Objectives and Study

Systematically assess the clinical and methodological variation in study design for eosinophilic esophagitis (EoE) medical therapies.

Methods

A search was conducted from our 2022 EoE Cochrane Review database (current through November 22, 2022).

Results

Of 2,638 reports that met search criteria, 275 met criteria for full-text review, and 41 RCTs met criteria for analysis. Ten RCTs included children <18 yo, and 28 RCTs included adolescents and adults. Reported outcome measures varied: clinical (15/41 dichotomous, 26/41 continuous), histologic (31/41 dichotomous, 25/41 continuous), and endoscopic outcomes (5/41 dichotomous, 16/41 continuous). Validated patient-reported (PROs) and endoscopic outcomes were used in 16/41 and 15/41 trials, respectively. Corticosteroid therapy results in increased dichotomous histological improvement relative to placebo with high certainty and low inter-study heterogeneity (406/652 vs. 9/326, RR [95%CI]=11.93 [6.66,21.40], I²=5%, p<0.00001, NNT=3), independent of a pre-induction phase PPI trial, concomitant PPI use, baseline atopy, length of therapy, or the eosinophil count threshold used for inclusion (≥24, ≥20, ≥15 eos/hpf) or to define response (<15, ≤6-5, ≤1 eos/hpf), (NNT=3-4, Table 1A). Subgroup analysis comparing budesonide to fluticasone or different delivery methods found no difference (NNT=2-4, Table 1B). Current instruments used to assess dichotomous clinical outcomes may not be appropriate for pediatric patients, independent of therapy (Table 1C). Anti-IL-13 or anti-IL-4r may result in dichotomous clinical improvement (66/106 vs 25/66, RR [95%CI]=1.37[1.02, 1.85], I²=0%, p=0.04, NNT=7, low certainty/imprecision), and result in increased clinical improvement measured as a continuous outcome (standardized mean difference=0.58, 95%CI=0.41 to 0.76, I²=0%, p<0.00001, NNT=3, high certainty).

Conclusions

There were significant differences in outcome measures for clinical, histologic and endoscopic response to medical therapy. Factors that clinicians have historically considered important to control for in EoE clinical trials did not significantly influence outcomes. A recently published core outcome set for EoE may enhance future certainty of synthesized RCT evidence.

Objectives and Study

Eosinophilic Esophagitis (EoE) is characterized by eosinophilic inflammation, but other cell types, such as T-cells, contribute to esophageal inflammation. Currently, proton-pump-inhibitors (PPI), elimination diet (ED) and topical steroids (TS) are offered to patients as first-line therapy. We investigated the immune cell compartment in PPI-induced compared to TS-induced remission.

Methods

Clinical data and esophageal biopsies were collected from 10 pediatric EoE-patients (baseline and up to four follow-up endoscopies), 10 patients each with gastroesophageal reflux disease (GERD) and functional disorders (FD), respectively. Active EoE was defined as 15 eosinophils/hpf and remission as <5 eosinophils/hpf.

Expression of eosinophil peroxidase (EPX), mast cell tryptase (MCT), CD3⁺-, CD8⁺- and Foxp3⁺ T-cells were determined by multiplex immunofluorescence staining using the OPAL 7-Color Automation IHC Kit (Akoya), image acquisition (Vectra Polaris) and quantitative and spatial analysis (QuPath-Software). Statistical analysis was performed using one-way ANOVA with Dunn’s multiple comparison test (GraphPad Prism).

Results

Follow-up of 10 EoE-patients resulted in 69 biopsies derived from 35 endoscopies (24 active EoE, 11 remission EoE): 10 baseline, 15 PPI-treated, 5 ED-treated, 3 TS-treated and 2 without treatment. Infiltration of eosinophils, mast cells and CD3⁺ T-cells was significantly higher in active EoE compared to remission EoE, GERD and FD (remission: EPX p=<0.0001, MCT p=0.0006, CD3 p=0.0009). Comparison of cell infiltrate in biopsies from patients in remission showed significant differences between PPI- and TS-treatment for the following cell-types: CD3⁺ (p<0.0001), CD8⁺ (p=0.0206), CD3⁺CD8^- (p=0.0001) and Foxp3⁺ (p=0.0358). T-cells remained significantly higher in PPI-remission than in TS-remission; TS- remission did not differ from FD (CD3⁺p=0.078). Spatial analyses showed a decreased distance of CD3⁺CD8^- cells to luminal surface (p<0.001) and CD8⁺ cells (p<0.001) in PPI-remission compared to TS-remission.

Conclusions

PPI-induced histologic remission in contrast to TS-induced remission is associated with persistent mucosal T-cell infiltrate. Our results challenge PPI as equivalent recommendation to TS as first line treatment for pediatric EoE-patients.

Objectives and Study

Studies of small populations of eosinophilic esophagitis (EoE) children treated with swallowed topical corticosteroids (STC) have reported conflicting results in relation to adrenal insufficiency (AI). Our aim was to assess AI in these patients using a standard dose (250µg) adrenocorticotropic hormone stimulation test (SDST) and to compare patients with normal response (G1) with those who developed AI (G2).

Methods

We retrospectively assessed the adrenal function in children <18 years with EoE who were treated with STS for at least 3 months. AI was defined by peak serum cortisol level <18µg/dL at 60 minutes after SDST or absolute increase from cortisol levels at baseline <7µg/dL. Clinical characteristics and medical history were recorded. Statistical analysis was performed using SPSSv28.

Results

We analyzed 153 SDST of a total of 65 children. The first test detected AI in 8 patients(12,3%). A second SDST was repeated in 52 patients with AI in 7(13,5%), a third one in 26 patients with AI in 2(7,7%) and a fourth one in 11 with AI in 1(9,1%). Age, sex, BMI, duration of therapy, type of corticosteroid, total daily dose of STC, exposure to other corticosteroids and histologic response were similar between patients with and without AI(p>0,05) (Table 1-2). Mean total IgE was lower in G1 vs G2 [210 KU/L(13,9-9620) vs. 791 KU/L(188-5000)p=0,05] and previous PPI response was less prevalent in G1 vs G2 [5,9%(n=3) vs. 33,3%(n=3)p=0,011]. Only one patient developed signs suggestive of AI. This patient received a 10 times higher dose (OVB 10mg/12h) than the one prescribed due to OVB pharmacy formulation error.

Conclusions

Prevalence of AI in our cohort was 7,7-13,4%. Total IgE levels was higher and previous PPI response was more prevalent in patients with AI. We should consider OVB overdose due to a formulation error in AI patients, especially when suggestive AI signs/symptoms are reported.

Objectives and Study

Systematically assess the efficacy and safety of medical therapies for EoE using published randomized controlled trials.

Methods

A Cochrane information specialist performed a literature search (through November 22, 2022). GRADE assessed the quality of evidence from meta-analyses, factoring in imprecision, heterogeneity, and bias.

Results

Of 2,638 reports that met criteria, 275 met criteria for full-text review, and 41 RCTs met criteria for analysis, 10 of which were in children ≤18 yo. Corticosteroid therapy compared with placebo: 1) may lead to clinical improvement (dichotomous outcome, study defined) (responders / treatment group, 210/380 vs. 71/203, RR=1.74, 95%CI=1.08 to 2.80, NNT=4, low certainty / inconsistency, imprecision); 2) leads to histological improvement (406/652 vs. 9/326), RR=11.93, 95%CI=6.66 to 21.40, NNT=3, high certainty); and 3) may lead to fewer adverse event withdrawals (withdrawals / treatment group, 49/678 vs. 41/354, RR=0.62, 95%CI=0.40 to 0.95, low certainty / imprecision). Anti-IL-5 therapy compared with placebo (Figure 1): 1) may be associated with little to no difference in clinical improvement (103/175 vs. 40/63, RR=0.92, 95%CI=0.73 to 1.15, low certainty / imprecision); and 2) probably results in histological improvement (104/174 vs. 20/63, RR=1.75, 95%CI=1.21 to 2.55, NNT=4, moderate certainty / imprecision). Anti-IL-13 or anti-IL-4r therapy compared with placebo (Figure 1): 1) increases clinical improvement (standardized mean difference=0.60, 95%CI=0.43 to 0.77, NNT=3, high certainty); and 2) results in histological improvement (169/308 vs 10/263, RR=9.62, 95%CI=5.73 to 16.17, NNT=3, high certainty). Adverse event withdrawals appear similar between biologics (all mechanisms) and placebo (9/522 vs. 6/274, RR=0.73, 95%CI=0.24 to 2.22, low certainty / imprecision).

Conclusions

Corticosteroid therapy compared to placebo may lead to increased clinical improvement (low certainty, NNT=4), increased histological improvement (high certainty, NNT=3), and fewer adverse event withdrawals (low certainty). Anti-IL-13 or anti-IL-4r therapy results in increased clinical improvement (high certainty, NNT=3) and histological improvement (high certainty, NNT=3).

Objectives and Study

The gut microbiome plays an important role in our intestinal and overall health. However, experimental data on microbiome-related effects in the human gut are minimal, due to the complexity and technical challenges of exposing intestinal cells or tissue, which need oxygen to survive, to gut microbiota that only survive in an oxygen-free environment. To tackle this, we developed an aerobic-anaerobic interface for our ex vivo tissue-based gut-on-a-chip model, the Intestinal Explant Barrier Chip (IEBC), and used this novel platform to evaluate host-microbe interactions in the gut.

Methods

The aerobic-anaerobic interface was established by connecting the apical recirculating flow of the IEBC to a conditioning chamber with anaerobic atmosphere , containing the medium reservoirs, sample inlets and oxygen sensors. Ex vivo gut colon tissue of human and porcine origin was incorporated into the IEBC and co-cultured with strict anaerobe bifidobacterium animalis for 24 hours.

Results

Low oxygen levels (<0.5%) in the apical medium confirmed that the aerobic-anaerobic interface was preserved. Tissue explants cultured in the aerobic-anaerobic interface showed proper tissue functionality (transcellular/paracellular transport >2), intact tissue integrity (FITC-dextran 4000 leakage <0.5%/h) and significant differences in microbial beta diversity compared to aerobic tissue conditions, with a higher abundance of e.g. bifidobacterium and lactobacillus species. Tissue functionality and integrity remained intact upon co-culture with bifidobacterium animalis, for which growth and tissue-attachment were shown by targeted qPCR analysis.

Conclusions

Here, we successfully demonstrated the use of our novel aerobic-anaerobic interface for the IEBC with the co-culture of strict anaerobic bacteria and human or porcine colon tissue explants. Next, we will use this novel platform to study the impact of the gut microbiome on gut health, by using different strains of bacteria or the complete microbiome of different populations (e.g. health vs. disease).

Objectives and Study

One step button per endoscopic gastrostomy (B-PEG) has become increasingly used in children but large series addressing complications on a long follow-up are missing. To assess the complications of one-step button percutaneous endoscopic gastrostomy (B-PEG) and determine risk factors for developing stomal infections or gastropexy complications.

Methods

A retrospective study of 679 children who underwent a B-PEG procedure in a single tertiary care center over a 10-year period to December 2020 was conducted. Patient characteristics, early complications (occurring £7 days after the procedure), late complications (>7 days after the procedure), and outcomes were collected from medical records. A list of potential risk factors, including age at procedure, prematurity, underlying neurological disease, and undernutrition, was determined a priori.

Results

At least 1 year of follow-up was available for 513 patients. Median follow-up duration was 2.8 years (interquartile range 1.0–4.9 years). Major complications were rare (<2%), and no death was related to B-PEG. Early complications affected 15.9% of the study population, and 78.0% of children presented late complications. Development of granulation tissue was the most common complication followed in frequency by tube dislodgment and T-fastener complications. Only 24 patients (3.5%) presented stomal infections. Young age at the time of PEG placement (odds ratio (OR) 2.34 [1.03–5.30], p = .042) and prematurity (OR 2.54 [1.10 – 5.83], p = 0.029) were risks factor for developing peristomal infection. T-fastener migration occurred in 17.3% of children, and we found underlying neurological disease was a protective factor (OR 0.59 [0.37–0.92], p = .019).

Conclusions

B-PEG is a safe method and associated with a low rate of local infection. However, T-fasteners are associated with significant morbidity and require particular attention in young and premature infants.