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BACKGROUND AND AIMS: Microscopic colitis (MC) is a common cause of chronic diarrhea; however, the clinical course of this disease is poorly understood. We aimed to investigate how patients diagnosed with MC were treated in routine clinical practice and how their symptoms compared to patients with other causes of chronic diarrhea at one year follow-up. METHODS: We conducted a case-control study of patients undergoing outpatient colonoscopy to evaluate diarrhea. The study pathologist determined whether patients were classified as MC cases or non-MC controls. One year after colonoscopy, we interviewed cases (n = 74) and controls (n = 162) about their diagnosis, medications for diarrhea, and symptom burden. RESULTS: At 1-year follow-up after colonoscopy, 10% of MC cases were unaware of the diagnosis, 60% had been prescribed a medication for diarrhea, 40% had fecal urgency, 32% had weight loss, and 21% had fecal incontinence. Among cases, 46% were treated with budesonide. Compared to cases, controls had worse symptoms based on the Microscopic Colitis Disease Activity Index score with a median score of 3.0 (interquartile range 1.9-4.2) vs 2.3 (interquartile range 1.4-3.2) at 1-year follow-up. Controls had more frequent stools, urgency, fecal incontinence, and abdominal pain. CONCLUSION: In a cohort of patients with biopsy-confirmed MC and diarrhea controls, we found that some cases remained unaware of their diagnosis, many cases had persistent symptoms, and controls had worse symptoms than cases. These findings suggest there are opportunities to improve management of this chronic disease.
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OBJECTIVE: We aimed to determine whether mepolizumab, an anti-IL-5 antibody, was more effective than placebo for improving dysphagia symptoms and decreasing oesophageal eosinophil counts in eosinophilic oesophagitis (EoE). METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled, trial. In the first part, patients aged 16-75 with EoE and dysphagia symptoms (per EoE Symptom Activity Index (EEsAI)) were randomised 1:1 to 3 months of mepolizumab 300 mg monthly or placebo. Primary outcome was change in EEsAI from baseline to month 3 (M3). Secondary outcomes included histological, endoscopic and safety metrics. In part 2, patients initially randomised to mepolizumab continued 300 mg monthly for 3 additional months (mepo/mepo), placebo patients started mepolizumab 100 mg monthly (pbo/mepo), and outcomes were reassessed at month 6 (M6). RESULTS: Of 66 patients randomised, 64 completed M3, and 56 completed M6. At M3, EEsAI decreased 15.4±18.1 with mepolizumab and 8.3±18.0 with placebo (p=0.14). Peak eosinophil counts decreased more with mepolizumab (113±77 to 36±43) than placebo (146±94 to 160±133) (p<0.001). With mepolizumab, 42% and 34% achieved histological responses of <15 and ≤6 eos/hpf compared with 3% and 3% with placebo (p<0.001 and 0.02). The change in EoE Endoscopic Reference Score at M3 was also larger with mepolizumab. At M6, EEsAI decreased 18.3±18.1 points for mepo/mepo and 18.6±19.2 for pbo/mepo (p=0.85). The most common adverse events were injection-site reactions. CONCLUSIONS: Mepolizumab did not achieve the primary endpoint of improving dysphagia symptoms compared with placebo. While eosinophil counts and endoscopic severity improved with mepolizumab at 3 months, longer treatment did not yield additional improvement. TRIAL REGISTRATION NUMBER: NCT03656380.
Subject(s)
Deglutition Disorders , Eosinophilic Esophagitis , Adult , Humans , Adolescent , Eosinophilic Esophagitis/drug therapy , Deglutition Disorders/drug therapy , Deglutition Disorders/etiology , Treatment Outcome , Antibodies, Monoclonal, Humanized , Eosinophils/pathology , Double-Blind MethodABSTRACT
BACKGROUND: Microscopic colitis (MC) is an increasingly common cause of watery diarrhea particularly in older individuals. The role of diet in MC has received little study. METHODS: We conducted a case-control study at a single institution enrolling patients referred for elective outpatient colonoscopy for diarrhea. Patients were classified as cases with MC or non-MC controls after a review of colon biopsies by 1 research pathologist. Study subjects were interviewed by a trained telephone interviewer using a validated food frequency questionnaire. Adherent microbes were evaluated from colonic biopsies using 16s rRNA sequencing. RESULTS: The study population included 106 cases with MC and 215 controls. Compared with controls, the cases were older, better educated, and more likely to be female. Cases with MC had lower body mass index and were more likely to have lost weight. Subjects in the highest quartile of dietary calcium intake had a lower risk of MC compared with those in the lowest quartile (adjusted odds ratio 0.22, 95% confidence interval 0.07-0.76). The findings were not explained by dairy intake, body mass index, or weight loss. We found that dietary calcium intake had significant associations with the abundance of Actinobacteria and Coriobacteriales in the microbial community of colonic biopsies. DISCUSSION: Compared with patients with diarrhea, cases with MC had a lower intake of dietary calcium. Diet can be associated with alterations in the gut microbiota and with luminal factors that could affect the risk of MC.
Subject(s)
Actinobacteria , Colitis, Microscopic , Aged , Female , Humans , Male , Calcium, Dietary , Case-Control Studies , Colitis, Microscopic/diagnosis , Colitis, Microscopic/epidemiology , Colitis, Microscopic/complications , Diarrhea/epidemiology , Diarrhea/etiology , Diarrhea/pathology , RNA, Ribosomal, 16S/geneticsABSTRACT
INTRODUCTION: Microscopic colitis is a relatively common cause of chronic diarrhea and may be linked to luminal factors. Given the essential role of the microbiome in human gut health, analysis of microbiome changes associated with microscopic colitis could provide insights into the development of the disease. METHODS: We enrolled patients who underwent colonoscopy for diarrhea. An experienced pathologist classified patients as having microscopic colitis (n = 52) or controls (n = 153). Research biopsies were taken from the ascending (ASC) and descending (DES) colon, and the microbiome was characterized with Illumina sequencing. We analyzed the associations between microscopic colitis and microbiome with a series of increasingly complex models adjusted for a range of demographic and health factors. RESULTS: We found that alpha diversity was significantly lower in cases with microscopic colitis compared with that in controls in the DES colon microbiome. In the DES colon, a series of models that adjusted for an increasing number of covariates found taxa significantly associated with microscopic colitis, including Proteobacteria that was enriched in cases and Collinsella that was enriched in controls. While the alpha diversity and taxa were not significantly associated with microscopic colitis in the ASC colon microbiome, the inference P values based on ASC and DES microbiomes were highly correlated. DISCUSSION: Our study demonstrates an altered microbiome in cases with microscopic colitis compared with that in controls. Because both the cases and controls experienced diarrhea, we have identified candidate taxa that could be mechanistically responsible for the development of microscopic colitis independent of changes to the microbial community caused by diarrhea.
Subject(s)
Colitis, Microscopic , Microbiota , Humans , Colitis, Microscopic/epidemiology , Colitis, Microscopic/complications , Colonoscopy/adverse effects , Diarrhea/etiology , Diarrhea/pathology , Biopsy/adverse effectsABSTRACT
BACKGROUND: Microscopic colitis is a leading cause of diarrhea in the older adults. There is limited information about risk factors. We hypothesized that obesity would be associated with microscopic colitis. AIM: To examine the association between obesity and microscopic colitis in men and women undergoing colonoscopy. METHODS: We conducted a case-control study at the University of North Carolina Hospitals. We identified and enrolled men and women referred for elective, outpatient colonoscopy for chronic diarrhea. We excluded patients with a past diagnosis of Crohn's disease or ulcerative colitis. A research pathologist reviewed biopsies on every patient and classified them as microscopic colitis cases or non-microscopic colitis controls. Patients provided information on body weight, height and exposure to medications via structured interviews or Internet based forms. The analysis included 110 patients with microscopic colitis (cases) and 252 non-microscopic colitis controls. Multivariable analyses were performed using logistic regression to estimate odds ratios and 95% confidence intervals. RESULTS: Cases were older and more likely than controls to be white race. Study subjects were well educated, but cases were better educated than controls. Cases with microscopic colitis had lower body mass index than controls and reported more weight loss after the onset of diarrhea. Compared to patients who were normal or under-weight, obese (BMI > 30 kg/m2) patients were substantially less likely to have microscopic colitis after adjusting for age and education, adjusted OR (aOR) 0.35, 95% confidence interval (CI) 0.18-0.66). When stratified by sex, the association was limited to obese women, aOR 0.21, 95%CI: 0.10-0.45. Patients with microscopic colitis were more likely to report weight loss after the onset of diarrhea. After stratifying by weight loss, there remained a strong inverse association between obesity and microscopic colitis, aOR 0.33, 95%CI: 0.10 - 1.11 among the patients who did not lose weight. Ever use of birth control pills was associated with lower risk of microscopic colitis after adjusting for age, education and BMI, aOR 0.38, 95%CI: 0.17-0.84. CONCLUSION: Compared to controls also seen for diarrhea, microscopic colitis cases were less likely to be obese. Mechanisms are unknown but could involve hormonal effects of obesity or the gut microbiome.
Subject(s)
Colitis, Microscopic , Aged , Body Mass Index , Case-Control Studies , Colitis, Microscopic/diagnosis , Colitis, Microscopic/epidemiology , Female , Humans , Male , Obesity/complications , Obesity/diagnosis , Obesity/epidemiology , Risk FactorsABSTRACT
BACKGROUND & AIMS: Single-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 human beings. METHODS: A total of 12,590 single epithelial cells from 3 independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and their capacity for response to extrinsic signals along the gut axis across different human beings. RESULTS: Cells were assigned to 25 epithelial lineage clusters. Multiple accepted intestinal stem cell markers do not specifically mark all human intestinal stem cells. Lysozyme expression is not unique to human Paneth cells, and Paneth cells lack expression of expected niche factors. Bestrophin 4 (BEST4)+ cells express Neuropeptide Y (NPY) and show maturational differences between the small intestine and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell junctions, and nutrient absorption genes show unappreciated regional expression differences across lineages. The differential expression of receptors and drug targets across lineages show biological variation and the potential for variegated responses. CONCLUSIONS: Our study identifies novel lineage marker genes, covers regional differences, shows important differences between mouse and human gut epithelium, and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomic regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.
Subject(s)
Intestinal Mucosa , Transcriptome , Animals , Colon , Epithelium , Humans , Intestinal Mucosa/metabolism , Intestine, Small , Mice , Transcriptome/geneticsABSTRACT
INTRODUCTION: Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and lamina propria on microscopy. We sought to determine whether T-cell percentage was associated with exposures or symptoms. METHODS: We conducted a case-control study that enrolled patients referred for colonoscopy for diarrhea. Patients were classified as microscopic colitis cases or controls by an experienced pathologist. Participants provided information on symptoms and exposures during a telephone or internet survey. Research biopsies from the ascending colon and descending colon were examined using immunofluorescence stains for CD3, CD8, and FOXP3 to determine percent T cells per total epithelial or lamina propria cells. Digital images were analyzed by regions of interest using Tissue Studio. RESULTS: There were 97 microscopic colitis cases and 165 diarrhea controls. There was no association between demographic factors and percentage of intraepithelial or lamina propria T cells. In cases, the mean percent T cells were similar in the right colon and left colon. There was no association between mean percent T cells and stool frequency or consistency. There was no association with irritable bowel syndrome, abdominal pain, or medications purported to cause microscopic colitis. DISCUSSION: The lack of association between the density of T cells and medications raises further doubts about their role in disease etiology. Loose and frequent stools in patients with microscopic colitis are not correlated with T-cell density.
Subject(s)
Colitis, Microscopic , Case-Control Studies , Colitis, Microscopic/diagnosis , Humans , Lymphocytes , Mucous MembraneABSTRACT
BACKGROUND: Endoscopic features of eosinophilic esophagitis (EoE) are measured using the validated EoE Endoscopic Reference Score (EREFS); however, a threshold for treatment response has not been defined. We aimed to determine a cut-point for endoscopic response as measured by EREFS. METHODS: We performed a secondary analysis of a randomized clinical trial comparing budesonide slurry with swallowed fluticasone multidose inhaler for initial treatment of EoE. In the parent trial, EREFS was determined before and after treatment (score range 0-9), as were histologic findings and dysphagia symptoms. We performed tabular, flexible trend, and dependent mixture analyses of measures of treatment response to select the best clinical EREFS threshold. RESULTS: In the 111 included patients (mean age 39 years; 67â% male; 96â% white), an EREFS threshold of ≤â2 was 80â% sensitive (95â% confidence interval [CI] 69â% to 88â%) and 83â% specific (95â%CI 67â% to 94â%) for histologic response (peak ofâ<â15 eosinophils per high-power field). Flexible trend analysis and dependent mixture modeling similarly suggested that a threshold of ≤â2 best captured the correlation of EREFS with histologic and symptomatic measures. Dependent mixture modeling found near-total membership in the response class at EREFS of 0 or 1 and >â75â% at EREFS of 2 or 3. CONCLUSIONS: An EREFS of ≤â2 was the best clinical threshold for endoscopic response to topical steroid treatment, and was consistent with clinical and histologic response. Therefore, future studies can report a binary outcome of endoscopic response when EREFS is 2 or less.
Subject(s)
Deglutition Disorders , Eosinophilic Esophagitis , Adult , Deglutition Disorders/complications , Eosinophilic Esophagitis/drug therapy , Eosinophilic Esophagitis/pathology , Eosinophils/pathology , Esophagoscopy , Female , Fluticasone/therapeutic use , Humans , MaleABSTRACT
BACKGROUND: Microscopic colitis is an increasingly common cause of watery diarrhoea. Several classes of medications have been associated with microscopic colitis in prior studies. AIMS: To determine the association between the use of previously implicated medications and microscopic colitis. METHODS: This was a case-control study of patients referred for elective, outpatient colonoscopy for diarrhoea. Patients were excluded for inflammatory bowel disease, C difficile, or other infectious diarrhoea. Colon biopsies were reviewed by the study pathologist and patients were classified as microscopic colitis cases or non-microscopic colitis controls. RESULTS: The study population included 110 microscopic colitis cases and 252 controls. The cases were older, better educated and more likely to be female. Cases reported a greater number of loose, watery, or liquid stools, nocturnal stools, more urgency and weight loss compared to controls. There was no association with proton pump inhibitors (PPIs), adjusted OR (aOR) 0.66, 95% CI 0.38-1.13 or nonsteroidal anti-inflammatory drugs, aOR 0.68, 95% CI 0.40-1.17. Cholecystectomy was less common in cases, aOR 0.33, 95% CI 0.17-0.64, but microscopic colitis cases had more frequent bowel movements following cholecystectomy. CONCLUSION: Compared to similar patients with diarrhoea, cases with microscopic colitis were not more likely to have taken previously implicated medications. They had more diarrhoea following cholecystectomy, suggesting that bile may play a role in symptoms or aetiology. We conclude that the appropriate choice of controls is crucial to understanding risk factors for microscopic colitis.
Subject(s)
Colitis, Microscopic , Case-Control Studies , Colitis, Microscopic/chemically induced , Colitis, Microscopic/diagnosis , Colitis, Microscopic/epidemiology , Colonoscopy , Diarrhea/chemically induced , Diarrhea/epidemiology , Female , Humans , Male , Proton Pump Inhibitors/adverse effectsABSTRACT
BACKGROUND: The relationship between histologic disease activity in eosinophilic esophagitis (EoE) and generic measures of quality of life (QoL) is unclear. AIMS: To determine differences in QoL in adults with EoE based on histologic activity and assess changes in QoL over time. METHODS: We performed an analysis of prospectively collected data from patients in the University of North Carolina EoE Registry. Patients were categorized with histologically active (≥ 15 eosinophils per high-power field [eos/hpf]) or inactive (< 15 eos/hpf) disease. Dysphagia severity was measured with a Likert scale. QoL was measured with 36-Item Short Form (SF-36), compared between active and inactive groups, and assessed longitudinally. RESULTS: Of 147 EoE cases, those with inactive disease (n = 56) reported less dysphagia severity (3.2 vs. 1.9; p = 0.003) and had lower endoscopic severity (3.8 vs. 1.0; p < 0.001) than those with active disease (n = 91). While SF-36 scores did not differ between active and inactive status, lower mental component scores (MCS) were seen in patients treated with empiric dietary elimination (44.9 vs. 50.8; p = 0.005). Dysphagia severity was negatively correlated with both physical component score (PCS) (r = -0.33; p < 0.001) and MCS (r = -0.18; p = 0.03). Despite more cases achieving histologic response over time, SF-36 scores did not improve on either raw or adjusted analyses. CONCLUSION: QoL measured by SF-36 in EoE was similar regardless of histologic disease activity and was in the range of population averages. General QoL metrics like the SF-36 do not appear to have substantial utility in EoE.
Subject(s)
Deglutition Disorders/pathology , Eosinophilic Esophagitis/pathology , Quality of Life , Adult , Eosinophilic Esophagitis/psychology , Female , Humans , Male , Middle Aged , North Carolina , Prospective Studies , Registries , Young AdultABSTRACT
BACKGROUND AND AIMS: Updated diagnostic guidelines for eosinophilic esophagitis (EoE) have eliminated the requirement for a proton pump inhibitor (PPI) trial, but there are no models to identify patients with EoE based on these new criteria. We aimed to develop a predictive model for diagnosis of EoE based on the updated EoE diagnostic guidelines. METHODS: We performed a secondary analysis of a prospective study of adult patients referred for outpatient esophagogastroduodenoscopy at University of North Carolina who had symptoms of esophageal dysfunction; patients with prevalent EoE were excluded. We analyzed data from 206 EoE cases (mean age 40.1, 62.6% male, 93.2% white) and 306 controls (mean age 52.3, 37.9% male, 79.7% white). We built predictive models for case-control status, using clinical, endoscopic, and histologic features, and defining EoE by either the new or historical definition of PPI non-response. Model discrimination was assessed by the area under the receiver-operator characteristic curve (AUC). RESULTS: Before endoscopy, younger age, male sex, history of atopic condition or food allergy, and dysphagia identified patients with EoE with an AUC of 0.83. When we included endoscopy findings suggestive of EoE, the model identified patients with EoE with an AUC of 0.92; this increased to 0.99 when histology was included. CONCLUSION: We developed a model to identify patients with EoE, without a trial of PPIs, based on updated diagnostic guidelines. Clinical features and endoscopic findings identified patients with EoE with an AUC of 0.92-even without histologic data and in the absence of dysphagia. This model can be used to select patients with upper gastrointestinal symptoms but without dysphagia for early diagnostic endoscopy. The model can also be used to identify cases of EoE when eosinophil counts are greater than 15 in biopsies but other causes of esophageal eosinophilia cannot necessarily be excluded.
Subject(s)
Eosinophilic Esophagitis , Adult , Endoscopy , Eosinophilic Esophagitis/diagnosis , Female , Humans , Male , Middle Aged , Prospective Studies , Proton Pump InhibitorsABSTRACT
INTRODUCTION: We investigated whether dilation modifies the association between symptoms and esophageal eosinophilia (peak esophageal eosinophils/high-power field [eos/hpf]) in patients with eosinophilic esophagitis enrolled into a randomized trial comparing the efficacy of budesonide and fluticasone. METHODS: Baseline Dysphagia Symptom Questionnaire and Eosinophilic Esophagitis Activity Index were available in 102 and 73 patients, respectively, of whom 56 and 39 underwent dilation at screening endoscopy before symptom assessment. The pair-wise relationship between Dysphagia Symptom Questionnaire, Eosinophilic Esophagitis Activity Index, and eos/hpf was analyzed with nonparametric correlations. RESULTS: In nondilated patients, the association between baseline eos/hpf and symptoms was moderate and significant, although it was abolished in dilated patients. DISCUSSION: Dilation modifies association between symptoms and eos/hpf (clinicaltrials.gov NCT02019758).
Subject(s)
Deglutition Disorders/therapy , Eosinophilia/therapy , Eosinophilic Esophagitis/therapy , Esophagoscopy , Deglutition Disorders/complications , Deglutition Disorders/diagnosis , Dilatation/methods , Eosinophilia/complications , Eosinophilia/diagnosis , Eosinophilic Esophagitis/complications , Eosinophilic Esophagitis/diagnosis , Esophagus , Female , Humans , Male , Severity of Illness Index , Symptom AssessmentABSTRACT
Inflammatory factors in eosinophilic esophagitis (EoE), including major basic protein (MBP), eotaxin-3 (EOT3) and mast cell tryptase (TRP), may predict treatment response to topical corticosteroids (tCS). We aimed to determine whether baseline levels of these markers predict response to tCS for EoE. To do this, we analyzed data from a randomized trial comparing two topical steroids for treatment of newly diagnosed EoE (NCT02019758). A pretreatment esophageal biopsy was stained for MBP, EOT3, and TRP to quantify tissue biomarker levels (cells/mm2). Levels were compared between histologic responders (<15 eos/hpf) and nonresponders (the primary outcome), and endoscopic responders (EREFS<2) and nonresponders. Complete histologic response (<1 eos/hpf) was also assessed, and area under the receiver operator characteristic curve (AUC) was calculated. We also evaluated whether baseline staining predicted symptom relapse in the trial's off-treatment observation phase. Baseline samples were evaluable in 110/111 subjects who completed the randomized trial. MBP levels were higher in nonresponders (n = 36) than responders (704 vs. 373 cells/mm2; P = 0.007), but EOT3 and TRP levels were not statistically different. The combination of all three stains had an AUC of 0.66 to predict response. For complete histologic response, baseline TRP levels were higher in nonresponders (n = 69) than responders (370 vs. 268 mast cells/mm2; P = 0.01), with an AUC of 0.65. The AUC for endoscopic response was 0.68. Baseline staining did not predict symptom recurrence after remission. Pretreatment MBP, EOT3, and TRP levels were not strongly or consistently associated with histologic or endoscopic response to topical steroids. While elevated TRP levels may be associated with nonresponse compared with complete response, the magnitude and predictive utilities were modest. Novel methods for predicting steroid response are still required.
Subject(s)
Biomarkers , Eosinophilic Esophagitis , Steroids , Chemokine CCL26 , Eosinophil Major Basic Protein , Eosinophilic Esophagitis/drug therapy , Humans , Staining and Labeling , Steroids/administration & dosage , Treatment Outcome , TryptasesABSTRACT
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is chronic and recurs if treatment is discontinued. We aimed to determine rates of recurrence, and whether initial treatment with oral viscous budesonide (OVB) resulted in less recurrence than fluticasone from a multidose inhaler (MDI). METHODS: This was the observation phase of a randomized, double-blind, double-dummy trial comparing OVB with MDI for initial EoE treatment. Subjects with a histologic response (<15 eosinophils/high-power field) in the trial entered an observation phase in which treatment was discontinued and symptoms were monitored. Patients underwent an endoscopy or a biopsy when symptoms recurred or at 1 year. We analyzed time to symptom recurrence and assessed endoscopic severity and histologic relapse (≥15 eosinophils/high-power field) at follow-up endoscopy. RESULTS: Thirty-three of the 58 subjects (57%) had symptom recurrence before 1 year. The overall median time to symptom recurrence was 244 days. There was no difference in the rate of symptom recurrence for subjects treated with OVB vs MDI (hazard ratio, 1.04; 95% CI, 0.52-2.08). At symptom recurrence, 78% of patients had histologic relapse. The patients had significant increases in mean Dysphagia Symptom Questionnaire score (3.8 vs 8.7; P < .001), and the EoE Endoscopic Reference Score (1.3 vs 4.6; P < .001) compared with end of treatment. CONCLUSIONS: EoE disease activity recurred rapidly after initial histologic response to topical steroids (either OVB or MDI). Because most subjects had recurrent endoscopic and histologic signs not reliably detected by symptoms, maintenance therapy should be recommended in EoE patients achieving histologic response to topical steroids. Clinicaltrials.gov no: NCT02019758.
Subject(s)
Eosinophilic Esophagitis , Anti-Inflammatory Agents/therapeutic use , Eosinophilic Esophagitis/drug therapy , Esophagoscopy , Humans , Recurrence , Treatment OutcomeABSTRACT
Non-dysphagia symptoms, such as heartburn and dyspepsia, are poorly characterized in adults with eosinophilic esophagitis (EoE). It is unclear if treatment improves these symptoms. The aim of this paper was to assess (i) heartburn and dyspepsia symptom severity in adult EoE patients using validated symptom measures; (ii) change in symptoms after treatment; and (iii) symptom association with endoscopic and histologic features. In a prospective cohort of adult EoE patients who were not responsive to proton pump inhibitor therapy, non-dysphagia symptoms were assessed with heartburn items from the validated GERD-HRQL (gastroesophageal reflux disease health-related quality of life) and SODA (severity of dyspepsia assessment) instruments. Subjects completed the questionnaires at baseline and after treatment. Association of baseline symptoms with endoscopic and histologic features, and before and after treatment with diet or topical steroids, was assessed. Eighty-six EoE patients (mean age 39 years, 57% male, 95% white) completed a baseline questionnaire and 62 completed the follow-up questionnaire. The mean baseline GERD-HRQL score was 4.5 ± 6.5 and the mean total SODA score was 41.0 ± 12.6. At baseline, there was a weak but significant correlation between peak eosinophils and the SODA score (r = 0.28; p = 0.03) and no association between heartburn and SODA scores and endoscopic or other histologic findings. After treatment, there was a decrease in GERD-HRQL heartburn (4.3 vs. 2.6; p = 0.04) and SODA (49.5 vs. 35.5; p = 0.04) scores in histologic responders, but not in nonresponders. In a prospective cohort of EoE patients, baseline eosinophils positively correlated with dyspepsia severity. Heartburn and dyspepsia symptoms improved after treatment in histologic responders.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Diet Therapy , Dyspepsia/diagnosis , Eosinophilic Esophagitis/therapy , Heartburn/diagnosis , Severity of Illness Index , Adult , Budesonide/therapeutic use , Combined Modality Therapy , Dyspepsia/etiology , Eosinophilic Esophagitis/complications , Eosinophilic Esophagitis/diagnostic imaging , Eosinophilic Esophagitis/pathology , Esophagoscopy , Female , Fluticasone/therapeutic use , Follow-Up Studies , Heartburn/etiology , Humans , Male , Middle Aged , Prospective Studies , Quality of Life , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Topical steroid treatments for eosinophilic esophagitis (EoE) include swallowed fluticasone from a multi-dose inhaler (MDI) or oral viscous budesonide (OVB) slurry, but the 2 have never been compared. We assessed whether OVB was more effective than MDI for initial treatment of patients with EoE. METHODS: In a double-blind, double-dummy trial, patients with a new diagnosis of EoE were randomly assigned to groups given 8 weeks of either OVB (1 mg/4 mL) twice daily plus a placebo inhaler (n = 56) or fluticasone MDI (880 µg) twice daily plus a placebo slurry (n = 55). Primary outcomes were post-treatment maximum eosinophil counts per high-power field (eos/hpf) and a validated dysphagia score (dysphagia symptom questionnaire [DSQ]) at week 8. Secondary outcomes included endoscopic severity (validated EoE endoscopic reference score), histologic response (<15 eos/hpf), and safety. RESULTS: In a modified intention-to-treat analysis, the subjects had baseline peak eosinophil counts of 73 and 77 eos/hpf in the OVB and MDI groups, respectively, and DSQ scores of 11 and 8. Post-treatment eosinophil counts were 15 and 21 in the OVB and MDI groups, respectively (P = .31), with 71% and 64% achieving histologic response (P = .38). DSQ scores were 5 and 4 in the OVB and MDI groups (P = .70). Similar trends were noted for post-treatment total EoE endoscopic reference scores (2 vs 3; P = .06). Esophageal candidiasis developed in 12% of patients receiving OVB and 16% receiving MDI; oral thrush was observed in 3% and 2%, respectively. CONCLUSIONS: In a randomized clinical trial, initial treatment of EoE with either OVB or fluticasone MDI produced a significant decrease in esophageal eosinophil counts and improved dysphagia and endoscopic features. However, OVB was not superior to MDI, so either is an acceptable treatment for EoE. ClinicalTrials.gov ID NCT02019758.
Subject(s)
Budesonide/therapeutic use , Eosinophilic Esophagitis/drug therapy , Fluticasone/therapeutic use , Glucocorticoids/therapeutic use , Administration, Oral , Administration, Topical , Adolescent , Adult , Eosinophilic Esophagitis/pathology , Esophagoscopy , Female , Humans , Male , Metered Dose Inhalers , Middle Aged , Treatment Outcome , Vascular Ring , Young AdultABSTRACT
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is assessed endoscopically (endoscopic activity), based on grades of edema, rings, exudates, furrows, and strictures (EREFS). We examined variations in endoscopic assessments of severity, developed and validated 3 EREFS-based scoring systems, and assessed responsiveness of these systems using data from a randomized placebo-controlled trial of patients with EoE. METHODS: For the development set, 5 gastroenterologists reviewed EREFS findings from 266 adults with EoE and provided endoscopist global assessment scores (EndoGA, scale of 0 to 10); variation (ΔEndoGA) was assessed using linear regression. We evaluated simple scores (features given arbitrary values from 0 to 3) and developed 2 scoring systems (adjusted score range, 0-100). We then fitted our linear regression model with mean EndoGA to data from 146 adults recruited in centers in Switzerland and the United States between April 2011 and December 2012. For the validation set, we collected data from 120 separate adults (recruited in centers in Switzerland and the United States between May 2013 and July 2014), assessing regression coefficient-based scores using Bland-Altman method. We assessed the responsiveness of our scoring systems using data from a randomized trial of patients with EoE given fluticasone (n=16) or placebo (n=8). RESULTS: The distribution of EndoGA values differed among endoscopists (mean ΔEndoGA, 2.6±1.8; range 0-6.6). We developed 2 regression-based scoring systems to assess overall and proximal and distal esophageal findings; variation in endoscopic features accounted for more than 90% of the mean EndoGA variation. In the validation group, differences between mean EndoGA and regression-based scores were small (ranging from -4.70 to 2.03), indicating good agreement. In analyses of data from the randomized trial, the baseline to end of study change in patients given fluticasone was a reduction of 24.3 in simple score (reduction of 4.6 in patients given placebo, P=.052); a reduction of 23.5 in regression-based overall score (reduction of 6.56 in patients given placebo, P=.12), and a reduction of 23.8 (reduction of 8.44 in patients given placebo, P=.11). CONCLUSION: Assessments of endoscopic activity in patients with EoE vary among endoscopists. In an analysis of data from a randomized controlled trial, we found that newly developed scoring systems are no better than simple scoring system in detecting changes in endoscopic activity. These results support the use of a simple scoring system in evaluation of endoscopic activity in patients with EoE. clinicaltrials.gov no: NCT00939263 and NCT01386112.
Subject(s)
Eosinophilic Esophagitis/diagnosis , Esophagoscopy/methods , Esophagus/pathology , Fluticasone/administration & dosage , Adolescent , Adult , Aged , Anti-Inflammatory Agents/administration & dosage , Dose-Response Relationship, Drug , Eosinophilic Esophagitis/drug therapy , Female , Humans , Male , Middle Aged , Prognosis , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND & AIMS: Few factors have been identified that can be used to predict response of patients with eosinophilic esophagitis (EoE) to topical steroid treatment. We aimed to determine whether baseline clinical, endoscopic, histologic, and molecular features of EoE can be used to predict histologic response. METHODS: We collected data from 97 patients with EoE, from 2009 through 2015, treated with a topical steroid for 8 weeks; 59 patients had a histologic response to treatment. Baseline clinicopathologic features and gene expression patterns were compared between patients with a histologic response to treatment (<15 eos/hpf) and non-responders (≥15 eos/hpf). We performed sensitivity analyses for alternative histologic response definitions. Multivariate logistic regression was performed to identify predictive factors associated with response to therapy, which were assessed with area under the receiver operator characteristic (AUROC) curves. RESULTS: Baseline dilation was the only independent predictor of non-response (odds ratio [OR], 0.30; 95% CI, 0.10-0.89). When an alternate response (<1 eos/hpf) and non-response (<50% decrease in baseline eos/hpf) definition was used, independent predictors of response status were age (OR, 1.08; 95% CI, 1.02-1.14), food allergies (OR, 12.95; 95% CI, 2.20-76.15), baseline dilation (OR, 0.17; 95% CI, 0.03-0.88), edema or decreased vascularity (OR, 0.20; 95% CI, 0.04-1.03), and hiatal hernia (OR, 0.07; 95% CI, 0.01-0.66). Using these 5 factors, we developed a predictive model that discriminated complete responders from non-responders with an AUROC of 0.88. Baseline gene expression patterns were not associated with treatment response and did not change with different histologic response thresholds. CONCLUSIONS: In an analysis of 97 patients with EoE, we found dilation to be the only baseline factor associated with non-response to steroid treatment (<15 eos/hpf). However, a model comprising 5 clinical, endoscopic, and histologic factors identified patients with a complete response (<1 eos/hpf). A baseline gene expression panel was not predictive of treatment response at any threshold.
Subject(s)
Budesonide/administration & dosage , Eosinophilic Esophagitis/drug therapy , Esophagus/pathology , Fluticasone/administration & dosage , Administration, Topical , Adult , Biomarkers/metabolism , Biopsy , Eosinophilic Esophagitis/metabolism , Eosinophilic Esophagitis/pathology , Esophagoscopy , Esophagus/drug effects , Female , Follow-Up Studies , Glucocorticoids/administration & dosage , Humans , Male , Prospective Studies , Treatment OutcomeSubject(s)
Eosinophilic Esophagitis/pathology , Mast Cells/pathology , Adult , Cell Count , Cohort Studies , Endoscopy , Eosinophils/pathology , Female , Histology , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND AND AIMS: No prospective studies substantiate 15 eos/hpf as an appropriate endpoint for treatment of eosinophilic esophagitis (EoE). We aimed to determine a histologic cutpoint that identifies successful treatment of EoE by assessing symptomatic and endoscopic improvement. METHODS: We performed a prospective cohort study of 62 consecutive adult patients undergoing outpatient esophagogastroduodenoscopy at the University of North Carolina from 2009 through 2014. At diagnosis of EoE and after 8 weeks of standard treatment, symptom and endoscopic responses were measured using a visual analogue scale and an endoscopic severity score (ESS), and eosinophil counts were assessed. Receiver operator curves and logistic regression models evaluated the histologic threshold that best predicted symptomatic and endoscopic response. For symptoms, analysis was limited to patients without baseline esophageal dilation. RESULTS: The mean eosinophil count at diagnosis was 124 eos/hpf, falling to 35 eos/hpf after treatment. The mean visual analogue scale decreased from 3.4 at baseline to 1.7 after treatment, and the mean ESS decreased from 3 to 1.6. Twenty-nine patients had symptom responses (47%) and 34 had endoscopic responses (55%). Post-treatment eosinophil count thresholds of 8, 15, and 5 eos/hpf best predicted symptom, endoscopic and combined responses, respectively. On logistic regression, decreasing eosinophil count was significantly associated with the probability of symptomatic (P = .01) and endoscopic response (P < .001). CONCLUSIONS: In a prospective study of patients with EoE, we found that a cutpoint of <15 eos/hpf identifies most patients with symptom and endoscopic improvements, providing support for the current diagnostic threshold. A lower threshold (<5 eos/hpf) identifies most patients with a combination of symptom and endoscopic responses; this cutpoint might be used in situations that require a stringent histologic threshold.