THERAPEUTIC APPROACHES TO MALNUTRITION ENTEROPATHY (TAME): A RANDOMISED CONTROLLED TRIAL IN CHILDREN WITH SEVERE ACUTE MALNUTRITION IN ZAMBIA AND ZIMBABWE

Background: While it is widely recognized that symptoms of eosinophilic esophagitis (EoE) differ in children versus adults, only a single case series has investigated symptoms of EoE in infants and toddlers, and few young children are included in studies of therapeutic response. Thus, the aims of the current study were 1) to characterize presentations of EoE in children < 2 years, and 2) to evaluate histologic and clinical response to treatment in this youngest pediatric age group.

Methods: This was a retrospective longitudinal study of children < 2 years diagnosed with EoE at a single tertiary center between 2016 and 2018. EoE was defined histologically by presence of > 15 eosinophils per high power field (eos/hpf) on at least one esophageal biopsy and a history suggestive of the diagnosis. Demographic characteristics, presenting symptoms, and EoE treatments were collected via chart review. Follow-up data were collected from all endoscopies after diagnosis, and histologic remission was defined as < 15 eos/hpf. Paired t-tests or Fisher exact tests for parametric data or Wilcoxin sign-rank test for non-parametric data were used to evaluate changes from baseline to follow-up in histology and clinical symptoms.

Results: Forty-two children ages 1.3 ± 0.4 years were followed for a mean of 3.6 ± 1.7 years and underwent 3.8 ± 2.3 (range 1 to 10) endoscopies under general anesthesia. Common presenting symptoms were feeding difficulties in 67% of patients (including gagging/coughing with feeding in 60% and difficulty with progression to pureed or solid foods in 43%), vomiting (57%), and coughing/wheezing (52%). Thirty-six children (86%) were male, and comorbidities included atopy (86%), reflux (74%), and a history of cow’s milk protein allergy (40%). Thirty-seven patients underwent repeat endoscopy after diagnosis, and 25/37 (68%) achieved histologic remission during the follow-up period. In addition to histologic improvement, there were significant reductions in all symptoms at follow-up compared to baseline (Figure 1). Treatment regimens were variable, and there was a significant effect of therapy type on histologic response (P = 0.004) with the best responses on combinations of diet/steroids or diet/proton pump inhibitor (PPI) and the worst response on PPIs alone (Figure 2). Of the 20 patients who underwent additional endoscopies after histologic remission, 13/20 (65%) had relapsed EoE on at least one follow-up endoscopy.

Discussion: The diagnosis of EoE should be considered in infants and toddlers presenting with feeding difficulties, vomiting, and cough or wheeze. EoE in this age group may mimic other common GI diagnoses, such as reflux or milk protein intolerance. Most patients show histologic and clinical improvements with standard therapies, but the endoscopic burden is significant and histologic response may not be maintained over time.

Background: Helicobacter pylori (H. pylori) eradication rates have declined globally making susceptibility testing increasingly important. Despite improvement in test availability of gastric biopsy-culture with susceptibility testing (gold standard) in the United States (US), culture requires an invasive procedure to obtain gastric biopsies, esophagogastroduodenoscopy (EGD), which is not devoid of potential endoscopic and anesthesia-related risks. Stool-based susceptibility testing offers a useful non-invasive option suitable for pediatric population in whom invasive diagnostic testing for the sole purpose of detecting H pylori infection is not recommended.
Methods: A total of 19 patients that underwent diagnostic endoscopic evaluation with positive resultant positive histology for H. pylori from a large pediatric tertiary care center in Boston, MA were included in the study. At our institution, we have standardized the process of gastric biopsy culture in patients with endoscopic findings of H. pylori. An antral and corpus biopsy are taken at the time of endoscopy for gastric biopsy-culture with susceptibility testing via agar dilution. Patients provided a stool sample within 2 weeks of the endoscopy, prior to the start of treatment. We evaluated agreement between the stool next generation sequencing (NGS)-based molecular testing and gastric biopsy-culture with susceptibility testing.
Results: From the 19 recruited patients, 6 (31.6%) did not have sufficient bacterial colony growth in gastric culture to run susceptibility testing. Sufficient H. pylori DNA for NGS analysis was detected in 18 (95%) patients. Thirteen patients (68.4%) had both stool NGS-based molecular test, and gastric biopsy-culture antimicrobial resistance data to compare (mean age 11.9 years [range 3-20], 6 (46%) Male, 6 (46%) Black, 4 (31%) Hispanic. Overall stool NGS-based molecular test was highly concordant with gastric biopsy-culture results for clarithromycin resistance (2 patients), and no resistance identified (11 patients). In addition, stool NGS-based molecular test was highly sensitive, providing antimicrobial resistance data in patients with poor bacterial growth in culture (5/6, 83%). All of the 5 patients were resistant to at least one antimicrobial.
Conclusion: Stool NGS-based molecular test is highly concordant with gastric biopsy-culture results, providing accurate H. pylori antimicrobial resistance data for clarithromycin non-invasively in pediatric patients.

Introduction:
Celiac disease is a gluten-mediated autoimmune enteropathy with an estimated prevalence of 2-3% of the population. Recent reports suggest that SARS-CoV-2 infections may increase the risk of celiac disease by increasing intestinal inflammatory responses that may alter intestinal permeability with potential post-inflammatory and autoimmune sequelae. ACE2 receptors, which have been associated with COVID-19, are widely expressed in enterocytes. SARS-CoV-2 infection has also been associated with the presence of tissue transglutaminase autoantibodies (TGA). The aim of this study was to evaluate the potential association of COVID-19 infection and celiac disease autoimmunity.

Methods:
Cross-sectional screening for SARS-CoV-2 antibodies and TGA IgA for celiac disease was offered to children in Colorado through the Autoimmunity Screening for Kids (ASK) study. From July 2020 through December 2021, 4717 Colorado children participated in antibody screening. Children were screened at Children’s Hospital Colorado, Denver Health community clinics, private pediatric practices, and other community sites. Previous SARS-CoV-2 infection was defined by presence of antibodies to the receptor-binding domain of the spike protein in unvaccinated subjects and presence of nucleocapsid antibodies in vaccinated subjects. Multivariable logistic regression was used to assess independent association between previous SARS-CoV-2 infection and celiac autoimmunity.

Results:
There were 109 participants who screened positive for celiac disease (2.3%) and 219 reported a first-degree relative with celiac disease (4.6%). Analysis showed previous SARS-CoV-2 infection in 1524 of 4717 children (32.3%) between July 2020 and December 2021 (median age 8.6 years; 50.3% female). Twenty-seven children of 1524 with prior COVID-19 infection were TGA positive. COVID-19 infection was more frequent in older children (p=<0.001 for age as a continuous variable), those without family history of celiac disease (p<0.0001), Hispanics (p<0.0001), and unvaccinated (p=0.0001).

In multivariable logistic regression, previous SARS-CoV-2 infection was not associated with presence of TGA in Colorado children (OR=1.02, 95% CI 0.63-1.59; p=0.95), adjusting for sex, age, race/ethnicity, and family history of celiac disease in first-degree relatives. (Table 1)

Conclusions:
Previous SARS-CoV-2 infection was not associated with celiac disease autoimmunity in Colorado children. To our knowledge, this is the first large-scale analysis of celiac disease autoimmunity during the COVID-19 pandemic. Longer prospective analysis will help assess whether there is a true association between SARS-CoV-2 infection and prevalence of autoimmunity in children.

Background Severe Acute Malnutrition (SAM) in African children carries high mortality when complicated by infection or metabolic derangements. As malnutrition enteropathy (diarrhoea, microbial translocation, malabsorption) is a prominent feature of complicated SAM we evaluated four novel interventions in children with complicated SAM.
Methods This was a multi-arm, phase II, non-blinded randomised controlled trial in two hospitals in Lusaka, Zambia, and Harare, Zimbabwe. Children were randomised to 14 days of i) bovine colostrum, ii) N-acetyl glucosamine, iii) budesonide, iv) subcutaneous teduglutide, or v) standard care alone. The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin and α₁-antitrypsin). Secondary endpoints were biomarkers of mucosal damage, inflammation, microbial translocation, clinical recovery, anthropometry, adverse events and mortality. A subgroup additionally underwent endoscopy for small intestinal biopsy. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P<0.10.
Results Between May 2020 and April 2021, 125 children were randomised and 122 (98%) contributed endpoint data. The faecal biomarker score (median at baseline 1.87) was reduced by teduglutide by 0.89 (95%CI -0.06, 1.85) compared with standard care (P=0.07 by ANCOVA). Teduglutide and colostrum increased crypt depth in mucosal biopsies compared to standard care (median 197mm (IQR 149,221) versus 151mm (IQR 136,162); P=0.02). Budesonide reduced plasma C-reactive protein and CD163, while colostrum and N-acetyl glucosamine reduced CRP only. N-acetyl glucosamine reduced diarrhoea by 89% (rate ratio 0.11; 90%CI 0.04, 0.33). Adverse Events were not different between treatment arms.
Conclusions All interventions were safe. Teduglutide reduced markers of malnutrition enteropathy, and budesonide reduced systemic inflammation. Further trials are warranted to establish clinical efficacy, optimal timing and duration of interventions for SAM.