esosinophilic esophagitis,clinical features,managmentpptx

esosinophilic esophagitis,clinical features,managment,diet elimination therapy,dupulimab

1. Eosinophilic esophagitis Dr. vijay k.c. Dm resident D ate: 2024 feb 16

2. Introduction EoE represents a chronic, antigen-driven, immune-mediated mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil- predominant inflammation. EoE in children is most often present in association with other manifestations of atopic diathesis (food allergy, asthma, eczema, chronic rhinitis, and environmental allergies) that also follows chronologic order . Spectrums: eosinophilic esophagitis (EoE) eosinophilic gastritis (EG) eosinophilic enteritis eosinophilic colitis (EC). Eosinophilic gastroenteritis : ≥1 segment of the GI tract is involved

3. 2013 ACG Guidelines definition D efine eosinophilic esophagitis as the following   : The presence of symptoms related to esophageal dysfunction such as dysphagia, food impaction, chest pain, etc Esophageal mucosa with eosinophil-predominant inflammation, up to 15 eosinophils per HPF. Mucosal eosinophils limited to the esophagus and persist after a trial of PPIs Exclusion of secondary causes of esophageal eosinophilia

4. epidemiology Common among both pediatric and adult patients A nnual EoE incidence rates :0.1-1.2 per 10,000 in several studies. EoE representing the second most common cause of chronic esophagitis. Common in male(M/F = 3:1) patients with evidence of atopy The first case of EoE was reported in 1977 in an adult patient , recognized in1990, as a distinct clinical entity. In 1993, Attwood et al reported first case series of eosinophilic esophagitis in 12 adult patients and suggested that this is an entity distinct from GERD. Increase prevalence in celiac disease and inverse relationship with H pylori prevalence.

5. EoE Subtypes EoEe1  – A mild subtype with normal-appearing esophagus, and mild histological, endoscopic, and molecular changes. EoEe2  – An inflammatory endotype with highest expression of inflammatory cytokines and steroid-responding genes and a steroid refractory phenotype. EoEe3  – A fibrostenotic endotype associated with a narrow-caliber esophagus, and characterized by the highest degree of endoscopic and histological severity and the lowest expression of epithelial differentiation genes.

6. GASTROINTESTINAL EOSINOPHILS IN HEALTHY STATES

7. Eosinophilic Esophagitis P rimary subtype is referred to as EoE and includes the atopic, nonatopic, and syndromic disorders, a/w inherited CTD such as hypermobility syndrome,and familial EoE variants. M endelian diseases associated with EoE: ERBIN deficiency, Netherton syndrome, PTEN hamartoma tumor syndrome, and severe atopy syndrome associated with metabolic wasting syndrome S econdary subtype : systemic eosinophilic disorders (i.e., HES) and noneosinophilic disorders. diagnosis of EoE originally required the presence of esophageal eosinophilia that was resistant PPI therapy. EoE can respond to PPI therapy, referred as PPI-responsive esophageal eosinophilia (PPI-REE) 

8. Etiology E tiology of EoE is poorly understood, but food allergy has been implicated as a primary contributor. positive skin tests and allergen-specific IgE are markers of the involved immunologic response T cells and mast cells are elevated in esophageal biopsies, s/o chronic Th2-associated inflammation. ↑TGF- β, produced by eosinophils & mast cells, contribute to tissue remodeling and smooth muscle dysfunction. E picutaneous antigen exposure primes the esophagus for marked eosinophilic inflammation . Dysregulated gene expression: eotaxin-3 , TSLP gene , CAPN14 gene C ommon food triggers in adult cohort: wheat (60%), milk (50%), soy (10%), nuts (10%), & eggs (5%). pediatric cohort, common triggers were milk (35%), eggs (13%), wheat (12%), and soy (9%)

9. Role of host immune system P ure immunoglobulin E ( IgE ) mediated and delayed T helper type 2 (Th2) responses. M ixed IgE and non- IgE –mediated allergic response to food and environmental allergens C ontributory roles for allergens, cytokines, microRNAs (miRNAs), chemokines, and polarization of Th2 immunity The role of type 2 immunity is underscored by FDA approval of  dupilumab

10. Genetics   Noel et al have proposed genetic predisposition as evidence of familial clustering and twin studies. G enetic defects at 2p23, encoding for the esophagus specific gene product, calpain 14.

11. pathogenesis Antigen(food/inhaled proteins)-driven Th2 cells also produce IL-5 and IL-13. IL-13 subsequently triggers resident cells in esophagus to produce a large set of proteins. I nduced gene eotaxin 3, recruits eosinophils from the peripheral blood into the tissue. IL-5 is a chief eosinophil growth and activation factor that primes eosinophils to have enhanced responsiveness to eotaxin 3 and prolongs their cellular survival. Th2 cytokine interleukin 13 (IL-13) to lungs induces eosinophilic esophagitis by inducing IL-5, eotaxin-1, through signal transducer and activation of a transcription (STAT)–6 dependent mechanism IL-13 induces key mediators of EoE including eotaxin 3 and calpain 14 ( CAPN14 )

12. Path ogenesis and therapeutic targets for EoE

13. pathogenesis IL-13 also decreases the expression of genes that encode proteins involved in barrier function such as filaggrin and components of esophageal desmosomes, such as desmoglein 1. D esmosome genes : periplakin and desmoplakin , are also associated with EoE Eosinophils play an integral role in remodeling of esophageal tissues, as as subepithelial fibrosis. Eosinophils cause fibrosis through degranulation and secretion of their granule cationic proteins, particularly major basic protein (MBP) and eosinophil peroxidase (EPO) and elaboration of fibrogenic growth factors such as TGF- β, PDGF-BB, and IL-1 β. 

14. Clinical Features Infants and toddlers often present with feeding difficulties school-aged children are more likely to present with vomiting or pain. Dysphagia is a predominant symptom in adolescents. Solid-food dysphagia continues to be the most common presenting symptom. Food impaction necessitating endoscopic bolus removal occurs in 33% to 54% of adults with EoE.

15. Clinical Features Vomiting as the most common presenting symptom in children and adolescents (61%) Dysphagia (39%) Abdominal pain (34%) Feeding disorders (14% H eartburn (14%) Food impaction (7%) Vague chest pain (5%) Diarrhea (5%) Journal of Gastroenterology  2013 January

16. Diagnosis Complete blood count and differential Total IgE Erythrocyte sedimentation rate and C-reactive protein (normal in EGIDs) Skin prick testing and tests for specific IgE (as part of comprehesive allergy workup) Infection workup (stool and colonic aspirate analysis) Upper and lower gastrointestinal endoscopy with biopsies pH probe impedance study EndoFLIP (compliance measure in esophagus) EoE diagnostic panel In the presence of hypereosinophilia Chromosomal and cytogenetic screen

17. Diagnosis All clinical and pathologic information needed Pediatric and adult patient populations, typically in male patients with evidence of atopy The diagnostic criteria for eoe in 2011 emphasized that eoe requires finding 15 or more eosinophils/HPF (peak value) in the esophagus. In 2017,ppi-responsiveness is not considered in the diagnosis of eoe ,. 15 eosinophils/ hpf (peak value) is considered a minimum threshold for a diagnosis of eoe . Mild peripheral eosinophilia in 5%-50% of children and adults.   Elevated total ige levels are seen in about 70% of patients. Esophagogastroduodenoscopy with biopsy confirms the diagnosis. Fluoroscopic studies may help in the setting of subtle findings and for evaluation of fibrotic remodeling changes.  

18. endoscopy Fixed esophageal rings/ trachealization ( a.K.A. Fibrostenotic complications) Transient esophageal rings Whitish exudates Longitudinal furrows (showing furrowing and exudates) Edema Diffuse esophageal narrowing Narrow-caliber esophagus Esophageal lacerations induced by passage of the endoscope Severe mucosal fragility gives the esophagus the appearance of crepe paper.

19. endoscopy In 2006, a multidisciplinary group at First International Gastrointestinal Eosinophil Research Symposium (FIGERS) proposed a histologic criterion of at least 15 eosinophils . 2017 a newly developed histologic scoring system (HSS) for EoE was validated. In addition to identifying 15 or more eosinophils/HPF, 8 other histologic feature. Severity and extent are scored using a 4-point scale, with 0 being normal and 3 denoting maximum change. The 8 HSS features: eosinophil density basal zone hyperplasia eosinophil abscesses eosinophil surface layering dilated intercellular spaces, surface epithelial alteration dyskeratotic epithelial cells amina propria fibrosis.

20. How many biopsies? Multiple biopsies may be necessary Adults: Sensitivity of 55% with one biopsy → 100% with 5 biosies Children: Sensitivity of 73% with one biopsy →84%, 97%, and 100% with 2, 3, and 6, respectively. A minimum of six biopsies( 3/3from proximal & distal) obtained from different anatomic sites within the esophagus is recommended for the diagnosis and monitoring of eosinophilic esophagitis.  Am j Gastroenterol. 2009 mar;104(3):716-21

21. Immunohistochemistry R ecommended diagnostic histologic criterion of at least 15 eosinophils/ hpf is based on hematoxylin and eosin–stained sections. T he use of MBP immunostaining (using monoclonal antibody against MBP) for detection of eosinophils has been shown to increase the yield of detection of eosinophils twofold. MBP expression in extracellular areas is thought to reflect foci of eosinophil degranulation. I ncrease in CD3 and CD8 T lymphocytes in the esophageal mucosa.

22. Barium Esophagram Radiographic examinations can provide valuable information on the fibrostenotic features of EoE, which may be missed on endoscopy. . Barium esophagrams , in particular, can help to visualize strictures as well as narrow-caliber esophagus

23. Molecular/Genetics Evolving concept. Eotaxin 3 causes tissue eosinophilia. Desmoglein 1 is an intracellular adhesion molecule, which is downregulated in eosinophilic esophagitis. Interleukin 13 upregulation leads to increased expression of periostin in esophageal fibroblasts. 

24. endoluminal functional lumen imaging probe ( EndoFLIP ) Offers a unique evaluation of esophageal function as it relates to EoE. This tool utilizes impedance planimetry to determine esophageal distensibility, defined by esophageal cross-sectional area as a function of intraluminal pressure during volumetric distension Esophageal distensibility has been shown to be significantly lower in patients with EoE than in controls Esophageal distensibility can also be used as a quantitative biomarker of disease severity. E sophageal distensibility was reduced in patients with food impactions Utilization of impedance planimetry may provide guidance for management of patients and clinical trials by serving as a quantitative marker of disease severity and risk of future complications

25. Novel Activity Measures Novel tools now exist to assess inflammatory activity and to decrease the burden associated with repeated and invasive endoscopic evaluation with biopsies Esophageal String Test: a small, swallowed capsule which deploys a string into the esophagus and can collect secretions containing quantifiable eosinophil-derived proteins . The Cytosponge : an ingestible capsule but contains a compressed mesh which expands when swallowed and then is withdrawn, thereby capturing fragments of esophageal epithelium

26. Future diagnostic options? Food-specific IgG4 Novel allergen-specific signature testing Uses lymphocyte proliferation assays, esophageal IgG4 levels Accuracy rates 53-75% Pilot testing: only 2-3 triggers needed to be eliminated, but histologic response rate only 25% Esophageal prick test Allergen extracts endoscopically injected into esophageal mucosa Acute and delayed responses seen in EoE pts, not controls

27. Differentials Gastroesophageal reflux disease (GERD) Achalasia and other disorders of esophageal dysmotility Infectious esophagitis (Herpes, Candida ) Parasitic infection Drug-induced esophagitis Autoimmune disease (vascular and connective tissue diseases) Eosinophilic gastroenteritis with involvement of the esophagus Hypereosinophilic syndrome with involvement of the esophagus Crohn disease with involvement of the esophagus

28. e0E vs GERD GERD may be a mimic of EoE, coexist with it, or contribute to it . Up to 7 eosinophils/HPF (400×) is most indicative of GERD, 7 to 15 eosinophils/HPF likely represents a combination of GERD and food allergy, and at least 15 eosinophils/HPF is characteristic of EoE. The anatomic location of eosinophils to both the proximal and distal esophagus denotes EoE Accumulation of eosinophils mainly in the distal esophagus is characteristic of GERD. Some studies have also identified that mast cells are increased in biopsy specimens from patients with EoE compared with those from patients with GERD. IgE -bearing cells are more common in biopsy specimens from patients with EoE compared with those from patients with GERD

29. Journal of Gastroenterology 2018;1–12

30. Allergy testing in eosinophilic esophagitis Several lines of evidence suggest that allergies play a significant role in EoE. An immune response to allergen/antigen is a primary factor in the pathogenesis of the disease, and there is evidence that both environmental allergies and food allergies are involved. In addition, the majority of patients with EoE are atopic, with concomitant asthma, allergic rhinitis, atopic dermatitis, and/or immunoglobulin E ( IgE ) mediated food allergy.

31. Allergy testing in eosinophilic esophagitis Mechanistic studies: examination of esophageal samples shows that classic allergic T2 cytokines and chemokines (IL4, IL-5, IL-13, eotaxin 3) Clinical response to dietary changes  : resolution of symptoms and normalization of esophageal biopsies. Association with environmental allergies: swallowed /inhaled allergens in the esophagus and/or through postnasal drainage from allergic rhinitis triggering symptomatic and histologic changes Atopic history: Multiple studies have found that 30-50 % of pediatric patients with EoE have clinician-diagnosed asthma, up to 20 % have atopic dermatitis, 50 to 75 % have allergic rhinitis, and 60 %have urticarial reactions or anaphylaxis to foods Adults population have 30 to 50 % having asthma, 50 to 75 % having allergic rhinitis, approximately 51 % having food pollen allergy syndrome, and 5-10 % having atopic dermatitis

32. FOOD ALLERGY TESTING IN EoE Identify patients who are also at risk for acute allergic reactions to foods ( eg , urticaria, anaphylaxis) when the foods are reintroduced after an empiric elimination diet. value of food allergy testing in EoE appears to decline with increasing age Skin prick testing   Specific IgE testing: Another small study found that patients with EoE and very low milk IgE (0.10 to 1.00 int. unit/mL) were more likely to respond to milk elimination than those with negative milk IgE (<0.10 int. unit/mL) or higher milk IgE (>1.00 int. unit/mL) Specific IgG4 testing Atopy patch testing

33. To address comorbid asthma and allergic rhinitis To identify potential aeroallergen triggers of EoE ( ie , seasonal exacerbations) To consider timing of diagnostic biopsies in relation to pollen seasons. Standard allergy testing is indicated in all patients that have signs and/or symptoms of allergic rhinitis. ENVIRONMENTAL ALLERGY TESTING IN EoE

34. Choosing Initial Therapy for Eosinophilic Esophagitis Patient preferences, disease severity, availability of resources for elimination diet therapy, and practicalities of insurance coverage for off-label use of medications . Patients who do not want to swallow topical corticosteroids each day, who are concerned about adverse effects of PPIs, W ho are inclined to use alternative medical approaches, might be motivated to try an elimination diet Patients with severe esophageal strictures <10 mm would benefit from initial esophageal dilation combined with medical or dietary therapy. Diet therapy can be selected based on practice patterns

35. Treatment F irst-line treatments : dietary therapy, topical glucocorticoids, and a PPI S pecific food allergen and aeroallergen avoidance in atopic EoE A voidance of the most common allergenic foods (cow milk, soy, wheat, egg, peanut/tree nuts, and seafood/shellfish), termed the 6-food elimination diet (SFED) E mpiric SFED is an effective therapy in adult EoE Goals of management: minimize symptoms and endoscopic histopathologic features of EoE

36. DIETARY THERAPY Empiric elimination diet   Testing-directed elimination diet Elemental diet  

37. Empiric elimination diet M ost commonly used dietary therapy for EoE E mpiric avoidance of those foods that most commonly cause immediate hypersensitivity  C ow's milk elimination only : most common initial empiric elimination approach S ix-food elimination diet [6FED]) that account for the majority of IgE -mediated food reactions ( ie , cow's milk, hen's egg, soy, wheat, peanuts/tree nuts, fish/shellfish) F our-food group elimination (4FED; cow's milk, hen's egg, soy +/- other legumes, and wheat).  E fficacy of cow's milk elimination alone is close to that of 4FED and is easier to follow. R esponse rate to the empiric SFED is similar to the response rate to skin test directed diet therapy (74% to 81% response rate). Less-restrictive diets like the 2-food elimination diet (dairy and gluten) and 4-food elimination diet (dairy, gluten, egg, and legumes) have been used with decent efficacy rates of 43% and 54%, respectively, in the pediatric population. 1-food elimination diet (OFED),cows milk, may have a role in the treatment of EoE . R esults of OFED have shown clinical and histologic remission in 65% of pediatric patients.

38. Testing-directed elimination diet   AKA directed elimination diet or testing-based elimination diet. It has become an increasingly uncommon approach due to limited utility, labor intensity, and greater success of empiric elimination diets. Skin prick testing (SPT), which examines immediate hypersensitivity to food antigens, A topy patch testing (APT), which attempts to elucidate delayed-type, cell-mediated reactions to foods . This approach met with some success in children but mixed results in adults Testing-directed elimination diet: comparable with that of empiric elimination diets; approx. 50-60 % of patients respond to this treatment M eta-analysis of 11 observational studies involving 830 patients Pooled failure rates (defined as not achieving histologic remission by six weeks) were lower in these studies compared with a contemporary control group (50 versus 88 percent; RR 0.52, 95% CI 0.37-0.74).

39. Elemental diet An amino acid-based (elemental) formula ,which eliminates all potential food allergens. M ost effective approach but is challenging to follow, particularly for adults, used rarely. These diets are used both as therapy and as a diagnostic tool to identify specific food triggers.  I nitial diet is typically followed for 4-8 weeks. Symptoms are assessed, and a repeat upper endoscopy with esophageal biopsies is performed at the end of the initial avoidance period.

40. Implicated foods Both empiric and directed methods for antigen elimination show that cow's milk is the most common food trigger for EoE. S tudy of 78 children with EoE who underwent empiric 4FED and single-food antigen reintroduction, histologic inflammation was triggered by cow's milk in 85 percent, hen's egg in 35 percent, wheat in 33 percent, and soy in 19 percent.

41. Most common causative foods in eosinophilic esophagitis

42. Efficacy of different dietary approaches   Empiric elimination diet  – Based upon observational data, empiric elimination diets appear to be more effective in achieving histologic remission compared with no treatment. Approx. 40 - 70 % of patients with EoE respond to empiric elimination diets For 6FED, the failure rate was 33 % vs 88 % in the control group (relative risk [RR] 0.38, 95% CI 0.32-0.43; nine studies, 633 participants). For 4FED, the failure rate was 43 % vs 88 % in the control group (RR 0.49, 95% CI 0.42-0.57; three studies, 426 participants). For two-food elimination diet (2FED), the failure rate was 58% vs 88 % in the control group (RR 0.66, 95% CI 0.57-0.77; two studies, 311 participants). For 1FED, the failure rate was 46 % vs 88 % in the control group (RR 0.52, 95% CI 0.37-0.74; two studies, 203 participants). Based upon limited clinical trial data, 1FED appears to have similar efficacy when compared with 4FED or 6FED, and it is easier to follow 

43. Instituting an elimination diet   An approach that involves allergy/immunology, gastroenterology, and a dietitian. D ifficult in the private practice or community health care setting. Growth should be monitored, and supplements may be necessary depending upon the foods avoided

44. Reintroduction of foods If symptoms and histology have improved, foods are then reintroduced one at a time. If symptoms and histology have not improved after the initial dietary eliminations, pharmacologic therapy may be started, or a more stringent elimination or elemental diet (if not the initial approach) may be undertaken. Reintroduction of the next food after symptoms have subsided (approx. 2-4weeks) R eintroduced food/food group in normal amounts for 8 to 12 weeks and then repeat the endoscopy if they are asymptomatic or if symptoms are still significantly decreased from baseline. If the patient's endoscopy is normal, we then reintroduce another food and repeat the process. R ecurrence of esophageal eosinophilia can occur within a relatively rapid timeframe of 3-7days after food reintroduction.

45. PHARMACOLOGIC THERAPY Acid suppression Topical glucocorticoids S ystemic glucocorticoids   Dupilumab ( IL-4 and IL-13 inhibitor)

46. EXPERIMENTAL TREATMENTS Biologic agents Monoclonal antibody against IL-13 Mepolizumab:  humanized monoclonal antibody against interleukin (IL)-5 Reslizumab : an IL-5 neutralizing antibody omalizumab, infliximab and vedolizumab Prostaglandin D2 receptor antagonist Montelukast : leukotriene inhibitor Purine analogues: : azathioprine  or  6-mercaptopurine

47. Acid suppression: PPI therapy first line treatment options, together with dietary modification and topical glucocorticoids. E stablish histologic remission & symptom amelioration in 50% and 60% of EoE pts, respectively 2017 European guidelines use high-dose PPI for 8 weeks as a first line in the treatment For patients treated with a PPI, initial treatment OD dose for 8 weeks. I f symptoms fail to improve after 4 weeks of therapy, we increase the dose to twice daily. P erform upper endoscopy 8 weeks after initiating therapy to assess for endoscopic and histologic improvement .

48. Acid suppression: PPI therapy In a meta-analysis of 33 studies that included 619 patients with symptomatic esophageal eosinophilia, PPI therapy was associated with pooled clinical response and histologic remission rates of 61 and 51 % , respectively Similar findings were observed in a subsequent multicenter observational study including 630 patients with EoE ; PPI therapy was associated with clinical response and histologic remission rates of 71 and 49 %, respectively.  Clin Gastroenterol Hepatol. 2016;14(1):13. Epub 2015 Aug 3. Aliment Pharmacol Ther . 2020;52(5):798. Epub 2020 Jul 17.

49. Topical glucocorticoids   Most patients respond to topical glucocorticoids, as demonstrated by ↓eosinophil counts  European Medicines Agency (EMA) and Health Canada approved  budesonide  in an orodispersible tablet formulation for adults with EoE . T opical glucocorticoids: Fluticasone, budesonide , Ciclesonide , Mometasone  furoate In a meta-analysis of six trials comparing topical glucocorticoids with placebo in 583 adult and pediatric patients with active EoE, patients who were treated with topical glucocorticoids were more likely to have symptomatic improvement after 2 to 12 weeks of therapy (risk ratio [RR] 1.74, 95% CI 1.08-2.80) Cochrane Database Syst Rev. 2023;7(7):CD004065. Epub 2023 Jul 20 .

50. Topical glucocorticoids   I n a meta-analysis of 12 trials including 978 patients with active EoE, patients who were treated with topical glucocorticoids were more likely to have histologic improvement (RR 11.94, 95% CI 6.56-21.75). In a meta-analysis of five trials including 206 children with EoE, topical glucocorticoid therapy resulted in higher rates of histologic response compared with placebo (49 vs 4 %; RR 11.05, 95% CI 3.8-32.15), while there was a nonsignificant trend toward higher rates of symptomatic response (34 versus 22 percent; RR 1.62, 95% CI 0.84-2.79) [ 25 ]. There were no major adverse effects. Pediatrics. 2020;146(5)

51. Fluticasone propionate placebo-controlled, double-blind clinical trial for EoE, swallowed topical fluticasone was found to be effective in inducing disease remission, including reductions in eosinophil, mast cell, and CD8 T cell levels, as well as the degree of epithelial hyperplasia Viscous O ral budesonide and budesonide effervescent tablets; Several clinical trials ongoing A dministered using a MDI without a spacer. The medication is sprayed into the patient’s mouth and then swallowed. The largest controlled trial included 36 children who were randomly assigned to swallowed  fluticasone  (880 mcg/day in two divided doses) or placebo for three months. Histologic remission was observed significantly more often in the fluticasone group Gastroenterology. 2006;131(5):1381. Epub 2006 Aug 16 .

52. Fluticasone propionate-dose Fluticasone induction therapy is given for 4 -8weeks, followed by assessment of symptomatic response ( eg , dysphagia) . P erform upper endoscopy 8 to 12 weeks after initiating therapy to assess for endoscopic and histologic improvement R eported relapse rates of 14 to 91 percent T apering after remission after 4 to 8 weeks of  fluticasone  therapy typically includes reducing the dose by 50 percent over a period of 8 to 12 weeks For episodic or seasonal flares,  fluticasone  may be given sos during the maintenance phase (rather than as daily therapy). For patients who do not respond to  fluticasone , options include a higher dose of fluticasone, a change to oral viscous  budesonide , a trial of PPI, or a dietary approach. Children ages 1 to 11 years – 110 mcg/spray, 8 sprays daily in divided in 2-4 doses. Children ages ≥12 years and adolescents – 220 mcg/spray, 8 sprays daily in divided in 2-4 doses. Patients ≥18 years of age – 220 mcg/spray, 4 sprays daily in 2 divided doses.

53. Budesonide Budesonide  can be administered as an oral viscous slurry Dose: 1 mg daily for children under the age of 10 years, up to 2 mg BD for older children and adults. Max dose is 4 mg/day in divided dose in adult. Patients should take the budesonide slowly, over 5 to 10 minutes N ot eat or drink for 30 minutes after taking the budesonide suspension Budesonide can also be administered as an effervescent tablet; availability is limited  Budesonide induction therapy is generally given for 12 weeks, followed by assessment of symptomatic response ( eg , dysphagia) . P erform upper endoscopy 8 to 12 weeks after initiating therapy to assess for endoscopic and histologic improvement Budesonide  also appears to be comparable with  fluticasone  in treatment efficacy

54. Budesonide In a phase 3 trial including 318 adolescent and adult patients with EoE, budesonide oral suspension (2 mg twice daily) resulted in significantly higher rates of histologic remission (53 versus 1 percent; absolute risk difference [ARD] 52 percent, 95% CI 43-59 percent) and higher rates of symptomatic response (52 versus 39 percent; ARD 13 percent, 95% CI 2-24 percent) after 12 weeks compared with placebo. In another trial including 93 adolescent and adult patients with EoE and dysphagia, budesonide oral suspension 2 mg twice daily resulted in higher rates of symptomatic, endoscopic, and histologic response compared with placebo . Clin Gastroenterol Hepatol. 2022;20(3):525. Epub 2021 Apr 19 Gastroenterology. 2017;152(4):776. Epub 2016 Nov 23.

55. Topical Glucocorticoid Maintenance therapy Maintenance therapy has been associated with benefit in children with EoE. Maintenance therapy with topical glucocorticoids and/or dietary restriction should be considered Indications: Severe dysphagia or food impaction High-grade esophageal stricture Rapid symptomatic/histologic relapse following initial therapy Optimal approaches to maintenance therapy have not been well established. In a trial including 204 adults with EoE in remission, patients treated with  budesonide   orodispersible tablet (0.5 or 1 mg twice daily) had higher rates of sustained clinical and histologic remission compared with placebo after 48 weeks (74, 75, and 4 percent, respectively) Gastroenterology. 2020;159(5):1672. Epub 2020 Jul 25

56. Considerations with steroid treatment No eating/drinking for at least 30 minutes after med Rinse mouth (swish, gargle, spit) to reduce thrush risk Treatment duration: 8-12 weeks If histologic/symptomatic response Consider discontinuing steroid (high relapse rate) Consider maintenance dosing Frequent relapsers  Fibrostenotic disease

57. Topical versus systemic glucocorticoids   Systemic glucocorticoids have a limited role in EoE, except severe disease. Oral  prednisone  may be slightly more effective than topical  fluticasone  for the treatment of EoE, but moreside effects . Due to high relapse rate, chronic or repeated therapy may be needed, preferential use of swallowed fluticasone. If systemic steroids are used, the typical dose is 1 to 2 mg/kg per day in divided doses (maximum 60 mg per day). 80 children with EoE who were randomly assigned to oral  prednisone  or swallowed  fluticasone . Almost all of the patients, regardless of treatment, were symptom free by four weeks. Histologic improvement was seen to a greater degree in the prednisone group. Relapse was observed in 45 percent of patients in both groups within 24 weeks of stopping therapy. Glucocorticoid side effects occurred in 40 percent of patients in the prednisone arm, whereas esophageal candidiasis was seen in 15 percent in the fluticasone arm. Clin Gastroenterol Hepatol. 2008;6(2):165.

58. Esophageal dilation C an provide relief of dysphagia in select patients with EoE. effective strategy for management of symptoms of dysphagia resulting from strictures associated with EoE. However, in the absence of high-grade esophageal stenosis, a trial of medical or dietary therapy before dilation is reasonable U se of both through-the-scope and bougie dilators. risk of perforation is low

59. Esophageal dilation Helpful with fibrostenotic disease Does not treat underlying inflammation Provides immediate symptom improvement Dilate until resistance, blood encountered Goal diameter 15-18mm (might need multiple sessions) Can be done as monotherapy or in conjunction with other treatments Clinical improvement/ dysphagia 95% Perforation 0.38%, hospitalization 0.67% Chest pain 17%

60. patients who might respond to treatment with dilation Patients with strictures identified endoscopically with symptoms of dysphagia clearly benefit symptoms of dysphagia in the absence of endoscopically apparent stricture but evident upon radiographic imaging or impedance planimetry. Patient who deny symptoms of dysphagia because of adaptive eating behaviors and food avoidance, despite presence of high- grade esophageal strictures (<10 mm).

61. What is refractory EoE ? ongoing symptoms, abnormal endoscopic findings ( FIG. 1 ) and persistent oesophageal eosinophilia after a PPI trial and after treatment with either topical steroids or dietary elimination therapy PPIs remain within the diagnostic algorithm for EoE and are not considered as treatment modalities T here are limited studies published specifically on this topic Depending on the treatment modality, non-response to topical steroid or dietary elimination in EoE can be in the range of 20–50% Topical steroid or dietary elimination treatments should be maximized before switching between treatment modalities Second-line treatment options include systemic corticosteroids, elemental formula, leukotriene antagonists, immunomodulators and experimental agents in clinical trials

62. Potential explanations for non-response For topical corticosteroids: Non-adherence Dose too low Inappropriate administration Suboptimal formulation (low dwell time) Persistent allergen exposure Superimposed infection (for example, with  Candida  spp. or herpes simplex virus) Stricture causing persistent symptoms Incorrect diagnosis of EoE For dietary elimination: Non-adherence Inadvertent contamination Correct trigger, or triggers, not eliminated and/or persistent allergen exposure Stricture causing persistent symptoms Incorrect diagnosis of EoE

63. humanized IL-5–specific antibodies Therapy directed against the eosinophil growth factor IL-5 M epolizumab and reslizumab Mepolizumab therapy resulted in a dramatic decline in blood eosinophilia and reduced esophageal eosinophil infiltration in patients with EoE but had variable effects on symptoms

64. humanized IL-13– specific antibody T herapies to reduce eosinophil tissue accumulation in EoE could potentially target IL-13 IL-13 is a key cytokine that regulates the recruitment of eosinophils at inflammatory sites, primarily through the induction of chemokine expression lebrikuzumab

65. human antibody against the IL-4 receptor α chain -dupilumab B locks IL-13 and the related cytokine IL-4, have been shown to improve histopathology (including esophageal eosinophilia), endoscopic and clinical features of EoE LIBERTY EoE TREET multicenter trial : Dupilumab leads to Improvements in histologic, symptomatic, endoscopic, and molecular features of eosinophilic esophagitis observed after 24 weeks of weekly dupilumab treatment were maintained or continued to improve to week 52 EoE KIDS trial.  : Approval of dupilumab in children aged 1-11 years. At 16 weeks, 66% of children who received higher dose dupilumab at tiered dosing regimens based on weight (n = 32) achieved histologic disease remission (≤6 eosinophils/high power field), the primary endpoint, compared with 3% for placebo (n = 29).

66. Dupilumab for refractory eosinophilic esophagitis (February 2024) Few data are available on the use of  dupilumab  for treating refractory eosinophilic esophagitis. In a cohort study of 46 patients with refractory EoE, dupilumab therapy was associated with histologic remission (defined as <15 eosinophils/HPF) in 37 patients (80 %) and with symptomatic improvement in 42 patients (91%) after a median of 6 months These data support our approach of using dupilumab for patients who have not responded to other therapies like topical glucocorticoids.

67. DUPILIMUAB

68. NATURAL HISTORY The natural history of EoE has not been fully delineated; however, a 15-year follow-up of esophageal eosinophilia from childhood into adulthood revealed ongoing symptoms in the vast majority of patients. P rogression of fibrostenosis in the majority of patients with over a decade of untreated disease Chronic inflammation that leads over time to progressive fibrostenosis in many but not all patients This progression appears to be gradual, allowing many patients to adopt coping strategies that often limit symptom reporting. In addition, genetic factors and individual host factors contribute to variability in disease progression. Spontaneous remission does occur but appears to be uncommon.

69. Prognosis EoE requires prolonged treatment, similar to allergic asthma. Thus, it is likely that chronic EoE, if left untreated, can develop into progressive esophageal scarring and dysfunction EoE complications include food impaction, esophageal stricture, narrow-caliber esophagus, and esophageal perforation. The duration of untreated EoE is a good predictor of stricture risk. Stricture prevalence in adults with EoE ranged from 11% to 31% The risk for developing Barrett’s esophagus, especially in patients with coexisting EoE and GERD, has not been determined but does not seem to be a concern In addition, patients with EoE are at increased risk for developing other forms of EGIDs

70. T ake home message MCC of dysphagia (western countries) in young patients Typically involves cervical esophagus Present with dysphagia > odynophagia Family/ personal history of atopy Empirical PPI does not respond Endoscopy : Multiple tracheal rings (Feline esophagus, Trachealisation of esophagus) Definitive diagnosis by biopsy : > 15% eosinophils/ high power field T reatment : 4D’s Dilatation Drugs ± steroids Diet+ Life style modifications Dupilimumab

71. Eosinophilic Gastritis, Enteritis, and Gastroenteritis EG, enteritis, and gastroenteritis are clinically similar characterized by the selective infiltration of eosinophils in the stomach and/or small intestine, with variable involvement of the esophagus and/ or large intestine EGE and EC were 5.1/100,000 persons and 2.1/100,000 persons, respectively. EGE is the second most common form of EGIDs The incidence and prevalence of EG, EGE, and EC are increasing Lwin et al. has proposed that EG can be diagnosed when at least 30 eosinophils/HPF is identified in at least 5 distinct HPFs in the stomach 1 Chehade et al. proposed at least 70 eosinophils/HPF in at 3 HPFs Secondary causes gastric eosinophilic infiltration parasitic and bacterial infections (e.g., Helicobacter pylori IBD HES myeloproliferative disorders polyarteritis nodosa allergic vasculitis Scleroderma drug injury drug hypersensitivity.

72. Etiology Most patients have positive skin tests to a variety of food antigens consistent with a delayed type of food hypersensitivity syndrome In one study, 23% of patients with EGE lacked peripheral eosinophilia, but up to 50% of patients with the mucosal form had a history of food allergy or intolerance. In another study of EG, increased levels of blood eosinophils were seen in nearly 90% of patients and shown to strongly correlate with levels of gastric eosinophils mice developed eosinophil-associated GI dysfunction including gastromegaly , delayed food transit, and weight loss, all strongly dependent upon the chemokine eotaxin-1.

73. Etiology IL-9–driven mast cells in the pathogenesis of this specific cardinal feature (allergic diarrhea) of EGIDs Increased secretion of IL-4 and IL-5 by peripheral blood T cells Th2 cytokines, especially IL-13, when stimulated with milk proteins. EGE can frequently a/w protein-losing enteropathy A/w with SLE.

74. Clinical Features Constellation of symptoms that are related to the degree and area of the GI tract affected M ucosal form: vomiting, abdominal pain that can even mimic acute appendicitis, diarrhea, blood loss in the stools, iron-deficiency anemia, malabsorption, protein-losing enteropathy, and failure to thrive M uscularis form : symptoms of GI obstruction mimicking pyloric stenosis or other causes of gastric outlet obstruction. S erosal form : exudative ascites with higher peripheral eosinophil counts compared with the other forms.

75. Diagnostic Studies comprehensive history and physical examination No standards for the diagnosis of EG, enteritis, or EGE exist Evaluation for intestinal parasites by examination of stool samples, intestinal aspirates obtained during colonoscopy infection with Strongyloides stercoralis should be ruled out as this infection can become life-threatening in the setting of systemic immunosuppression total IgE levels ↑atopic variants of EGIDs skin prick testing to a panel of food allergens and aeroallergens helps to identify sensitizations to specific allergens.

76. Diagnostic Studies presence of elevated eosinophils in biopsy specimens from the GI tract wall I nfiltration of eosinophils within intestinal crypts and gastric glands; the lack of involvement of other organs E xclusion of other causes of eosinophilia (e.g., infections, IBD). Patients with EG can have micronodules (and/or polyposis) noted on endoscopy, and these lesions often contain marked aggregates of lymphocytes and eosinophils.

77. Pediatr Integral 2023; XXVII (2): 106 – 113

78. Treatment Eliminating the dietary intake of the foods implicated by skin prick tests complete resolution is generally achieved with amino acid–based elemental diets Once disease remission has been obtained by dietary modification, the specific food groups are slowly reintroduced (at ∼3-week intervals for each food group), and endoscopy is performed every 3 months to identify either sustained remission or disease flare-up. eosinophil-depleting antibody (anti–IL-5 receptor α) benralizumab Drugs: cromoglycate, montelukast, ketotifen, suplatast tosilate , mycophenolate mofetil, and “alternative Chinese medicines”.

79. Treatment successful long-term remission of EGE following montelukast treatment has been reported trial of food elimination if sensitization to food is found by skin prick tests and/or measurement of specific IgE levels. systemic and topical glucocorticoids, nonglucocorticoid anti-inflammatory therapy Anti-inflammatory drugs (systemic or topical glucocorticoids) are the main therapy if diet restriction is not feasible or has failed to improve the disease. For systemic steroid therapy, a course of 2 to 6 weeks of therapy better than a 7-day course of burst glucocorticoids. A ntimetabolite therapy: azathioprine or 6-mercaptopurine . even if GERD is not present, neutralization of gastric acidity with PPI

80. Prognosis diseases wax and wane chronically. the disease presents in infancy and specific food sensitization can be identified, there is a high likelihood of disease remission by late childhood

81. Eosinophilic Colitis bimodal age distribution, with the infantile @ approx 60 days On endoscopic examination, patchy erythema, loss of vascularity, and lymphonodular hyperplasia are mostly localized to the rectum but may extend to the entire colon Histologic examination often reveals that the overall architecture of the mucosa is well preserved; however, there are focal aggregates of eosinophils in the lamina propria, crypt epithelium, and muscularis mucosa occasionally, the presence of multinucleated giant cells in the submucosa peripheral blood eosinophilia or eosinophils in the stool are suggestive of EC.

82. Etiology EC is usually a non- IgE -associated disease. Some studies point to a T lymphocyte–mediated process exact immunologic mechanisms responsible for this condition have not been identified. colonic T cells have been shown to transfer the disease to naive mice by a STAT-6– depen - dent mechanism. Cow’s milk and soy proteins are the foods most frequently implicated in allergic colitis of infancy, but other food proteins can also provoke the disease. EC is considered more aligned with autoimmune processes including IBD

83. Clinical Features and Diagnostic Studies A variety of symptoms associated with EC are noted depending upon the degree and location of tissue involvement. Classic symptom: diarrhea is a classic symptom abdominal pain weight loss anorexia.

84. Treatment EC of infancy is generally a benign disease. Upon withdrawal of the offending protein trigger in the diet, the gross blood in the stools usually resolves within 72 hours Anti-inflammatory drugs including 5-aminosalicylates and systemic or topical glucocorticoids are commonly used I mmunosuppressive antimetabolite therapy: azathioprine or 6-mercaptopurin

85. Prognosis When EC presents in the first year of life / upto to 3 years of age. The prognosis for EC that develops later in life is more guarded than the infantile subtype. Chronic waxing and waning disorder. routine clinical surveillance of the cardiopulmonary systems is important and periodic upper and lower GI endoscopy may be warranted.

86. T ake home message MCC of dysphagia (western countries) in young patients Typically involves cervical esophagus Present with dysphagia > odynophagia Family/ personal history of atopy Empirical PPI does not respond Endoscopy : Multiple tracheal rings (Feline esophagus, Trachealisation of esophagus) Definitive diagnosis by biopsy : > 15% eosinophils/ high power field T reatment : 4D’s Dilatation Drugs ± steroids Diet+ Life style modifications Dupilimumab

87. References Sleisenger and fordtran’s gas trointestinal and liver disease, 11th Edition Up to date 2024 Merdscape 2024 AGA Institute and the Joint Task Force on Allergy-Immunology Practice Parameters Clinical Guidelines 2020. ACG Clinical Guideline 2013

88. T hank you!