The authors retrospectively studied a cohort of children (n=782) with eosinophilic gastrointestinal disorders (EGID) including 592 with isolated eosinophilic esophagitis (EoE), 190 with EGID which included esophageal involvement (“EI”) and 35 EGD without esophageal involvement (“Non-EI”).
Key findings:
Abdominal pain was more frequent in EI than isolated EoE: 61% vs 45%, p=.002)
EI patients had more dense esophageal eosinophil infiltrate (peak) than isolated EoE: 115 vs 92; P=.036) and higher peripheral blood eosinophil level (0.44 vs 0.38; p=0.027)
94-Gene expression profiles from esophageal biopsies from a 168 subgroup showed that EoE and EI were not significantly different. The heat map for upregulated and downregulated gene expression was different based on disease activity but not significantly different between EoE or EI in either state.
My take (borrowed from authors): The similar molecular transcriptome between EI and EoE are indicative of a shared pathogenesis.
Part A -In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age (n=102) with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups)
Part B- At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks
Key findings:
In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group
The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo
The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A
Similar adverse effects were noted across all groups. There was an increased rate (at least 10%) of COVID infections in participants receiving dupilumab whereas the incidence of vomiting was at least 10 percentage points lower among patients who received dupilumab (either group) than among those who received placebo
My take: Dupilumab is an effective option for eosinophilic esophagitis.
In this 10-year retrospective review (2013-2023), the authors reviewed children with EoE referred for high-resolution impedance manometry (HRIM) due to persistent dysphagia despite histologic healing (i.e., <15 Eos/hpf).
Key findings:
Among a cohort of ~1500 children, only 4 patients met inclusion criteria: histologic remission (<15 eos/hpf) and absence of fibrostenotic features on endoscopic evaluation
Thus, the estimated prevalence of post-remission dysphagia in this cohort was exceedingly rare (<0.05%).
On HRIM, all four patients had a hypomotile esophagus and abnormal bolus clearance. Lower esophageal sphincter integrated relaxation pressure values were normal in three patients and elevated in one. Two patients were diagnosed with ineffective esophageal motility, one with aperistalsis and one with achalasia type 1.
Manometry findings from 12 yo diagnosed with Achalasia Type 1
Discussion:
“Endoscopic evaluation of fibrosis is somewhat limited as less than 50% of biopsies contain an adequate sample of the lamina propria for evaluation..[Also, these] patients did not undergo endoluminal functional lumen imaging (Endoflip) which has been recently shown to correlate with fibrotic changes of the esophagus in pediatric patients…Nonetheless, this case series highlights the fact that esophageal dysmotility can persist, even in the absence of endoscopic or histologic findings”
The authors “did not study all EoE patients treated in our facility who had persistent dysphagia despite histologic remission of EoE, but rather explored just those who were referred for manometry. This methodology creates a risk of referral bias.”
My take: Though there is a referral bias due to the methodology, this study suggests that persistent dysphagia is rare in children who achieve EoE histologic remission. In addition, in those with significant dysphagia despite improvement in EoE, manometry is worthwhile.
This study of 171 adult patients (mean age 38 years) who had FLIP at time of an EGD determined the degree of esophageal distensibility and its association with eosinophilic esophagitis disease duration.
Key findings:
The median symptom duration was 8 (interquartile range, 3–15) years and diagnostic delay was 4 (interquartile range, 1–12) years
Symptom duration and diagnostic delay were negatively correlated with distensibility plateau (DP) (rho = –0.326 and –0.309; P values < .001)
Abnormal esophageal distensibility (DP ≤17 mm) was more prevalent with increased duration of symptoms (P < .004): 23% at <5 years to 64% at ≥25 years
Patients with ≥15 eos/hpf had significantly lower DP with greater symptom duration (P = .004), while there was not a significant difference among patients with <15 eos/hpf (P = .060).
My take: Longer duration of disease increases the risk of esophageal fibrosis and lack of distensibility. We need better tools to predict who is at most risk for developing fibrosis.
This was a retrospective analysis on a prospectively enrolled cohort of children at a single center who were treated as part of routine clinical care. I-SEE was calculated at the diagnostic and follow-up endoscopies over a mean of 6.6 years.
Key findings:
Of 67 children who met study criteria of at least 3 endoscopies over at least 2 years of follow-up time, 43%, 36%, and 21% had mild, moderate, and severe I-SEE scores at baseline, respectively.
By the last instance, the overall I-SEE score dropped to 3.9 (P < .001). Body mass index <5% and poor feeding were more common in the children with severe I-SEE scores at baseline, and both improved by the last instance.
The discussion notes that I-SEE metric was developed to determine EoE severity and for tracking purposes to gauge effectiveness of therapy. They note that most patients improved but a score of 0, indicating deep remission, was difficult to achieve at the population level. They also anticipate further modifications to I-SEE “such as age or an assessment of symptoms that reflects inflammatory or fibrotic disease.”
My take: I-SEE provides a way to objectively assess and follow EoE severity at all ages.
The summary with nine “best practice advice” statements is not very helpful. However, Figure 2 and Table 1 are very useful.
From Figure 2 -not shown below (but in article) are Prague classification for Barrett’s and EREFS for eosinophilic esophagitis. The remaining parts of this figure include the Los Angeles classification for erosive esophagitis, the Hill classification of the gastroesophageal flap, and the Forrest classification of peptic ulcers:
From Table 1:
Table 1 also gives guidance for biopsies with peptic ulcer disease, Barrett’s esophagus, gastric preneoplasia, and for gastric polyps.
My take: When suspicious of underlying disease, this article recommends taking more biopsies and in more jars.
Best Approach for Identifying Eosinophilic Esophagitis Prior studies have shown higher yield when taking 5 or 6 biopsies rather than fewer biopsies; thus, the location of biopsies may not be as important as the number of specimens. Also, prior studies have shown that having another pathologist review the slides can increase the yield by ~20%; this indicates that careful review of specimens by itself is helpful. Perhaps, more specimen containers will increase the time that a pathologist reviews the biopsies.
Rationale for the retrospective study: ” Although it is the first Food and Drug Administration–approved treatment for EoE, eligibility criteria for the clinical trial program excluded several characteristics of the most severe EoE patients seen in clinical practice…Therefore, the purpose of this study was to determine the real-world efficacy of dupilumab in patients with severe, treatment-refractory, and fibrostenotic EoE.”
This cohort of 46 patients with severe disease including 39 (85%) who had prior esophageal dilatation (mean of 9). Patients had a mean age of 39 and had had symptoms for a mean of 13 years. Patients were considered treatment-refractory as all had received PPIs and topical steroids; in addition, most (87%) had tried elimination diets.
Key findings:
The peak eosinophil counts decreased markedly, and postdupilumab histologic response rates were 80% and 57% for fewer than 15 eosinophils per high-power field and 6 or fewer eosinophils per high-power field, respectively. Mean eosinophil count dropped from 70 to 9 following dupilumab treatment.
The Endoscopic Reference Score (EREFS) decreased from 4.62 to 1.89 with improvement in all categories: exudates, rings, edema, furrows and strictures.
Global symptom improvement was reported in 91% (P < .001).
My take: Many clinical studies are not representative of typical patients with various ailments, often excluding those with the most severe manifestations. This study indicates that dupilumab is an effective agent for patients with severe fibrostenotic eosinophilic esophagitis.
We recently had Glenn Furuta, MD give our group a terrific lecture on eosinophilic esophagitis (EoE).
Some of the key points:
The burden of EoE continues to increase.
There are clearly several phenotypes of EoE. Some patients may never develop stricturing/fibrostenotic disease but natural history data continues to evolve.
After treatment response, many patients can continue with symptoms. In adults and adolescents, this has been termed ‘esophageal hypervigilance.’ Feeding therapy may be helpful in this circumstance.
Adrenal insufficiency: Currently their group tries to screen for this after 4 months of topical corticosteroids and then yearly. It is unusual for them identify adrenal insufficiency if the patient is receiving only a single steroid agent; patients receiving steroids for other conditions like asthma are at higher risk.
An esophagram with a barium coated pill can be a useful adjunct to determine if there is esophageal narrowing (this can be missed on endoscopy).
For select patients, endoFLIP can characterize distensibility/esophageal function
Esophageal strictures: Their group uses Bougie dilators and has had a good experience. No perforations. ~15% with chest pain afterwards.
Corticosteroids (topical) can reduce the risk of food impactions in adults.
Reviewed use of Dupilimab and its recent approval in EoE for children as young as 1 yr of age (>15 kg)
“Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced that the U.S. Food and Drug Administration (FDA) has approved Dupixent® (dupilumab) for the treatment of pediatric patients aged 1 to 11 years, weighing at least 15 kg, with eosinophilic esophagitis (EoE).”
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
This research utilized 40 studies which met the eligibility criteria, including over 288 million participants and 147,668 patients with EoE from 15 countries across the five continents.
Key findings:
The global pooled incidence and prevalence of EoE were 5.31 cases per 100,000 inhabitant-years and 40.04 cases per 100,000 inhabitant-years, respectively.
The pooled prevalence and incidence of EoE were higher in high-income countries, males, and North America.
The pooled prevalence and incidence of EoE have increased from 1976 to 2022.
Time trends of incidence (A) and prevalence (B) of EoE, 1976 to 2022. Pooled estimates, cases per 100,000 inhabitant-years.
“This review summarizes the data leading to FDA approval for dupilumab and provides a practical approach for clinical use of dupilumab.” Dupilumab, a humanized monoclonal antibody that blocks interleukin (IL)-4 receptor alpha, is currently the only FDA-approved medication for EoE. It is noted that in the trials leading to FDA approval, all patients were PPI refractory and ~70% had received topical steroids (with about half either intolerant or nonresponsive).
Dosing: 300 mg weekly injection with a single-dose prefilled autoinjector pen or a syringe with a needle shield. It is recommended that refrigerated medicine is brought to room temperature for at least 45 minutes prior to injection. It “can remain unrefrigerated up to 14 days.”
In Figure 1, the articles details positioning of use of dupilumab in EoE management algorithm:
New diagnosis, patient preference
Additional atopic condition with approved dupilumab use (strong indication)
Lack of response to current treatment (diet, PPI, swallowed steroids) or adverse effects from current treatment (strong indications)
“It is reasonable to repeat endoscopy with biopsy 24 weeks after initiation of dupilumab in many patients…However, endoscopy may be completer earlier” in selected patients.
At least 5 other biologics are in phase 2 or phase 3 studies (listed in Table 1).
My take: EoE is increasing in prevalence and new therapies (often expensive) are emerging.
Also, there is a fairly good patient education 7-page pamphlet from the makers of Dupixent encouraging patients with symptoms suggestive of EoE to speak with their physicians.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
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