Development of the Pediatric Quality of Life Inventory™ Eosinophilic Esophagitis module items: qualitative methods.

BACKGROUND: Currently there is no disease-specific outcome measure to assess the health-related quality of life (HRQOL) of pediatric patients with Eosinophilic Esophagitis (EoE). Therefore, the objective of this qualitative study was to further develop and finalize the items and support the content validity for the new Pediatric Quality of Life Inventory™ (PedsQL™) Eosinophilic Esophagitis Module. METHODS: Multiphase qualitative methodology was utilized in the development of the PedsQL™ EoE Module conceptual model. Focus interview transcripts of pediatric patients with EoE and their parents and expert review were previously used to develop the initial items and domains for the PedsQL™ EoE Module. In the current investigation, utilizing the respondent debriefing methodology, cognitive interviewing was conducted individually with pediatric patients with EoE and their parents on each newly developed item. RESULTS: Information from a total of 86 participants was obtained in combination from the previous investigation and the current study. From the previous 42 focus interviews, items were developed around the domain themes of symptoms, difficulties with eating food, treatment adherence, worry about symptoms and illness, feelings of being different than family and peers, and problems discussing EoE with others. In the current study's cognitive interviewing phase, a separate cohort of 44 participants systematically reviewed and provided feedback on each item. Items were added, modified or deleted based on this feedback. Items were finalized after this feedback from patients and parents. CONCLUSIONS: Using well-established qualitative methods, the content validity of the new PedsQL™ Eosinophilic Esophagitis Module items was supported in the current investigation. In the next iterative instrument development phase, the PedsQL™ Eosinophilic Esophagitis Module is now undergoing multisite national field testing.

Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods.

BACKGROUND: Previous attempts to measure symptoms in pediatric Eosinophilic Esophagitis (EoE) have not fully included patients and parents in the item development process. We sought to identify and validate key patient self-reported and parent proxy-reported outcomes (PROs) specific to EoE. METHODS: We developed methodology for focus and cognitive interviews based on the Food and Drug Administration (FDA) guidelines for PROs, the validated generic PedsQL™ guidelines, and the consolidated criteria for reporting qualitative research (COREQ). Both child (ages 8-12 and 13-18) and parent-proxy (ages 2-4, 5-7, 8-12, and 13-18) interviews were conducted. RESULTS: We conducted 75 interviews to construct the new instrument. Items were identified and developed from individual focus interviews, followed by cognitive interviews for face and content validation. Initial domains of symptom frequency and severity were developed, and open-ended questions were used to generate specific items during the focus interviews. Once developed, the instrument construct, instructions, timeframe, scoring, and specific items were systematically reviewed with a separate group of patients and their parents during the cognitive interviews. CONCLUSIONS: To capture the full impact of pediatric EoE, both histologic findings and PROs need to be included as equally important outcome measures. We have developed the face and content validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESS™ v2.0). The PEESS™ v2.0 metric is now undergoing multisite national field testing as the next iterative instrument development phase.

Long-term outcomes in pediatric-onset esophageal eosinophilia.

BACKGROUND: Pediatric eosinophilic esophagitis (EoE) is a newly recognized antigen-induced form of chronic esophagitis (CE). OBJECTIVE: Characterization of long-term clinical outcomes in patients with pediatric EoE is needed. METHODS: From histologic review of 3817 pediatric esophageal biopsy specimens from 1982-1999, we conducted a nested case-control study of patients with retrospectively identified histologic eosinophilic esophagitis (rEoE) and CE, as well as an age-matched control cohort. Participants were asked to complete validated health-related outcome questionnaires. RESULTS: At an average of 15 years after initial endoscopy, both cohorts (42/198 patients with rEoE and 67/468 patients with CE, as well as 100 age-matched control subjects) completed questionnaires. Compared with control subjects, quality of life was significantly decreased among patients with rEoE (P < .001) and patients with CE (P < .001). Rates of dysphagia (patients with rEoE, 49%; patients with CE, 37%; control subjects, 6%) and food impaction (patients with rEoE, 40%; patients with CE, 14%; control subjects, 3%) were significantly increased in the rEoE cohort compared with those seen in control subjects (P < .001 and P < .001, respectively). Increased esophageal eosinophil counts (odds ratio [OR], 1.6; 95% CI, 1.1-2.5; P < .05) during childhood were predictive of dysphagia during early adulthood. Food allergy (OR, 2.7; 95% CI, 1.2-6.0; P < .01), allergic rhinitis (OR, 3.5; 95% CI, 1.8-6.8; P < .001), and asthma (OR, 2.1; 95% CI, 1.04-4.3; P = .04) were associated with dysphagia. Food impaction was more common among patients with reported food allergy than among those without (OR, 3.1; 95% CI, 1.2-7.8; P = .02). CONCLUSIONS: Esophageal eosinophilia is associated with reduced quality of life and persistent symptoms 15 years after presentation. Increased esophageal eosinophil counts and the occurrence of food allergy and atopy in childhood increase the rate of dysphagia in young adulthood.

Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982-1999.

BACKGROUND: Eosinophilic esophagitis (EE) is now a commonly encountered disorder that was rarely diagnosed a decade ago. OBJECTIVE: We aimed to determine the epidemiologic and histologic features of retrospective pediatric esophageal eosinophilia before the first case of EE at our institution was recognized. METHODS: Esophageal biopsy specimens obtained between 1982 and 1999 with reflux esophagitis were re-examined and reorganized into 2 groups based on peak esophageal eosinophil number (<15 eosinophils per high-powered field [hpf] and > or =15 eosinophils/hpf). The epidemiology and histology of the entire cohort and a population-based cohort were evaluated. RESULTS: Eight hundred seven biopsy specimens from 666 patients were re-examined; 198 patients had 15 eosinophils/hpf or greater. Among a population-based cohort of patients with 15 eosinophils/hpf or greater, there was a modest increase in incidence (P < .001; incidence rate ratio, 1.18; 95% CI, 1.09-1.28). After correcting for a 40-fold increase in the number of endoscopies during this time period, the proportion of biopsy specimens with 15 eosinophils/hpf or greater did not change (0.08 in 1982 vs 0.08 in 1996 [peak]; P = .9; incidence rate ratio, 1.02; 95% CI, 0.73-1.44). Patients who had as few as 5 eosinophils/hpf were more likely to have persistent esophageal eosinophilia on repeat esophagogastroduodenoscopy, evidence of basal layer hyperplasia, and lamina propria fibrosis compared with patients with less than 5 eosinophils/hpf (P < .001). CONCLUSIONS: Esophageal eosinophilia at levels consistent with EE was present among 30% of patients given diagnoses of reflux esophagitis, and the incidence of esophageal eosinophilia did not change over time. Patients with 5 eosinophils/hpf or greater had evidence of other histologic abnormalities and were likely to have persistent esophageal eosinophilia.

Allergy and eosinophil-associated gastrointestinal disorders (EGID).

Eosinophil-associated gastrointestinal disorders (EGIDs) are characterized by an inappropriate accumulation of eosinophils within the gastrointestinal tract. The underlying etiology and pathophysiology that lead to the development of EGID are far from elucidated. However, there is growing evidence to support the role of aeroallergens and food allergens in the pathogenesis of these disorders. Recent advances have highlighted the role of Th2-driven cytokines in the development of EGID, and clinical studies have verified that children and adults with EGID often have positive skin testing to food allergens. The most common form of EGID, eosinophilic esophagitis (EE), has garnered intense investigation following an increased recognition over the past decade. Recently, there have been several important studies providing insight into both the cellular mechanisms governing EE and clinical therapies directed toward the treatment of EE. In the article herein, we will review the most recent scientific advances influencing our understanding of EGID with special emphasis on the role of allergens in the pathogenesis of EGID.

Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung.

Resistin-like molecule (RELM)-beta is a cysteine-rich cytokine implicated in insulin resistance and asthmatic responses, but its function remains an enigma. We now report that RELM-beta has a role in promoting airway inflammation and lung remodeling in the mouse lung. RELM-beta is strongly induced by diverse allergens and T helper type 2 (Th2) cytokines by an IL-13- and STAT6-dependent mechanism. To understand the in vivo role of RELM-beta, we delivered recombinant murine RELM-beta intratracheally to naïve mice. RELM-beta induced dose-dependent leukocyte accumulation (most prominently involving macrophages) and goblet cell hyperplasia. The most prominent effect induced by RELM-beta was increased perivascular and peribronchial collagen deposition. Mice genetically deficient in RELM-beta had reduced accumulation of collagen and goblet cell hyperplasia in an experimental model of allergic airway inflammation. In vitro experiments demonstrated that RELM-beta had fibroblast motogenic activity. These results identify RELM-beta as a Th2-associated cytokine with potent inflammatory and remodeling activity.

Quantity and distribution of eosinophils in the gastrointestinal tract of children.

There are a lack of data on the quantity and location of eosinophils in the gastrointestinal tract of healthy individuals. Accordingly, we examined gastrointestinal biopsies obtained during endoscopic evaluation of pediatric patients. Biopsies were previously interpreted as having no diagnostic abnormality. The presence of extracellular eosinophil constituents and the quantity of eosinophils in atopic versus nonatopic individuals was determined. In the esophagus, eosinophils were present in only 2.7% of high-power fields (hpf), with a mean value of 0.03+/-0.10 eosinophils/hpf (mean+/-standard deviation) and a maximum of 1 eosinophil/hpf. Examination of the antrum and fundus revealed similar numbers of eosinophils in the lamina propria (1.9+/-1.3 and 2.1+/-2.4 eosinophils/hpf, respectively), with no eosinophils observed in the surface epithelium. In the small intestine, there were 9.6+/-5.3 (maximum, 26 eosinophils/hpf) and 12.4+/-5.4 eosinophils/hpf (maximum, 28 eosinophils/hpf) in the intercryptal lamina propria of the duodenum and ileum, respectively. The number of eosinophils in the surface epithelium and crypt epithelium was minimal. In the large intestine, the highest concentration of eosinophils was observed in the cecum (20.3+/-8.2 eosinophils/hpf; maximum, 50 eosinophils/hpf), and there were lower concentrations in the transverse and sigmoid colon (16.3+/-5.6 and 8.3+/-5.9 eosinophils/hpf, respectively). The percentage of fields demonstrating extracellular eosinophil granules in all gastrointestinal segments was 70% to 93%, and extracellular granules were most numerous at the edge of the biopsy (P<0.05). Atopic and nonatopic patients had comparable numbers of eosinophils. These data establish baseline gastrointestinal eosinophil values in pediatric patients without apparent pathological disease.

A study of variable hydration states in topotecan hydrochloride.

Topotecan hydrochloride, a pharmaceutical compound developed as a treatment for cancer, exhibits variable hydration states in a crystalline solid form chosen for manufacturing. This variability requires additional controls for successful development, and presents a characterization and detection challenge for analytical methods. In this study, overall water content was determined by Karl Fischer titration and thermogravimetric analysis (TGA) on topotecan HCl equilibrated at different relative humidity levels. These results, when combined with information obtained from dynamic water vapor sorption and differential scanning calorimetry (DSC), indicate that this form of topotecan HCl contains 3 mol of water integral to the crystalline structure and up to two additional moles of water depending on the relative humidity. Powder X-ray diffraction experiments did not detect significant differences in topotecan HCl samples equilibrated at trihydrate and pentahydrate states, and showed that the crystal lattice dimensions are not affected unless the form is dried below the trihydrate state. This behavior is typical of crystal structures with channels that can accommodate additional loosely bound water. To study the role of the loosely bound water in the crystal structure in more detail, solid-state (13)C and (15)N nuclear magnetic resonance (NMR) were used to examine the differences between the hydration states. Both the trihydrate and pentahydrate states yielded similar solid-state NMR spectra, consistent with the lack of change in the crystal lattice. However, minor but readily detectable differences in the (13)C spectra are observed with changes in water content. Interpretation of this data suggests that the loosely bound channel water is hydrogen-bonding to specific portions of the topotecan parent molecule. Topotecan HCl trihydrate was hydrated with D(2)O vapor to confirm the nature and location of the channel water using (13)C and (2)H solid-state NMR. Despite the detectable association of the channel water with hydrogen bonding sites on the topotecan molecule, (2)H quadrupolar echo experiments indicate that the channel water is highly mobile at room temperature and at -60 degrees C.

Structural analysis of polymorphism and solvation in tranilast.

Five polymorphic forms of tranilast were characterized by thermal, diffractometric, and spectroscopic techniques. The crystal structures of the most stable anhydrous form (Form I), a chloroform solvate, and a dichloromethane solvate were determined from single-crystal X-ray analysis. Two additional anhydrous forms of tranilast (Forms II and III) were also studied, but were not amenable to SCXRD. All five forms were also analyzed using solid-state nuclear magnetic resonance, Fourier transform infrared, and Fourier transform-Raman spectroscopy, and thermal methods. From the trends observed in the crystal structures and the spectral data, some conclusions can be made about hydrogen bonding, molecular conformation, and crystal packing differences in the polymorphs and solvates. Form II was found to be a spectroscopically distinctive polymorph that is probably missing an important intramolecular hydrogen bond coupled with a conformational change. In contrast, Form III was found to be more similar to the crystallographically characterized forms, and is more likely a packing and hydrogen-bonding polymorph with a weakened intermolecular hydrogen-bonding interaction relative to the other forms. From a pharmaceutical development perspective, it is shown that although the anhydrous forms of tranilast have similar thermal properties, they can be reliably distinguished by spectroscopic methods.