Characterization of Eosinophilic Esophagitis in Infants and Toddlers.

OBJECTIVES: The objective of this study is to determine demographic and clinical characteristics of infants and toddlers <2 years with eosinophilic esophagitis (EoE) and to assess treatment response in this rarely studied pediatric age group. METHODS: Retrospective study of children <2 years diagnosed with EoE at a single center from 2016 to 2018. EoE was defined by ≥15 eosinophils per high power field (eos/hpf) on at least 1 esophageal biopsy. Demographics, symptoms, and endoscopic findings were collected via chart review. EoE treatment [proton pump inhibitor (PPI), swallowed steroids, dietary restriction, or a combination] and treatment responses on all follow-up endoscopies were reviewed, with remission defined as <15 eos/hpf. RESULTS: Forty-two children ages 1.3 ± 0.4 years underwent 3.8 ± 2.3 endoscopies over 3.6 ± 1.7 years of follow-up. Thirty-six children (86%) were male, and comorbidities included atopy (86%), reflux (74%), and a history of cow's milk protein allergy (40%). Common symptoms were feeding difficulties in 67% of patients (with gagging or coughing with feeding in 60% and difficulty with progression to pureed or solid foods in 43%), vomiting (57%), and coughing/wheezing (52%). Of the 37 patients with follow-up endoscopies, 25 (68%) had histologic remission. There was an effect of therapy type on histologic response ( P = 0.004) with the best responses seen on combinations of diet/steroids or diet/PPI and the worst response seen on PPIs alone. All patients showed improvement in ≥1 symptom at the time of first follow-up endoscopy. CONCLUSIONS: EoE should be considered in young children with feeding difficulties, vomiting, or respiratory symptoms. All patients improved clinically with standard medical or dietary interventions, however there is dissociation between clinical and histologic response with only 2 of 3 patients achieving histologic remission.

Every-other-day Dosing of Oral Viscous Budesonide Is not Effective in the Management of Eosinophlic Esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by esophageal eosinophilia. Oral viscous budesonide (OVB) is an effective treatment with remission rates reported between 55% and 87%; however, topical corticosteroids are associated with increased risk of candidal esophagitis and adrenal suppression. Attempts to decrease the daily dose of topical steroids have resulted in disease relapse. The objective of this study was to determine whether or not reducing the frequency of OVB administration would be effective in controlling esophageal eosinophilia in children and adolescents. METHODS: Data were obtained by retrospective chart review of patients at Boston Children's Hospital diagnosed with EoE, based on endoscopic findings of >15 eosinophils per high power field (eos/HPF) on esophageal biopsies while on acid blockade. Patients with histologic evidence of response (<15 eos/HPF) while on daily OVB had been offered the option of maintenance therapy based on a Monday-Wednesday-Friday (MWF) dosing regimen. Changes in peak esophageal eosinophil counts over time were examined. RESULTS: Eight male patients ages 5 to 18 years attained clinical response while receiving daily OVB and were subsequently maintained on a MWF OVB dosing regimen for 3 to 7 months. All 8 patients showed an increase in peak esophageal eosinophils, with 7 of 8 (88%) experiencing disease relapse. In fact, the distribution of peak esophageal eosinophils after MWF dosing was not statistically different from peak levels at diagnosis (P = 0.95). CONCLUSIONS: An MWF dosing regimen of OVB was not effective at maintaining histologic response in children and adolescents with EoE. Larger prospective studies are warranted to confirm these results.

Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency.

BACKGROUND: Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients. METHODS: Information collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response. RESULTS: Forty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 10(9)/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 10(9)/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77 ± 33 versus 29 ± 65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients. CONCLUSIONS: HAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea. TRIALS REGISTRATION: The data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.The following trials have been registered at http://www.clinicaltrials.gov: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

Comparison of 2 delivery vehicles for viscous budesonide to treat eosinophilic esophagitis in children.

OBJECTIVES: Oral viscous budesonide (OVB) using Splenda as a delivery vehicle has become an attractive therapeutic option for children with eosinophilic esophagitis (EoE). Many families are wary of giving the artificial sweetener in high doses to their children. The aim of the present study was to determine whether OVB mixed with Neocate Nutra, a hypoallergenic nutritional supplement, is at least as efficacious as OVB mixed with Splenda at healing EoE. METHODS: Our institutional review board approved a retrospective chart review of patients with well-documented EoE treated with OVB at the Boston Children's Hospital Eosinophilic Gastrointestinal Disorder program between June 2008 and June 2013. Primary outcome measured was histologic response defined as change in peak eosinophil count to <15 eosinophils per high-power field (eos/HPF) after at least 10 weeks of OVB therapy. RESULTS: A total of 46 children were treated with OVB mixed with Splenda, and 14 were treated with OVB mixed with Neocate Nutra. The 2 groups were not significantly different in their demographic (race, age, sex) or clinical (initial eosinophil count, proton pump inhibitor use, or concomitant dietary elimination) characteristics. On follow-up endoscopy, 30 of 46 patients on Splenda and 13 of 14 patients on Neocate Nutra achieved histologic response. Mean pretreatment and posttreatment peak eosinophil counts for the children taking Neocate Nutra were 62 eos/HPF ([high-power field] range 20-120 eos/HPF) and 9 eos/HPF (range 0-100 eos/HPF), respectively. Mean pretreatment and posttreatment peak eosinophil counts for the Splenda group were 59.5 eos/HPF (range 20-180 eos/HPF) and 25.5 eos/HPF (range 0-200 eos/HPF), respectively. The odds ratio (OR) of success with Neocate Nutra as compared with Splenda was 6.93 (95% CI 0.83-57.91, P = 0.0728), demonstrating the noninferiority of Neocate Nutra. CONCLUSIONS: We demonstrate that OVB mixed with Neocate Nutra is at least as effective as OVB mixed with Splenda at treating children with EoE. Neocate Nutra is an innovative, effective, and palatable mixing agent to create a viscous budesonide slurry for families who prefer not to use the standard recipe with Splenda.

Real World Experience With Dupilumab in Eosinophilic Esophagitis in Children and Young Adults at a Tertiary Care Pediatric Medical Center.

Dupilumab is one of a number of biologics currently under investigation for the treatment of eosinophilic esophagitis (EoE). We report on a group of 7 pediatric and young adult patients with EoE who were treated with dupilumab for a primary indication of asthma or atopic dermatitis, all of whom previously failed swallowed topical corticosteroid therapy dietary for management of their EoE. All 7 patients demonstrated histologic improvement in their EoE while on dupilumab, with a drop in median peak esophageal eosinophil count from 50 eosinophils per high-powered field (eos/hpf) (IQR 48-95 eos/hpf) to 2 eos/hpf (IQR 0-5 eos/hpf) off swallowed topical corticosteroid. Additionally, improvements in EoE symptoms and endoscopic findings were noted. This report highlights the effectiveness of dupilumab in a group of multiply atopic pediatric and young adult patients with difficult-to-treat EoE in real world practice.

Siglec-F inhibition reduces esophageal eosinophilia and angiogenesis in a mouse model of eosinophilic esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a disorder characterized histologically by tissue eosinophilia. Sialic acid-binding immunoglobulin-like lectin (Siglec-F) is a receptor highly expressed on mouse eosinophils and mediates eosinophilic apoptosis. We investigated whether administration of an anti-Siglec-F Ab would reduce esophageal eosinophilic inflammation and remodeling in a mouse model of egg ovalbumin (OVA)-induced EoE. SUBJECTS AND METHODS: Three groups of mice were studied (no OVA, OVA + anti-Siglec-F Ab, and OVA + isotype control Ab). Mice were sensitized intraperitoneally and then challenged chronically with intraesophageal OVA. Levels of esophageal eosinophils and features of remodeling (angiogenesis, vascular endothelial growth factor expression, deposition of fibronectin, basal zone hyperplasia, and fibrosis) were quantitated by immunohistochemistry and image analysis. RESULTS: Administration of an anti-Siglec-F Ab to OVA-challenged mice significantly reduced levels of esophageal eosinophils, down to levels noted in non-OVA-challenged mice. The anti-Siglec-F Ab also reduced features of OVA-induced remodeling, including angiogenesis, basal zone hyperplasia, and fibronectin deposition. The reduced angiogenesis in anti-Siglec-F Ab-treated mice was associated with reduced numbers of vascular endothelial growth factor-positive cells in the esophagus. The anti-Siglec-F antibody did not significantly reduce esophageal fibrosis as assessed by trichrome staining. CONCLUSIONS: Administration of an anti-Siglec-F antibody significantly decreased the number of eosinophils in the esophagus in a mouse model of OVA-induced EoE. The reduction in eosinophilic inflammation was associated with a significant decrease in levels of angiogenesis, deposition of fibronectin, and basal zone hyperplasia. Studies in this pre-clinical model of EoE suggest that Siglec-F (and its human paralog Siglec-8) may be novel therapeutic targets to reduce eosinophilic inflammation in EoE.

Respiratory symptoms associated with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an atopic condition diagnosed based on eosinophilic infiltration in the esophagus and symptoms of esophageal dysfunction. Typical clinical manifestations of EoE include feeding refusal, vomiting, and dysphagia however recent reports highlight an associations with extraesophageal symptoms. By definition the inflammatory response in EoE is restricted to the esophagus. However, accounts of symptoms such as chronic refractory cough, recurrent croup, hoarseness as well as subglottic stenosis, and an increase in otolaryngologic surgeries in patients with EoE raise the possibility of extraesophageal manifestations of the disease. These symptoms have been reported at times in the absence of typical gastrointestinal symptoms. While the condition is usually managed by gastroenterologist and/or allergist, the presence of extraesophageal symptoms and comorbid conditions may result in patients presenting initially to providers in other subspecialties such as pulmonology and otorhinolaryngology. The use of proton pump inhibitors and corticosteroids are part of the management of EoE. Awareness of the possibility of EoE before the empiric use of these therapies is important as there use can make identifying and diagnosing patients with EoE correctly challenging. We review the medical literature regarding extraesophageal manifestations of EoE and highlight the importance of awareness for subspecialist outside of gastroenterology and allergy for the condition.

The utility of endoscopy and multichannel intraluminal impedance testing in children with cough and wheezing.

BACKGROUND: Gastroesophageal reflux (GER) has been implicated as a causal factor in respiratory disease but prior studies have focused on the role of acid alone in the genesis of symptoms. Prior studies have relied on pH probe testing but this is blind to non-acid reflux which has been implicated in the genesis of extraesophageal symptoms. The objective of this prospective, cross-sectional study is to determine the utility of gastroesophageal reflux testing, including multichannel intraluminal impedance with pH (pH-MII) and upper gastrointestinal endoscopy (EGD), in the child with intractable cough and wheezing. We hypothesize that there is a high rate of pathologic reflux testing in these patients. METHODS: Children ages 1-18 with chronic cough and wheezing who were undergoing bronchoscopy for the evaluation of cough and wheezing were recruited into this prospective, cross-sectional study. They underwent identical reflux testing with pH-MII and EGD at the time of bronchoscopy. Reflux burden, symptom association, and rates of esophageal pathology were determined. Results 58% of patients had abnormal reflux testing; 67% of patients had an abnormal pH-MII test and 32% of patients had abnormal esophageal biopsies. The most common pH-MII abnormality was an abnormal symptom association between cough and reflux and the most common endoscopic abnormality was reflux esophagitis. Seven percent of patients presenting only with cough were diagnosed with eosinophilic esophagitis. CONCLUSIONS: There is a high yield to reflux testing in children with chronic cough and wheezing.

Hepatic, cardiovascular, and endocrine outcomes of the histological subphenotypes of nonalcoholic fatty liver disease.

This review covers the diagnosis and outcomes of histological subphenotypes of nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) in both children and adults. Serious outcomes of NAFLD include cirrhosis, hepatocellular carcinoma, coronary heart disease, and diabetes. The ability to determine differential outcomes by NAFLD subtypes is dependent upon both the adequate assessment of histological subtypes, as well as the appropriate measure of the outcome of interest. Steatohepatitis, which can only be diagnosed by liver biopsy, has a greater risk for both hepatic and systemic complications than simple steatosis. Differences in subphenotypes between children and adults and among children have only recently been described. Careful future attention should be given to determine their influence on clinical outcomes. Enhanced understanding of the epidemiology of NAFLD subphenotypes may help organize collaborative efforts between hepatologists, pathologists, cardiologists, endocrinologists, and primary care physicians to develop clinical management protocols.

Intracellular survival of persistent group A streptococci in cultured epithelial cells.

Group A streptococcus (GAS) is the principle etiologic agent of bacterial pharyngotonsillitis and a wide range of other diseases. Failure to eradicate GAS from patients has been documented in 5-30% of patients with pharyngotonsillitis, in spite of the continued sensitivity of GAS to penicillin and other beta-lactams. It was recently proposed that eradication failure might be attributed to the ability of GAS to maintain an intracellular reservoir during antibiotic treatment. We have previously shown that strains derived from patients with bacterial eradication failure, despite antibiotic treatment (persistent strains), adhered to and were internalized by cultured epithelial cells more efficiently than strains that were successfully eradicated. Since, penicillin and other beta-lactams do not penetrate well into mammalian cells, intracellular survival of GAS is crucial in order to persist during prolonged antibiotic treatment. In this study, we compared the survival of GAS strains from cases of eradication failure and eradication success, using an epithelial cell culture model. We found that persistent strains show significantly increased intracellular survival, compared to the 'eradication success' strains. This finding supports the idea that an intracellular reservoir of GAS plays a role in the etiology of antibiotic eradication failure.