Potential of Blood Eosinophils, Eosinophil-Derived Neurotoxin, and Eotaxin-3 as Biomarkers of Eosinophilic Esophagitis
2006; Elsevier BV; Volume: 4; Issue: 11 Linguagem: Inglês
10.1016/j.cgh.2006.08.013
ISSN1542-7714
AutoresMichael R. Konikoff, Carine Blanchard, Cassie Kirby, Bridget K. Buckmeier, Mitchell B. Cohen, James E. Heubi, Philip E. Putnam, Marc E. Rothenberg,
Tópico(s)IL-33, ST2, and ILC Pathways
ResumoBackground & Aims: Eosinophilic esophagitis (EE) is an increasingly recognized disorder characterized by eosinophilic inflammation of the esophageal mucosa, and typically requires serial invasive endoscopic biopsy examinations to document the characteristic histologic features of the disorder. The aim of this study was to identify noninvasive biomarkers that correlated with disease activity and response to treatment as measured by esophageal eosinophilia. Methods: A prospective, cross-sectional analysis was performed on 47 pediatric patients undergoing endoscopic evaluation of possible EE. Blood samples were collected for measurement of peripheral blood absolute eosinophil count (AEC) and levels of eosinophil-derived neurotoxin (EDN), eotaxin-1, -2, and -3, and interleukin-5. Stool samples were collected for measurement of EDN. Biomarker levels were correlated with esophageal eosinophil density, and differences in biomarker levels based on disease activity and treatment were determined. Results: AEC, plasma EDN levels, and eotaxin-3 levels significantly correlated with esophageal eosinophil density (AEC: r = 0.56, P < .0001; EDN: r = 0.54, P < .0001; eotaxin-3: r = 0.32, P = .04), and were increased in patients with active EE vs controls (AEC: 440 vs 140 eosinophils/μL, P < .05; EDN: 50.3 vs 31.1 ng/mL, P = .01; eotaxin-3: 37.7 vs 11.5 pg/mL, P = .01). Cut-off values were established to maximize the sensitivity, specificity, and predictive values of these biomarkers alone and in combination. Eotaxin-1, eotaxin-2, interleukin-5, and fecal EDN levels did not correlate with esophageal eosinophil density, and were not increased in active EE vs controls or those with inactive EE. Conclusions: These data show that blood levels of AEC, EDN, and eotaxin-3 may have value as noninvasive biomarkers for monitoring EE. Background & Aims: Eosinophilic esophagitis (EE) is an increasingly recognized disorder characterized by eosinophilic inflammation of the esophageal mucosa, and typically requires serial invasive endoscopic biopsy examinations to document the characteristic histologic features of the disorder. The aim of this study was to identify noninvasive biomarkers that correlated with disease activity and response to treatment as measured by esophageal eosinophilia. Methods: A prospective, cross-sectional analysis was performed on 47 pediatric patients undergoing endoscopic evaluation of possible EE. Blood samples were collected for measurement of peripheral blood absolute eosinophil count (AEC) and levels of eosinophil-derived neurotoxin (EDN), eotaxin-1, -2, and -3, and interleukin-5. Stool samples were collected for measurement of EDN. Biomarker levels were correlated with esophageal eosinophil density, and differences in biomarker levels based on disease activity and treatment were determined. Results: AEC, plasma EDN levels, and eotaxin-3 levels significantly correlated with esophageal eosinophil density (AEC: r = 0.56, P < .0001; EDN: r = 0.54, P < .0001; eotaxin-3: r = 0.32, P = .04), and were increased in patients with active EE vs controls (AEC: 440 vs 140 eosinophils/μL, P < .05; EDN: 50.3 vs 31.1 ng/mL, P = .01; eotaxin-3: 37.7 vs 11.5 pg/mL, P = .01). Cut-off values were established to maximize the sensitivity, specificity, and predictive values of these biomarkers alone and in combination. Eotaxin-1, eotaxin-2, interleukin-5, and fecal EDN levels did not correlate with esophageal eosinophil density, and were not increased in active EE vs controls or those with inactive EE. Conclusions: These data show that blood levels of AEC, EDN, and eotaxin-3 may have value as noninvasive biomarkers for monitoring EE. Eosinophilic esophagitis (EE) is a disorder that selectively affects the esophagus with eosinophil-rich inflammation in the absence of known causes of eosinophilia.1Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-29Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar Patients with EE may present with a variety of clinical findings including dysphagia, food impaction, vomiting, abdominal pain, and weight loss.1Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-29Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar, 2Markowitz J.E. Liacouras C.A. Eosinophilic esophagitis.Gastroenterol Clin North Am. 2003; 32: 949-966Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 3Liacouras C.A. Eosinophilic esophagitis in children and adults.J Pediatr Gastroenterol Nutr. 2003; 37: S23-S28Crossref PubMed Scopus (100) Google Scholar Although the cause of EE is unknown, several lines of evidence support an allergic cause, including the high incidence of atopy in patients with EE,2Markowitz J.E. Liacouras C.A. Eosinophilic esophagitis.Gastroenterol Clin North Am. 2003; 32: 949-966Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar the improvement in symptoms and esophageal histology after institution of an allergen-free diet,4Kelly K.J. Lazenby A.J. Rowe P.C. et al.Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (916) Google Scholar, 5Markowitz J.E. Spergel J.M. Ruchelli E. et al.Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.Am J Gastroenterol. 2003; 98: 777-782Crossref PubMed Scopus (515) Google Scholar and the induction of experimental EE in animal models by allergen challenge.6Mishra A. Hogan S.P. Brandt E.B. et al.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Crossref PubMed Scopus (544) Google Scholar Although the epidemiology of EE has not been studied thoroughly until recently, there appears to be a significant increase in the diagnosis of EE in the past decade.7Fox V.L. Nurko S. Furuta G.T. Eosinophilic esophagitis: it’s not just kid’s stuff.Gastrointest Endosc. 2002; 56: 260-270Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Whether this reflects increasing disease incidence or recognition is unclear, but this increase also coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical gastroesophageal reflux disease or other disorders are now being recognized as having EE.7Fox V.L. Nurko S. Furuta G.T. Eosinophilic esophagitis: it’s not just kid’s stuff.Gastrointest Endosc. 2002; 56: 260-270Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar Although EE is a chronic disease, little has been documented on its natural history.8Straumann A. Spichtin H.P. Grize L. et al.Natural history of primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years.Gastroenterology. 2003; 125: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar The diagnosis of EE requires endoscopy and biopsy specimens to document the characteristic histologic features of esophageal mucosal eosinophilia and epithelial proliferative changes. Current treatment regimens include food-antigen elimination,9Spergel J.M. Andrews T. Brown-Whitehorn T.F. et al.Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.Ann Allergy Asthma Immunol. 2005; 95: 336-343Abstract Full Text PDF PubMed Scopus (414) Google Scholar exclusive elemental (amino acid–based formula) diets,4Kelly K.J. Lazenby A.J. Rowe P.C. et al.Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula.Gastroenterology. 1995; 109: 1503-1512Abstract Full Text PDF PubMed Scopus (916) Google Scholar, 5Markowitz J.E. Spergel J.M. Ruchelli E. et al.Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.Am J Gastroenterol. 2003; 98: 777-782Crossref PubMed Scopus (515) Google Scholar and anti-inflammatory medications.10Liacouras C.A. Wenner W.J. Brown K. et al.Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids.J Pediatr Gastroenterol Nutr. 1998; 26: 380-385Crossref PubMed Scopus (462) Google Scholar, 11Faubion Jr, W.A. Perrault J. Burgart L.J. et al.Treatment of eosinophilic esophagitis with inhaled corticosteroids.J Pediatr Gastroenterol Nutr. 1998; 27: 90-93Crossref PubMed Scopus (297) Google Scholar, 12Noel R.J. Putnam P.E. Collins M.H. et al.Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2004; 2: 568-575Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 13Teitelbaum J.E. Fox V.L. Twarog F.J. et al.Eosinophilic esophagitis in children: immunopathological analysis and response to fluticasone propionate.Gastroenterology. 2002; 122: 1216-1225Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar Because no noninvasive biomarkers of EE disease activity currently exist, frequent surveillance endoscopies with biopsy examinations are necessary to monitor the effects of therapy and the degree of ongoing gastrointestinal inflammation.5Markowitz J.E. Spergel J.M. Ruchelli E. et al.Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.Am J Gastroenterol. 2003; 98: 777-782Crossref PubMed Scopus (515) Google Scholar, 7Fox V.L. Nurko S. Furuta G.T. Eosinophilic esophagitis: it’s not just kid’s stuff.Gastrointest Endosc. 2002; 56: 260-270Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 10Liacouras C.A. Wenner W.J. Brown K. et al.Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids.J Pediatr Gastroenterol Nutr. 1998; 26: 380-385Crossref PubMed Scopus (462) Google Scholar Eosinophils contain unique cytotoxic granules composed of a number of proteins, one of which is eosinophil-derived neurotoxin (EDN), a cytotoxic protein with ribonuclease activity.14Rothenberg M.E. Eosinophilia.N Engl J Med. 1998; 338: 1592-1600Crossref PubMed Scopus (941) Google Scholar EDN is increased in the serum and urine of children with asthma, and in the stool of children with inflammatory bowel disease.15Bischoff S.C. Grabowsky J. Manns M.P. Quantification of inflammatory mediators in stool samples of patients with inflammatory bowel disorders and controls.Dig Dis Sci. 1997; 42: 394-403Crossref PubMed Scopus (87) Google Scholar, 16Koller D.Y. Halmerbauer G. Frischer T. et al.Assessment of eosinophil granule proteins in various body fluids: is there a relation to clinical variables in childhood asthma?.Clin Exp Allergy. 1999; 29: 786-793Crossref PubMed Scopus (56) Google Scholar EDN is stable in stool, and its concentration remains unchanged in stool samples stored at room temperature for at least 7 days, facilitating its use as a clinical biomarker.17Peterson C.G. Eklund E. Taha Y. et al.A new method for the quantification of neutrophil and eosinophil cationic proteins in feces: establishment of normal levels and clinical application in patients with inflammatory bowel disease.Am J Gastroenterol. 2002; 97: 1755-1762Crossref PubMed Google Scholar Although normal levels of fecal EDN have been examined in healthy individuals, levels in EE have not been established.17Peterson C.G. Eklund E. Taha Y. et al.A new method for the quantification of neutrophil and eosinophil cationic proteins in feces: establishment of normal levels and clinical application in patients with inflammatory bowel disease.Am J Gastroenterol. 2002; 97: 1755-1762Crossref PubMed Google Scholar Murine models have suggested that EE is a TH2-associated disease, with interleukin (IL)-5 and the eotaxin subfamily of chemokines (composed of eotaxin-1, eotaxin-2, and eotaxin-3), being vital for its pathogenesis.18Mishra A. Hogan S.P. Brandt E.B. et al.IL-5 promotes eosinophil trafficking to the esophagus.J Immunol. 2002; 168: 2464-2469PubMed Google Scholar, 19Mishra A. Rothenberg M.E. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.Gastroenterology. 2003; 125: 1419-1427Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar IL-5 is a relatively specific cytokine for the eosinophil lineage and is responsible for selective growth and differentiation of eosinophils.14Rothenberg M.E. Eosinophilia.N Engl J Med. 1998; 338: 1592-1600Crossref PubMed Scopus (941) Google Scholar In a mouse model of EE,6Mishra A. Hogan S.P. Brandt E.B. et al.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Crossref PubMed Scopus (544) Google Scholar transgenic overexpression of IL-5 induces marked esophageal eosinophilia, whereas mice deficient in IL-5 have complete abolishment of allergen-induced esophageal eosinophilia.18Mishra A. Hogan S.P. Brandt E.B. et al.IL-5 promotes eosinophil trafficking to the esophagus.J Immunol. 2002; 168: 2464-2469PubMed Google Scholar IL-5 is increased in the plasma of adults with asthma,20Joseph J. Benedict S. Safa W. et al.Serum interleukin-5 levels are elevated in mild and moderate persistent asthma irrespective of regular inhaled glucocorticoid therapy.BMC Pulm Med. 2004; 4: 2Crossref PubMed Scopus (29) Google Scholar and has been found to be overexpressed by infiltrating inflammatory cells in the esophagus of adults with EE.21Straumann A. Bauer M. Fischer B. et al.Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.J Allergy Clin Immunol. 2001; 108: 954-961Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar A genome-wide microarray expression study of esophageal tissue from patients with EE (and control individuals) revealed a striking TH2-associated transcript profile in EE; notably, levels of eotaxin-3 correlated with disease severity and distinguished EE from control individuals.22Blanchard C. Wang N. Stringer K.F. et al.Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.J Clin Invest. 2006; 116: 536-547Crossref PubMed Scopus (740) Google Scholar In collaboration with IL-5, the eotaxin chemokines induce eosinophil trafficking and accumulation by promoting chemoattraction.1Rothenberg M.E. Eosinophilic gastrointestinal disorders (EGID).J Allergy Clin Immunol. 2004; 113: 11-29Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar In 2 separate mouse models of EE, eotaxin-1–deficient mice had significantly diminished esophageal eosinophilia.6Mishra A. Hogan S.P. Brandt E.B. et al.An etiological role for aeroallergens and eosinophils in experimental esophagitis.J Clin Invest. 2001; 107: 83-90Crossref PubMed Scopus (544) Google Scholar, 19Mishra A. Rothenberg M.E. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.Gastroenterology. 2003; 125: 1419-1427Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar Plasma eotaxin-1 is increased in adults with asthma and inflammatory bowel disease.23Jahnz-Royk K. Plusa T. Mierzejewska J. Eotaxin in serum of patients with asthma or chronic obstructive pulmonary disease: relationship with eosinophil cationic protein and lung function.Mediators Inflamm. 2000; 9: 175-179Crossref PubMed Scopus (23) Google Scholar, 24Mir A. Minguez M. Tatay J. et al.Elevated serum eotaxin levels in patients with inflammatory bowel disease.Am J Gastroenterol. 2002; 97: 1452-1457Crossref PubMed Google Scholar Based on these observations, we measured levels of several candidate biomarkers in the plasma and stool of children with EE with the aim of identifying noninvasive markers of EE disease activity that could be used to monitor esophageal inflammation without the need for invasive serial surveillance endoscopies in this population. Forty-seven patients were enrolled at Cincinnati Children’s Hospital Medical Center from May 23, 2005 to July 21, 2005. Eligible patients were between the ages of 1 and 21 years, undergoing upper gastrointestinal endoscopy for any indication. Patients were excluded if they had a known diagnosis of any systemic or gastrointestinal inflammatory condition other than eosinophilic gastrointestinal disorders. Patients with symptoms consistent with EE or who were known to have EE were enrolled consecutively, whereas normal controls were enrolled randomly from all patients undergoing upper endoscopy. The Cincinnati Children’s Hospital Medical Center Institutional Review Board approved the study, and all participants (or their parents or guardian) gave written informed assent/consent. Upper gastrointestinal endoscopy was performed in all patients through the use of standard instruments (Olympus GIF-160; Olympus America Inc., Melville, NY) by pediatric gastroenterologists. Multiple-grasp biopsy specimens were obtained at the discretion of the endoscopist from the proximal and distal esophagus, and from the stomach and duodenum. Biopsy specimens for histopathologic examination were immediately placed in formalin and labeled by location. Five-micron sections were cut from routinely processed formalin-fixed paraffin-embedded tissue blocks, and were stained with H&E. Slides of the proximal and distal esophagus were examined in random order by a single blinded investigator (M.K.). Intraepithelial eosinophils in all 400× high-power fields (HPF) were counted in one histologic section of each biopsy specimen, and the mean eosinophil density was calculated. The peak eosinophil count for each biopsy specimen was defined as the maximum number of eosinophils in any single HPF. An HPF was counted only if at least half of the field was occupied by tissue. An average of 18 ± 5.2 (mean ± SD) fields were assessed per specimen. Disease activity was classified by the maximum eosinophil count in any HPF in both the proximal and distal esophagus: inactive, 0–6/HPF; intermediate, 6–23/HPF; active 24/HPF or more.12Noel R.J. Putnam P.E. Collins M.H. et al.Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.Clin Gastroenterol Hepatol. 2004; 2: 568-575Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 25Ruchelli E. Wenner W. Voytek T. et al.Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy.Pediatr Dev Pathol. 1999; 2: 15-18Crossref PubMed Scopus (181) Google Scholar Biopsy specimens from the stomach and duodenum were obtained from all study subjects and were free of significant histologic abnormalities. Unaffected controls had no abnormalities reported on histopathologic examination of the upper gastrointestinal tract by an experienced pathologist and no previous diagnosis of EE. Blood samples were obtained from patients during upper endoscopy after a fast of at least 4 hours. Samples for biomarker measurements were collected in heparinized tubes, and plasma was extracted and stored at −70°C until processing. Samples for peripheral blood absolute eosinophil count were collected in tubes containing potassium ethylenediaminetetraacetic acid and immediately processed. Patients were mailed stool collection kits before endoscopy. Stool samples were obtained in the 2 weeks before or the 2 weeks immediately after the endoscopy, refrigerated until transport, and then returned to our institution. Sample aliquots were stored at −70°C until processing. All samples were frozen within 3 days of collection. Peripheral blood absolute eosinophil count (AEC) was determined by an automated hematology analyzer (Cell-Dyn 4000; Abbott Laboratories, Abbott Park, IL) at the Cincinnati Children’s Hospital Medical Center Clinical Laboratory. Plasma samples were thawed and EDN was measured by an EDN enzyme-linked immunosorbent assay (ELISA) kit, according to the manufacturer’s instructions (ALPCO Diagnostics, Windham, NH). Fecal samples were thawed, and EDN was extracted and measured by the EDN ELISA kit, according to the manufacturer’s instructions (ALPCO Diagnostics). The sensitivity of the ELISA was 0.6 ng/mL. Plasma IL-5 levels were determined by OptEIA ELISA kit, according to the manufacturer’s instructions (BD Biosciences Pharmingen, San Diego, CA). The sensitivity of the ELISA was 7.8 pg/mL. Eotaxin-1 and -2 protein levels in 100 μL of plasma were quantified using respective ELISA kits (R&D Systems, Minneapolis, MN) according to the manufacturer’s instructions. Eotaxin-3 protein levels in 100 μL of plasma were quantified using the Eotaxin-3 Quantikine kit (R&D Systems) according to the manufacturer’s instructions. The sensitivities of the ELISAs were 62.5 pg/mL, 200 pg/mL, and 7.8 pg/mL for eotaxin-1, -2, and -3, respectively. The overall mean esophageal eosinophil counts for each patient were calculated by averaging the mean eosinophil counts obtained from both the proximal and distal esophagus. The correlation of individual biomarker levels with the overall mean esophageal eosinophil counts and with each other were assessed using the Spearman correlation test. Continuous biomarker levels were compared between groups with the Mann–Whitney test, whereas dichotomous biomarker levels in those with active or inactive EE and unaffected controls were compared with the Fisher exact test. The Kruskal–Wallis test with Dunn’s multiple comparison post-test was used to compare biomarker levels in those with active EE, inactive EE on diet therapy, inactive EE on topical corticosteroid therapy, and unaffected controls. Continuous variables are expressed as medians (interquartile range). All tests were 2 sided, and P values less than .05 were considered statistically significant. Statistical tests were performed using SAS (version 8.1; SAS Institute, Cary, NC) and GraphPad Prism (version 4.01; GraphPad Software, Inc., San Diego, CA). Forty-seven patients were enrolled in the study (Table 1). Blood samples were collected from 46 patients, and fecal samples were collected from 35 patients. One patient did not have a blood sample collected and 12 patients did not return stool samples. Nine patients were considered unaffected controls (6 boys; median age, 6.8 y; range, 1–10 y), 33 patients had a previous diagnosis of EE (27 males; median age, 7.9 y; range, 2–20 y), 4 patients had a previous diagnosis of eosinophilic enteropathy without esophageal involvement, and 1 patient had a previous diagnosis of eosinophilic colitis without esophageal involvement. Of the 33 patients with a previous diagnosis of EE, 16 patients had active EE, 1 patient had intermediate EE, and 16 patients had inactive EE (8 patients on diet therapy, 8 patients on topical corticosteroid therapy).Table 1Patient Characteristics and Biomarker LevelsPatientSexAge, yaAge at study enrollment.Atopic phenotypePrimary therapy for EE or EGID at time of endoscopyOverall mean eosinophilsbOverall mean eosinophil count per HPF (average of mean eosinophil count in both the proximal and distal esophagus) at endoscopy.AEC (μL)PlasmaStoolIL-5 (pg/mL)Eotaxin 1 (pg/mL)Eotaxin 2 (pg/mL)Eotaxin 3 (pg/mL)EDN (pg/mL)EDN (pg/mL)Unaffected controls (n = 9)5M1SPT− As− AD− AR− AC−None0170ND25570611.532.884110M8N.D.None01402.8957936ND31.15038F10N.D.None0061061<20024.950.5941F10N.D.None01208.34846642.532.2ND47M3N.D.None014018.5761<200029.88611M6As+ AD− AR−None0100063061744.322.24514M7SPT+ As+ AD+ AR+ AC+None03902.3479<20013.747.944229M1As− AD− AR−None0380110.21003583ND22.378340F3N.D.None08020.2440741918.3NDInactive EEcInactive EE was defined as a previous diagnosis of EE with a peak eosinophil count ≤6 in both the proximal and distal esophagus at endoscopy. (n = 16)22F6SPT+ As+ AD− AR+Elemental + Food0401.7822<200125.410.133242F7N.D.Elimination0096877731.9151ND2M4SPT+ As− AD− AR+ AC+Elemental0NDNDNDNDNDND145318F5As− AD+ AR+ AC+Elemental0290ND430739ND33.75419M7SPT+ As− AD+ AR+ AC+Elemental02101.2591650ND33.333832M15SPT+ As+ AD+ AR+ AC−Elimination1ND1.156682821865636M15SPT− As− AD− AR+Elemental11000.86236265.225.14920M5SPT+ As− AD− AR+Elimination12500.65515014.116.73244M10SPT+ As+ AD− AR− AC−FP0380ND25364439.336.6ND8M14SPT+ As+ AR+ AC+FP05700.9556765135.568.1ND23M18SPT+ As− AD− AR− AC−FP01000.1735<20015.817.4ND30M8As+ AD+ AR+FP05066.21479<200483.812.621945F9SPT− As+ AD− AR+ AC−FP0603.1906<2004.911.2ND24F3As+FP04801.639772143.223.4464417M11N.D.FP1190ND363910949.61217M13SPT− As+ AD+ AR− AC−FP12800.8310 6 and ≤23 in both the proximal and distal esophagus at endoscopy. (n = 1)28M6SPT+ As− AD− AR+FP25301.561467644.53530Active EEeActive EE was defined as a previous diagnosis of EE with a peak eosinophil count ≥24 in both the proximal and distal esophagus at endoscopy. (n = 16)6M10SPT− As− AD− AR− AC−None243100.68738961.524.2114046M12SPT+ As− AD− AR+ AC+None4351043.31124<20028.438.3ND12M14SPT− As− AD− AR− AC−None713000.254066270.777.45715M3SPT+ As+ AR+ AC+Elemental42900.4416<20026.534.6162144M2SPT+ As− AD+ AR−Elemental + Food44200.870663215.646.2429834M6SPT+ As+ AD− AR+ AC+Elemental1200.64679566.657.96337F2SPT+ As+ AD+Elimination1573018.7607<20061.772.340235M18SPT+ AR+Elemental673202.356780637.4121.840143M15SPT− As+ AD− AR+FP211065.91136772218.827.964613M6SPT+ As− AD− AR+FP1451019805781285.558.97739M6N.D.FP20580027872033.392.919161M6SPT− As+ AD+ AR+FP21680ND10714ND39.11233M20SPT− As+ AD− AR− AC−FP234600.9453777156.828.7ND16M3SPT+ As+ AD+ AR+FP41200ND55266259.546.4ND25M16SPT As− AR+ AC+FP906601.561177137.754.2ND21M6SPT+ As+ AD+ AR+ AC+FP11613005.26716466.3241.9NDOtherfPatients 26, 27, 33 and 39 had a previous diagnosis of eosinophilic enteropathy without esophageal involvement. Patient 31 had a previous diagnosis of eosinophilic colitis without esophageal involvement. (n = 5)26M3N.D.Elemental0100ND4551159.815.6131327M4As+ AD+ AR+Elemental03200.63517186.631.4507533M5SPT+ AD+Elemental + Prednisone000.5123801ND16.830239M14SPT+ As+FP01001.41003<2006.813.626031F9SPT+ As+Elemental + Budesonide0801.1645 6 and ≤23 in both the proximal and distal esophagus at endoscopy.e Active EE was defined as a previous diagnosis of EE with a peak eosinophil count ≥24 in both the proximal and distal esophagus at endoscopy.f Patients 26, 27, 33 and 39 had a previous diagnosis of eosinophilic enteropathy without esophageal involvement. Patient 31 had a previous diagnosis of eosinophilic colitis without esophageal involvement. Open table in a new tab SPT, skin prick testing; As, asthma; AD, atopic dermatitis; AR, allergic rhinitis; AC, allergic conjunctivitis; ND, not determined; Elimination, foods restricted from diet based on allergy testing (skin prick ± skin patch); Elemental, diet consists exclusively of elemental formula; Food, undergoing trial of particular foods having improved on an elemental diet; FP, fluticasone propionate swallowed from metered dose inhaler (various doses). Eosinophil density was quantified in the proximal and distal esophagus for each patient. The mean eosinophil counts in the proximal and distal esophagus were 10 ± 24 and 16 ± 35 eosinophils/HPF, respectively, and were not significantly different (P = .36). For this reason, the overall mean eosinophil density (defined as the average of the mean eosinophil densities obtained from both the proximal and distal esophagus) was used for the remainder of the comparisons in the study. AEC, plasma EDN, and eotaxin-3 levels significantly correlated with esophageal eosinophil density, as shown in Figure 1, Figure 2 (AEC: r = 0.56, P < .0001; EDN: r = 0.54, P < .0001; eotaxin-3: r = 0.32, P = .04). Notably, plasma eotaxin-3 did not strongly correlate with esophageal eosinophil levels. While the Spearman correlation was significant (P = .04), the slope of the linear regression line was not significant (P = .72). Eotaxin-1, eotaxin-2, IL-5, and fecal EDN levels did not correlate with esophageal eosinophil density. Plasma EDN did not correlate with fecal EDN (r = −0.06, P = .73) or eotaxin-3 (r = 0.13, P = .41), but AEC correlated with plasma EDN (r = 0.51, P = .0003), fecal EDN (r = 0.37, P = .03), and eotaxin-3 (r = 0.33, P = .04).Figure 2Correlation of (A) AEC, (B) plasma EDN, and (C) eotaxin-3 levels with the mean esophageal eosinophil density in the proximal and distal esophagus (regression line shown). Data are from all individuals in Table 1. R values represent Spearman correlation.View Large Image Figure ViewerDownload (PPT) The atopic phenotype of study patients was determined from available data (Table 1). Skin prick testing for a large panel of foods and/or environmental allergens was performed in 32 of the 47 patients. Information on the presence of asthma, eczema, allergic rhinitis, and allergic conjunctivitis was available in 36, 31, 33, and 19 individuals, respectively. AEC, plas
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