fluticasone and Fibrosis

Recent research shows that both pediatric and adult patients with eosinophilic esophagitis (EoE) experience esophageal remodeling marked by increased collagen deposition in which TGF-β plays an important role. However, limited data are available on the intensity and reversibility of fibrous remodeling in adults with EoE.. We sought to analyze differences in collagen deposition in the lamina propria (LP) and profibrogenic cytokine gene expression along with other changes induced by prolonged treatment with fluticasone propionate in adults with EoE.. Ten adults given consecutive diagnoses of EoE were studied prospectively. Deep esophageal biopsy specimens were obtained before and after 1 year of treatment with fluticasone propionate. Collagen deposition in the LP was assessed in tissue sections with the aid of the Masson trichrome technique. IL5, TGFB1, fibroblast growth factor 9 (FGF9), and CCL18 gene expression was quantified through real-time PCR. EoE results were compared among samples from 10 adult patients with gastroesophageal reflux disease and 10 control subjects with healthy esophagi.. Patients with EoE showed a significant increase in subepithelial collagen deposition; this correlated positively with eosinophil density in the LP and the patient's age. Prolonged steroid treatment induced a nonsignificant reduction in subepithelial fibrosis, which remained significantly higher than in control subjects. Profibrogenic cytokine gene expression also increased in patients with EoE, with IL5 (P < .001), FGF9 (P = .005), and CCL18 (P = .008) all significantly upregulated. After 1 year of treatment, a reduction was observed in gene expression; for CCL18 expression, this decrease was statistically significant (P < .001).. Esophageal remodeling is associated with upregulated gene expression of profibrogenic cytokines in adults with EoE. Prolonged treatment with fluticasone propionate leads to a nonsignificant reduction in subepithelial collagen deposition accompanied by downregulation of profibrogenic cytokine gene expression, with that of CCL18 being especially significant.

Topics: Adolescent; Adult; Androstadienes; Anti-Inflammatory Agents; Collagen; Cytokines; Eosinophilic Esophagitis; Female; Fibrosis; Fluticasone; Gene Expression; Humans; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Young Adult

Although effective in the treatment of eosinophilic esophagitis (EoE) in children, limited data exist on long-term safety and efficacy of swallowed topical corticosteroids. We investigated whether long-term use of swallowed fluticasone in children with EoE leads to sustained reduction in esophageal eosinophils, and endoscopic and clinical improvement.. In an open-label, prospective, single-center study, we offered pediatric patients with active EoE fluticasone 2 puffs to swallow twice a day (strengths in μg/puff: 2-4 years: 44, 5-11 years: 110, ≥12 years: 220). Clinical, endoscopic, and histological assessments were performed at baseline and shortly after therapy. If histological remission was seen, fluticasone was continued with clinical follow-ups every 4 months and endoscopic and histological follow-ups yearly. Clinical scores were derived from eight symptoms (abdominal pain, nausea, vomiting, regurgitation, chest pain, dysphagia, food impaction, and early satiety). Endoscopic scores were derived from six features (rings, exudates, furrows, edema, stricture, and shearing). Scores were expressed as ratio (features present/total). In addition to peak eosinophils/high power field (HPF) (primary outcome), histological features (eosinophilic microabscesses, degranulation, superficial layering, basal zone hyperplasia, dilated intercellular spaces, and lamina propria fibrosis) were assessed. Median clinical and endoscopic scores and individual histologic features were compared over 4 time intervals: <4 months, 4-12 months, 13-24 months, and >24 months. Growth and adverse effects were monitored.. We enrolled 54 patients, 80% male, median age 6.5 years (range 2-17 years), 85% atopic (57% asthma, 68% allergic rhinitis, and 31% atopic dermatitis), and 74% with food allergy. Mean follow-up was 20.4 months, the longest being 68 months (5.7 years). Esophageal eosinophil counts significantly decreased (median peak eosinophils/HPF at baseline 72, <4 months: 0.5, 4-12 months: 1.75, 13-24 months: 10, and >24 months: 12, all P<0.01). All histological features significantly decreased from baseline to all follow-up time points (all P<0.01). Lamina propria fibrosis significantly decreased (% patients with fibrosis at baseline 92, <4 months: 41, 4-12 months: 50, 13-24 months: 45, and >24 months: 39, all P<0.01). Endoscopic features improved (score at baseline 0.37, <4 months: 0.17, 4-12 months: 0.17, 13-24 months: 0, and >24 months: 0.1, all P<0.01, except at >24 months: P<0.05). Symptoms improved (score at baseline 0.22, <4 months: 0, 4-12 months: 0.11, 13-24 months: 0.11, and >24 months: 0.11, all P<0.05 except at >24 months: P=0.05). In a mixed linear regression model that accounts for correlation of repeated observations in the patient in a per-patient analysis, we found that treatment with swallowed fluticasone led to a statistically significant and sustained decrease in peak esophageal eosinophil counts. Asymptomatic esophageal candidiasis was seen in three children but resolved with anti-fungal therapy. Height and weight z-scores followed expected growth curves.. We demonstrate that swallowed fluticasone is effective as a long-term maintenance therapy for children with EoE, without growth impediment or serious side effects.

Topics: Abdominal Pain; Administration, Oral; Adolescent; Anti-Inflammatory Agents; Chest Pain; Child; Child, Preschool; Deglutition Disorders; Eosinophilic Esophagitis; Eosinophils; Esophageal Stenosis; Esophagoscopy; Esophagus; Female; Fibrosis; Fluticasone; Humans; Maintenance Chemotherapy; Male; Mucous Membrane; Nausea; Prospective Studies; Remission Induction; Treatment Outcome; Vomiting

Symptoms of vomiting and dysphagia in children with eosinophilic esophagitis may be related to the development of mucosal fibrosis.. Our aims were to (1) investigate esophageal fibrosis in children with EoE compared to patients with gastroesophageal reflux disease and normal individuals, and (2) to assess the degree of mucosal fibrosis in patients with EoE before and after medical treatment.. A retrospective analysis of esophageal biopsies from patients with EoE, GERD, and normal mucosa was performed. Demographic data, clinical information, eosinophil number, and sub-epithelial fibrosis was compared among the groups. A similar comparison was performed in EoE patients, before and after therapy.. Esophageal biopsies from 53 children were included, of which 17 with EoE, 17 GERD, and 19 were normal. A significantly higher number of eosinophils and greater fibrosis was found in EoE patients vs. GERD and normal (fibrosis grade 2: 13 patients in the EoE group vs. one patient for each control group; p=0.0001). After therapy, a significant decrease in fibrosis and eosinophils number was noted in EoE patients [fibrosis grade 2: 10 (71.5%) patients vs. one (7.1%) patient, and eosinophil count was 35.5/HPF vs. 13.4/HPF, pre- and post-therapy, respectively; p<0.05]. The decrease in esophageal fibrosis paralleled the improvement in the related clinical symptoms.. A higher degree of esophageal fibrosis was found in patients with EoE compared to GERD or normal esophagus. Conventional therapy in EoE improved obstructive symptoms, decreased eosinophils count, and reversed the degree of fibrosis. We suggest that appropriate therapy in patients with EoE will improve clinical symptoms and histology.

Topics: Adolescent; Allergens; Androstadienes; Anti-Inflammatory Agents; Biopsy; Case-Control Studies; Child; Child, Preschool; Eosinophilic Esophagitis; Eosinophils; Esophagus; Female; Fibrosis; Fluticasone; Food Hypersensitivity; Gastroesophageal Reflux; Humans; Infant; Male; Mucous Membrane; Retrospective Studies; Treatment Outcome

There is increasing in vitro evidence to support a role for vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, as a mediator of fibrosis associated with neovascularization.. We tested the hypothesis that VEGF is involved both in increased airway mucosal vascularity and in the subepithelial fibrosis of asthmatic patients.. Bronchial biopsies were performed in 24 asthmatic patients and eight healthy controls. Immunostaining, using computerized image analysis, was performed using monoclonal antibodies against VEGF(+) cells, type IV collagen, to outline the basement membrane thickness, and tryptase and EG2, to identify mast cells and eosinophils, respectively.. The counts of VEGF(+) cells (P<0.05), mast cells and EG2(+) cells (both P<0.01) were higher in asthmatics than in controls. The number of vessels, the vascular area in the lamina propria, and the basement membrane thickness were significantly higher in asthmatics than in healthy volunteers (P<0.01). Moreover, in asthmatic patients, the number of VEGF(+) cells was significantly related to the number of vessels (P<0.01), to mast cells (P<0.01) and to basement membrane thickness (P<0.01). A colocalization study also revealed that mast cells were a relevant cellular source of VEGF. High doses of inhaled fluticasone propionate significantly reduced VEGF(+) cells (P<0.05), vessel number (P<0.05), vascular area (P<0.05) and basement membrane thickness (P<0.05) in a subgroup of asthmatic patients.. This study shows that VEGF, in addition to being involved in the vascular component of airway remodelling, may play a role in the thickening of the basement membrane in asthma.

Topics: Administration, Inhalation; Adult; Androstadienes; Asthma; Basement Membrane; Biopsy; Bronchi; Bronchodilator Agents; Bronchoscopy; Cell Count; Eosinophils; Female; Fibrosis; Fluticasone; Humans; Male; Mast Cells; Mucous Membrane; Up-Regulation; Vascular Endothelial Growth Factor A