safe for pediatric GI endoscopy. Serious adverse events are rare and no patient required hospitalization.