Extraesophageal Manifestations Philip E Putnam MD FAAP Professor of Pediatrics University of Cincinnati CCHMC Division of Gastroenterology Hepatology and Nutrition Medical Director Cincinnati Center for Eosinophilic Disorders ID: 1047603
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1. Eosinophilic Esophagitis: Esophageal and Extraesophageal ManifestationsPhilip E Putnam, MD, FAAPProfessor of PediatricsUniversity of CincinnatiCCHMCDivision of Gastroenterology, Hepatology, and NutritionMedical Director, Cincinnati Center for Eosinophilic Disorders
2. Normal EsophagusStratified squamous, non-keratinized epitheliumSurrounded bylamina propriamuscularis mucosa submucosa muscularis propria
3. Normal esophagus
4. Normal Esophageal HistologyStratified squamous, non-keratinized, epitheliumSuprabasal layerBasal cell layerRete pegLamina propriaLumen
5. Normal EsophagusEsophagitis
6. Esophagus: Inflammatory Disorders EsophagitisAcute Infectious (e.g., Herpes, Candida) Pill-induced (e.g., tetracyclines, oral contraceptives)Caustic ingestionChronic GERD—reflux esophagitisEosinophil-predominant inflammationOther inflammatory bowel disease (e.g., Crohn’s, celiac)
7. EsophagitisSymptoms are non-specificPainOdynophagiaChest painEpigastric painReferred pain to the back (interscapular)Dysphagia
8. Esophageal Inflammatory Disorders—Factors to ConsiderAge at onsetDuration of symptomsEsophageal SymptomsNon-esophageal GI complaintsDiarrhea, for exampleNon-GI complaintsEvidence for systemic diseaseMedication useHistory of immune or atopic conditionsAsthma, Atopic dermatitisPhysical examDiagnostic StudiesContrast examEndoscopy with biopsyManometryMII-pH
9. Focus: Eosinophilic Esophagitis (EoE)
10. 2011—Revised Consensus Definition of EoEChronic, immune-mediated disorderClinical features Esophageal dysfunctionPathologic featuresEosinophil-predominant mucosal inflammation (15eos/hpf)Not due to acid-induced injuryNot responsive to PPIIsolated to the esophagusLiacouras C, et al. JACI 2011
11. What it really is:Disorder of epithelial homeostasisGenetically susceptible individualsImpaired barrier function: cell-cell adhesionDysregulation of the immune response toward Th2 mediated hypersensitivityInitiation and perpetuation of inflammation by dietary antigen exposureesophageal dysfunction (motor and sensory)mural remodeling with loss of compliancelumenal narrowing (focally or diffusely)Disease with eosinophils, not a disease of eosinophils
12. Rothenberg, Gastro 2015
13. EoEPrevalence: 10 per 10,000 children in Hamilton CountyEstimated: 55 per 100,000 overall prevalence in USSpergel et al., 2011 JPGNDellon et al., Clin Gastro Hepatol 2014
14. Eosinophilic EsophagitisMale predominant (~75% )Familial clustering2/3 are otherwise atopic: Food allergies (IgE-mediated immediate hypersensitivity)Environmental allergiesAsthmaEczemaChronic rhinitisFood antigen-induced eosinophilia95% respond to antigen removalRecurrent disease upon reintroduction of provocative antigens
15. EoE the Disease: Clinical, Endoscopic, Histologic
16. EoE SymptomsNon-specific:DysphagiaUsually chronicAcute presentation with food impactionAcute presentation with esophageal foreign bodyRarely, dysphagia for liquidsLaryngeal cleft, Chiari malformation, foreign body obstructionFeeding problemsVomitingPain
17. Esophageal SymptomsFeeding disorderInfants and toddlersAversion, refusal, gagging, choking, vomitingVomitingChronic, intermittent, orConsistently associated with particular foods, orCyclical (not attributed to food)PainChest painEpigastric painOdynophagia is NOT common
18. Eosinophilic Esophagitis: Primary presenting complaint, by ageNoel, et al, 2004 NEJM
19. Dysphagia—What kids sayFood “sticking”Food goes down slowFood gets ”stuck”Eventually goes downRetched back upEndoscopically retrievedASK ABOUT COMPENSATORY MANEUVERSEat slowlyChew excessivelyDrink excessively to ‘wash it down’Take small bitesAvoid specific food texturesBread, meat, pasta, rice
20. Common Complaints in Children who have EoESore throat or ‘throat tightening’Globus sensationThroat clearingCough with eating
21. “Aerodigestive” EvaluationForty patients with recurrent croup or cough53% had airway abnormalities38% had esophagitis 4 (27%) of which met criteria for eosinophilic esophagitis There was no significant difference in the presence of gastrointestinal complaints, abdominal pain and/or FTT (p>0.05) with or without esophagitis Greifer M, et al. Pediatric patients with chronic cough and recurrent croup: the case for a multidisciplinary approach. Int J Pediatr Otorhinolaryngol. 2015 May;79(5):749-52
22. EoE in an Aerodigestive programBetween 2003 and 2012, 376 children with persistent symptoms undergoing triple scope 14 (3.7%) were eventually diagnosed as having EoEThe children with EoE who presented with airway symptomscough (n = 6; 42.9%). Inflammatory subglottic stenosis due to EoE was identified in 1 patient. Subsequent treatment including food allergy challenge and elimination diet resulted in a clinical improvement in half of the cases identified.Hill CA, et al. Prevalence of eosinophilic esophagitis in children with refractory aerodigestive symptoms. JAMA Otolaryngol Head Neck Surg. 2013 Sep;139(9):903-6.
23. EoE in the ENT population 92 children were diagnosed with EoE (3.8% of total children biopsied). 73% were boys and 27% girls. presenting symptom Cough(46%) hoarseness, throat clearing, burping/vomiting, and abdominal pain.43% with asthma17% with a history of GERD. Otteson TD(1), Mantle BA, Casselbrant ML, Goyal A. The otolaryngologic manifestations in children with eosinophilic esophagitis. Int J Pediatr Otorhinolaryngol. 2012 Jan;76(1):116-9.
24. “Aerodigestive” Complaints in EoENon-specificReferred from esophagus, orAssociated with comorbid conditionsGERDChronic rhinitis with post nasal drainageInfection (e.g., candida)CoughReactive airwaysGERDInfection, etc. etc. etc…Referral bias!
25. Retained Esophageal Foreign ObjectsDuration of symptomsProlonged symptoms and/or unwitnessed ingestionShould it have passed?Pre-existing dysphagia or feeding problems?Infants and ToddlersPre-existing anatomic abnormality (e.g. stricture)
26. Esophageal foreign bodies and food impactionsApproach to all foreign bodies presenting for endoscopic retrievalCareful historyExamine the rest of the esophagus!Biopsy the esophagus away from the point of impactionChildren with food impactions have EoE til proven otherwise!Meat: 100% with EoEInanimate objects: 45% with EoEWilliams P, al. Esophageal foreign bodies and eosinophilic esophagitis--the need for esophageal mucosal biopsy: a 12-year survey across pediatric subspecialties. Surg Endosc. 2013 Jun;27(6):2216-20
27. Esophageal foreign body, characteristics in EoEfood impaction (89%)older age (average 12.2 years)male sex (78%),atopic disease (61%)previous esophageal foreign body or frequent dysphagia (83%)endoscopic abnormalities (100%). Hudson S, et al. Foreign body impaction as presentation of eosinophilic esophagitis. Otolaryngol Head Neck Surg. 2013 Nov;149(5):679-81
28. Endoscopy in EoE
29. FurrowsRings
30. Mucosal rings
31. Endoscopic photograph of distal esophagus with thickening and furrowing
32. Exudate
33. Endoscopic photograph showing typical exudate (‘white specks’)
34. Patchy furrowing with exudate, distal esophagus
35. EREFS—Scoring the endoscopic findingsEdemaRingsExudateFurrowsStrictureHirano I et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. . Gut. 2013 Apr;62(4):489-95.
36. EoE, GERD, or both?
37. Normal EsophagusEsophagitis
38. Eosinophilic Esophagitis: Not just eosinophilsReactive ChangesExpansion of the basal cell layer (proliferation)Extension of the rete pegs toward surfaceDilated intercellular spacesInflammatory cell infiltrateLymphocytesEosinophils, microabscessMast cellsRemodelingLamina propria fibrosis
39. Esophageal histology overlapGERDBasal zone hyperplasiaRete peg elongationDilated intercellular spacesInflammatory cell infiltrateNeutrophilsLymphocytes (squiggle cells)EosinophilsSurface ulcerationEoEBasal zone hyperplasiaRete peg elongationDilated intercellular spacesInflammatory cell infiltrateEosinophilsLymphocytesMast cellsEosinophilic microabscessesSurface layering of eos
40. Symptoms vs. histologySymptoms correlate poorly with histologyMany patients with active inflammation have no symptomsSome patients with no inflammation still complain of pain or dysphagiaThe absence of symptoms does not imply the absence of inflammation Pentiuk S, et al. 2008 JPGN
41. EoE Diagnosis
42. EoE DiagnosisEoE has characteristic symptoms, endoscopic findings, and histology BUT, they are all nonspecific, individually and collectively.Ultimately, the final clinical diagnosis requiresComprehensive evaluation of the childComorbidity determinationDistribution of eosinophilia in the gut Histologic response to therapeutic intervention8 week trial of PPI 1mg/kg/dose bid 30 minutes before b/d
43. Eosinophilic esophagitis (EoE) vs. esophageal eosinophiliaThere is a differential diagnosis when eosinophils are present in the esophagusEosinophils are not specific for any particular conditionPathologists don’t diagnose EoEThey describe esophageal eosinophiliaClinician correlates histology with relevant dataThe number of eosinophils/hpf DOES NOT discriminate EoE from other conditionsHistologic eosinophil-predominant esophagitis is not sufficient to diagnose clinical EoE
44. If reflux is the most common confounding diagnosis, why not just do MII-pH in all?Negative resultConfirms the absence of reflux But, doesn’t account for “PPI-responsive esophageal eosinophilia”PPI trial is still required for diagnosisPositive resultConfirms presence of reflux events, but not the pathogenesis, and Can’t identify those who have coincident EoE plus GERD
45. EoE DiagnosisHx, PE, Clinical assessmentEndoscopy with biopsyPPI trialNon-invasive testing and clinical symptoms alone cannot make the diagnosisNo blood tests (CBC, AEC, IgE, etc.)No x-raysNo allergy test(s)
46. Treatment of Children who have EoE
47. EoE Management PrinciplesChronic disease requires chronic, consistent, effective therapyGoals:Symptom improvement Mucosal healingPrevent ComplicationsLiacouras, et al., JACI, 2011
48. EoE Management OptionsDietary Antigen EliminationSteroidsSystemicTopicalCombination therapy with dietary antigen elimination and topical steroidsImmunomodulators?Biologics?Anti-IL5, Anti-IgE, Anti-TNF (ineffective!) Anti-IL13 Dilatation of the esophagusAnti TGF-beta?
49. Initial Antigen Elimination DietThe starting diet upon confirmation of the diagnosis (after PPI trial)Simultaneous elimination of single or multiple antigens to induce remissionMUST NOT be done before, or with, initial PPI trial or steroids
50. Dietary Management PrinciplesThe final diet achieved is the one that isLeast restrictive without provoking EoEMeets all the child’s nutritional needs
51. “Starting” DietRemissionReintroduction of selected antigens followed byEndoscopy*“Final” Diet* Disparity between starting diet and final diet determines the number of cycles of reintroduction/endoscopy
52. ConceptIn a perfect world, the Starting Diet would be the Final Diet “Testing” would precisely identify all provocative antigensPositives would be true positives and always cause esophagitisNegatives would be true negatives and never cause esophagitis
53. Dietary Management Principles:THE PROBLEMEoE is a non-IgE mediated disorder, so IgE-based tests are of little valueSkin Prick Testing50% false positivesSerum specific IgEAtopy patch testing is not standardized and remains at best controversialWe no longer recommend allergy testing to drive decision-making regarding dietary management of EoE.
54. Henderson et alJACI, 2012
55. Topical Steroids for EoEFluticasone440mcg bid-880mcg bid‘Hold your breath, squirt and swallow’NPO for 30 minutes post doseBudesonide250mcg-1mg bidMix contents of vial with 3-5 packets of SplendaNPO for 30 minutes post dose
56. Response to swallowed fluticasone: distal esophagusKonikoff, M. et al. Gastroenterology 2006
57. Which therapy?Which form of therapy is feasible for child and family? Educate, negotiate, understand the family dynamicDon’t prescribe—let the family chooseSupportNurse, dietician, psychologist, social workModify the plan for clinical failures, recurrent/persistent esophagitis, social failures
58. The Implications of BiopsiesBiopsy results reflect the response to what is being eatenNormal biopsies confirm that provocative antigens must be in the group being avoidedAbnormal biopsies only confirm that provocative antigens are still being ingestedNothing can be assumed regarding the avoided foodsNothing goes back in the diet til the biopsies are normal
59. Biopsies in EoEBecause of the poor correlation between symptoms and histology, esophageal biopsies are required to assess the response to any change in therapy
60. Desirable Esophageal MonitoringNon-invasiveNothing inserted into the nose/mouth/esophagusNo need for anesthesia, x-rayNo need for tissueAccurateEqual to biopsies in detecting early EoE recurrence with food challenge or drug changeAble to discriminate among all causes of esophagitisRecognizes EoE and EoE plus GERD and PPI-REEReasonable cost covered by insurance
61. Esophageal monitoring after diagnosis—Repeat EndoscopyThe only method available to assess the esophageal lining for esophagitis that is sensitive enough to detect EoE.Biomarkers?Blood test?Saliva?Stools?Impedance?String test?
62. Esophageal impedance“Impedance” is a measurement of the resistance to electrical current flow between two pointsCatheters with the ability to measure ImpedanceDetect and quantitate retrograde bolus flow attributed to GERD in the esophageal lumen (MII-pH studies)Observe esophageal emptying during esophageal manometry testingDirect measurement of mucosal impedance Katzka DA et al. Endoscopic Mucosal Impedance Measurements Correlate With Eosinophilia and Dilation of Intercellular Spaces in Patients With Eosinophilic Esophagitis. Clin Gastroenterol Hepatol. 2015 Jul;13(7):1242-1248.e1
63. Natural History?Chronic disorderRequires constant, consistent, effective therapyAdult EoEDysphagia is the predominant complaintPersistent esophagitis with recurrent symptoms requiring dilatation“Remodeling” of the esophagusStrauman, A. 2008, Gastrointest Clin N Am
64. EoE: RemodelingChronic dysphagiaSmall caliber esophagusEsophageal strictureREVERSIBLE early on with either diet or pharmacotherapy
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