Browsing by Author "Martin, Lisa J."
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Item Development and Validation of Web-Based Tool to Predict Lamina Propria Fibrosis in Eosinophilic Esophagitis(Wolters Kluwer, 2022) Hiremath, Girish; Sun, Lili; Correa, Hernan; Acra, Sari; Collins, Margaret H.; Bonis, Peter; Arva, Nicoleta C.; Capocelli, Kelley E.; Falk, Gary W.; King, Eileen; Gonsalves, Nirmala; Gupta, Sandeep K.; Hirano, Ikuo; Mukkada, Vincent A.; Martin, Lisa J.; Putnam, Philip E.; Spergel, Jonathan M.; Wechsler, Joshua B.; Yang, Guang-Yu; Aceves, Seema S.; Furuta, Glenn T.; Rothenberg, Marc E.; Koyama, Tatsuki; Dellon, Evan S.; Medicine, School of MedicineIntroduction: Approximately half of esophageal biopsies from patients with eosinophilic esophagitis (EoE) contain inadequate lamina propria, making it impossible to determine the lamina propria fibrosis (LPF). This study aimed to develop and validate a web-based tool to predict LPF in esophageal biopsies with inadequate lamina propria. Methods: Prospectively collected demographic and clinical data and scores for 7 relevant EoE histology scoring system epithelial features from patients with EoE participating in the Consortium of Eosinophilic Gastrointestinal Disease Researchers observational study were used to build the models. Using the least absolute shrinkage and selection operator method, variables strongly associated with LPF were identified. Logistic regression was used to develop models to predict grade and stage of LPF. The grade model was validated using an independent data set. Results: Of 284 patients in the discovery data set, median age (quartiles) was 16 (8-31) years, 68.7% were male patients, and 93.4% were White. Age of the patient, basal zone hyperplasia, dyskeratotic epithelial cells, and surface epithelial alteration were associated with presence of LPF. The area under the receiver operating characteristic curve for the grade model was 0.84 (95% confidence interval: 0.80-0.89) and for stage model was 0.79 (95% confidence interval: 0.74-0.84). Our grade model had 82% accuracy in predicting the presence of LPF in an external validation data set. Discussion: We developed parsimonious models (grade and stage) to predict presence of LPF in esophageal biopsies with inadequate lamina propria and validated our grade model. Our predictive models can be easily used in the clinical setting to include LPF in clinical decisions and determine its effect on treatment outcomes.Item Esophageal Epithelium and Lamina Propria Are Unevenly Involved in Eosinophilic Esophagitis(Elsevier, 2023-03-24) Hiremath, Girish; Sun, Lili; Collins, Margaret H.; Bonis, Peter A.; Arva, Nicoleta C.; Capocelli, Kelley E.; Chehade, Mirna; Davis, Carla M.; Falk, Gary W.; Gonsalves, Nirmala; Gupta, Sandeep K.; Hirano, Ikuo; Leung, John; Khoury, Paneez; Mukkada, Vincent A.; Martin, Lisa J.; Spergel, Jonathan M.; Wechsler, Joshua B.; Yang, Guang-Yu; Aceves, Seema S.; Furuta, Glenn T.; Rothenberg, Marc E.; Koyama, Tatsuki; Dellon, Evan S.; Medicine, School of MedicineBackground & Aims The nature of the involvement of esophageal tissue in eosinophilic esophagitis (EoE) is unclear. We estimated the intrabiopsy site agreements of the EoE Histologic Scoring System (EoEHSS) scores for the grade (degree) and stage (extent) of involvement of the esophageal epithelial and lamina propria and examined if the EoE activity status influenced the intrabiopsy site agreement. Methods Demographic, clinical, and EoEHSS scores collected as part of the prospective Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages study were analyzed. A weighted Cohen’s kappa agreement coefficient (k) was used to calculate the pairwise agreements for proximal:distal, proximal:middle, and middle:distal esophageal biopsy sites, separately for grade and stage scores, for each of the 8 components of EoEHSS. A k > 0.75 was considered uniform involvement. Inactive EoE was defined as fewer than 15 eosinophils per high-powered field. Results EoEHSS scores from 1263 esophageal biopsy specimens were analyzed. The k for the stage of involvement of the dilated intercellular spaces across all 3 sites in inactive EoE was consistently greater than 0.75 (range, 0.87–0.99). The k for lamina propria fibrosis was greater than 0.75 across some of the biopsy sites but not across all 3. Otherwise, the k for all other features, for both grade and stage, irrespective of the disease activity status, was 0.75 or less (range, 0.00–0.74). Conclusions Except for the extent of involvement of dilated intercellular spaces in inactive EoE, the remaining epithelial features and lamina propria are involved unevenly across biopsy sites in EoE, irrespective of the disease activity status. This study enhances our understanding of the effects of EoE on esophageal tissue pathology.Item Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study(American Heart Association, 2021-05-04) Ware, Stephanie M.; Wilkinson, James D.; Tariq, Muhammad; Schubert, Jeffrey A.; Sridhar, Arthi; Colan, Steven D.; Shi, Ling; Canter, Charles E.; Hsu, Daphne T.; Webber, Steven A.; Dodd, Debra A.; Everitt, Melanie D.; Kantor, Paul F.; Addonizio, Linda J.; Jefferies, John L.; Rossano, Joseph W.; Pahl, Elfriede; Rusconi, Paolo; Chung, Wendy K.; Lee, Teresa; Towbin, Jeffrey A.; Lal, Ashwin K.; Bhatnagar, Surbhi; Aronow, Bruce; Dexheimer, Phillip J.; Martin, Lisa J.; Miller, Erin M.; Sleeper, Lynn A.; Razoky, Hiedy; Czachor, Jason; Lipshultz, Steven E.; Pediatrics, School of MedicinePediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.Item International consensus recommendations for eosinophilic gastrointestinal disease nomenclature(Elsevier, 2022-02-16) Dellon, Evan S.; Gonsalves, Nirmala; Abonia, J. Pablo; Alexander, Jeffrey A.; Arva, Nicoleta C.; Atkins, Dan; Attwood, Stephen E.; Auth, Marcus K.H.; Bailey, Dominique D.; Biederman, Luc; Blanchard, Carine; Bonis, Peter A.; Bose, Paroma; Bredenoord, Albert J.; Chang, Joy W.; Chehade, Mirna; Collins, Margaret H.; Di Lorenzo, Carlo; Dias, Jorge Amil; Dohil, Ranjan; Dupont, Christophe; Falk, Gary W.; Ferreira, Cristina T.; Fox, Adam T.; Genta, Robert M.; Greuter, Thomas; Gupta, Sandeep K.; Hirano, Ikuo; Hiremath, Girish S.; Horsley-Silva, Jennifer L.; Ishihara, Shunji; Ishimura, Norihisa; Jensen, Elizabeth T.; Gutiérrez-Junquera, Carolina; Katzka, David A.; Khoury, Paneez; Kinoshita, Yoshikazu; Kliewer, Kara L.; Koletzko, Sibylle; Leung, John; Liacouras, Chris A.; Lucendo, Alfredo J.; Martin, Lisa J.; McGowan, Emily C.; Menard-Katcher, Calies; Metz, David C.; Miller, Talya L.; Moawad, Fouad J.; Muir, Amanda B.; Mukkada, Vincent A.; Murch, Simon; Nhu, Quan M.; Nomura, Ichiro; Nurko, Samuel; Ohtsuka, Yoshikazu; Oliva, Salvatore; Orel, Rok; Papadopoulou, Alexandra; Patel, Dhyanesh A.; Pesek, Robert D.; Peterson, Kathryn A.; Philpott, Hamish; Putnam, Philip E.; Richter, Joel E.; Rosen, Rachel; Ruffner, Melanie A.; Safroneeva, Ekaterina; Schreiner, Philipp; Schoepfer, Alain; Schroeder, Shauna R.; Shah, Neil; Souza, Rhonda F.; Spechler, Stuart J.; Spergel, Jonathan M.; Straumann, Alex; Talley, Nicholas J.; Thapar, Nikhil; Vandenplas, Yvan; Venkatesh, Rajitha D.; Vieira, Mario C.; von Arnim, Ulrike; Walker, Marjorie M.; Wechsler, Joshua B.; Wershil, Barry K.; Wright, Benjamin L.; Yamada, Yoshiyuki; Yang, Guang-Yu; Zevit, Noam; Rothenberg, Marc E.; Furuta, Glenn T.; Aceves, Seema S.; Pediatrics, School of MedicineBackground & Aims Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGID), particularly the catchall term “eosinophilic gastroenteritis”, limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature. Methods This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in two consensus meetings, the framework was updated, and re-assessed in a second Delphi vote, with a 70% threshold set for agreement. Results Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but two statements. “EGID” was the preferred umbrella term for disorders of GI tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an “Eo” abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term “eosinophilic gastroenteritis” is no longer preferred as the overall name (96% agreement). When >2 GI tract areas are involved, the name should reflect all of the involved areas. Conclusions This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term rather than “eosinophilic gastroenteritis”, and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science.Item Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms Following Dilation in Adults with Eosinophilic Esophagitis(Elsevier, 2021-05-29) Safroneeva, Ekaterina; Pan, Zhaoxing; King, Eileen; Martin, Lisa J.; Collins, Margaret H.; Yang, Guang-Yu; Capocelli, Kelley E.; Arva, Nicoleta C.; Abonia, J. Pablo; Atkins, Dan; Bonis, Peter A.; Dellon, Evan S.; Falk, Gary W.; Gonsalves, Nirmala; Gupta, Sandeep K.; Hirano, Ikuo; Leung, John; Menard-Katcher, Paul A.; Mukkada, Vincent A.; Schoepfer, Alain M.; Spergel, Jonathan M.; Wershil, Barry K.; Rothenberg, Marc E.; Aceves, Seema S.; Furuta, Glenn T.; Pediatrics, School of MedicineBackground and aims Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and esophageal eosinophil count (eos/hpf). Methods Adults enrolled in a multisite, prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers OMEGA observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsies. Patients were stratified based on dilation status as absent, performed ≤1 and >1 year before endoscopy. Assessments included Spearman’s correlations of the relationship between symptoms and eos/hpf and linear regression with EEsAI as the outcome, eos/hpf as predictor, and interaction for dilation and eos/hpf. Results Amongst 100 patients (n=61 male, median age 37 years), 15 and 40 patients underwent dilation ≤1 year and >1 year before index endoscopy, respectively. In non-dilated patients, association between eos/hpf and symptoms was moderate (Rho=0.49, p-value<0.001); for 10 eos/hpf increase, the predicted EEsAI increased by 2.69 (p-value=0.002). In patients dilated ≤1 and >1 year before index endoscopy, this association was abolished (Rho=-0.38, p-value=0.157 for ≤1 year and Rho=0.02, p-value=0.883 >1 year); for 10 eos/hpf increase, the predicted EEsAI changed by -1.64 (p-value=0.183) and 0.78 (p-value=0.494), respectively). Dilation modifies association between symptoms and eos/hpf (p-value=0.005 and p-value=0.187 for interaction terms of eos/hpf and dilation ≤1 year and >1 year before index endoscopy, respectively). Conclusion In non-dilated EoE adults, eos/hpf correlates modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than one year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up.Item Mucosal Microbiota Associated With Eosinophilic Esophagitis and Eosinophilic Gastritis(Wiley, 2023) Furuta, Glenn T.; Fillon, Sophie A.; Williamson, Kayla M.; Robertson, Charles E.; Stevens, Mark J.; Aceves, Seema S.; Arva, Nicoleta C.; Chehade, Mirna; Collins, Margaret H.; Davis, Carla M.; Dellon, Evan S.; Falk, Gary W.; Gonsalves, Nirmala; Gupta, Sandeep K.; Hirano, Ikuo; Khoury, Paneez; Leung, John; Martin, Lisa J.; Menard-Katcher, Paul; Mukkada, Vincent A.; Peterson, Kathryn; Spergel, Jonathan M.; Wechsler, Joshua B.; Yang, Guang-Yu; Rothenberg, Marc E.; Harris, J. Kirk; Pediatrics, School of MedicineObjective: The aim of the study was to determine the mucosal microbiota associated with eosinophilic esophagitis (EoE) and eosinophilic gastritis (EoG) in a geographically diverse cohort of patients compared to controls. Methods: We conducted a prospective study of individuals with eosinophilic gastrointestinal disease (EGID) in the Consortium of Eosinophilic Gastrointestinal Disease Researchers, including pediatric and adult tertiary care centers. Eligible individuals had clinical data, mucosal biopsies, and stool collected. Total bacterial load was determined from mucosal biopsy samples by quantitative polymerase chain reaction (PCR). Community composition was determined by small subunit rRNA gene amplicons. Results: One hundred thirty-nine mucosal biopsies were evaluated corresponding to 93 EoE, 17 EoG, and 29 control specimens (18 esophageal) from 10 sites across the United States. Dominant community members across disease activity differed significantly. When comparing EoE and EoG with controls, the dominant taxa in individuals with EGIDs was increased ( Streptococcus in esophagus; Prevotella in stomach). Specific taxa were associated with active disease for both EoE ( Streptococcus , Gemella ) and EoG ( Leptotrichia ), although highly individualized communities likely impacted statistical testing. Alpha diversity metrics were similar across groups, but with high variability among individuals. Stool analyses did not correlate with bacterial communities found in mucosal biopsy samples and was similar in patients and controls. Conclusions: Dominant community members ( Streptococcus for EoE, Prevotella for EoG) were different in the mucosal biopsies but not stool of individuals with EGIDs compared to controls; taxa associated with EGIDs were highly variable across individuals. Further study is needed to determine if therapeutic interventions contribute to the observed community differences.Item One Food versus Six Food Elimination Diet Therapy for Treatment of Eosinophilic Esophagitis: A Multicenter Randomized Clinical Trial(Elsevier, 2023) Kliewer, Kara L.; Gonsalves, Nirmala; Dellon, Evan S.; Katzka, David A.; Abonia, Juan P.; Aceves, Seema S.; Arva, Nicoleta C.; Besse, John A.; Bonis, Peter A.; Caldwell, Julie M.; Capocelli, Kelley E.; Chehade, Mirna; Cianferoni, Antonella; Collins, Margaret H.; Falk, Gary W.; Gupta, Sandeep K.; Hirano, Ikuo; Krischer, Jeffrey P.; Leung, John; Martin, Lisa J.; Menard-Katcher, Paul; Mukkada, Vincent A.; Peterson, Kathryn A.; Shoda, Tetsuo; Rudman Spergel, Amanda K.; Spergel, Jonathan M.; Yang, Guang-Yu; Zhang, Xue; Furuta, Glenn T.; Rothenberg, Marc E.; Pediatrics, School of MedicineBackground: Empirical elimination diets are effective for achieving histological remission in eosinophilic oesophagitis, but randomised trials comparing diet therapies are lacking. We aimed to compare a six-food elimination diet (6FED) with a one-food elimination diet (1FED) for the treatment of adults with eosinophilic oesophagitis. Methods: We conducted a multicentre, randomised, open-label trial across ten sites of the Consortium of Eosinophilic Gastrointestinal Disease Researchers in the USA. Adults aged 18-60 years with active, symptomatic eosinophilic oesophagitis were centrally randomly allocated (1:1; block size of four) to 1FED (animal milk) or 6FED (animal milk, wheat, egg, soy, fish and shellfish, and peanut and tree nuts) for 6 weeks. Randomisation was stratified by age, enrolling site, and gender. The primary endpoint was the proportion of patients with histological remission (peak oesophageal count <15 eosinophils per high-power field [eos/hpf]). Key secondary endpoints were the proportions with complete histological remission (peak count ≤1 eos/hpf) and partial remission (peak counts ≤10 and ≤6 eos/hpf) and changes from baseline in peak eosinophil count and scores on the Eosinophilic Esophagitis Histology Scoring System (EoEHSS), Eosinophilic Esophagitis Endoscopic Reference Score (EREFS), Eosinophilic Esophagitis Activity Index (EEsAI), and quality of life (Adult Eosinophilic Esophagitis Quality-of-Life and Patient Reported Outcome Measurement Information System Global Health questionnaires). Individuals without histological response to 1FED could proceed to 6FED, and those without histological response to 6FED could proceed to swallowed topical fluticasone propionate 880 μg twice per day (with unrestricted diet), for 6 weeks. Histological remission after switching therapy was assessed as a secondary endpoint. Efficacy and safety analyses were done in the intention-to-treat (ITT) population. This trial is registered on ClinicalTrials.gov, NCT02778867, and is completed. Findings: Between May 23, 2016, and March 6, 2019, 129 patients (70 [54%] men and 59 [46%] women; mean age 37·0 years [SD 10·3]) were enrolled, randomly assigned to 1FED (n=67) or 6FED (n=62), and included in the ITT population. At 6 weeks, 25 (40%) of 62 patients in the 6FED group had histological remission compared with 23 (34%) of 67 in the 1FED group (difference 6% [95% CI -11 to 23]; p=0·58). We found no significant difference between the groups at stricter thresholds for partial remission (≤10 eos/hpf, difference 7% [-9 to 24], p=0·46; ≤6 eos/hpf, 14% [-0 to 29], p=0·069); the proportion with complete remission was significantly higher in the 6FED group than in the 1FED group (difference 13% [2 to 25]; p=0·031). Peak eosinophil counts decreased in both groups (geometric mean ratio 0·72 [0·43 to 1·20]; p=0·21). For 6FED versus 1FED, mean changes from baseline in EoEHSS (-0·23 vs -0·15; difference -0·08 [-0·21 to 0·05]; p=0·23), EREFS (-1·0 vs -0·6; difference -0·4 [-1·1 to 0·3]; p=0·28), and EEsAI (-8·2 vs -3·0; difference -5·2 [-11·2 to 0·8]; p=0·091) were not significantly different. Changes in quality-of-life scores were small and similar between the groups. No adverse event was observed in more than 5% of patients in either diet group. For patients without histological response to 1FED who proceeded to 6FED, nine (43%) of 21 reached histological remission; for patients without histological response to 6FED who proceeded to fluticasone propionate, nine (82%) of 11 reached histological remission. Interpretation: Histological remission rates and improvements in histological and endoscopic features were similar after 1FED and 6FED in adults with eosinophilic oesophagitis. 6FED had efficacy in just less than half of 1FED non-responders and steroids had efficacy in most 6FED non-responders. Our findings indicate that eliminating animal milk alone is an acceptable initial dietary therapy for eosinophilic oesophagitis.Item The genetic architecture of pediatric cardiomyopathy(Elsevier, 2022) Ware, Stephanie M.; Bhatnagar, Surbhi; Dexheimer, Phillip J.; Wilkinson, James D.; Sridhar, Arthi; Fan, Xiao; Shen, Yufeng; Tariq, Muhammad; Schubert, Jeffrey A.; Colan, Steven D.; Shi, Ling; Canter, Charles E.; Hsu, Daphne T.; Bansal, Neha; Webber, Steven A.; Everitt, Melanie D.; Kantor, Paul F.; Rossano, Joseph W.; Pahl, Elfriede; Rusconi, Paolo; Lee, Teresa M.; Towbin, Jeffrey A.; Lal, Ashwin K.; Chung, Wendy K.; Miller, Erin M.; Aronow, Bruce; Martin, Lisa J.; Lipshultz, Steven E.; Pediatric Cardiomyopathy Registry Study Group; Pediatrics, School of MedicineTo understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.