Miriam Davis

Predictors of Response to Proton Pump Inhibitor Therapy among Children with Significant Esophageal Eosinophilia

OBJECTIVES To determine predictors of histological response to proton pump inhibitor (PPI) therapy among children with significant esophageal eosinophilia (SEE), defined as >or=15 eosinophils per high powered field (eos/hpf) on esophageal mucosal biopsy (EMB). STUDY DESIGN Response to PPI therapy among children with SEE treated with PPI who underwent repeat EMB was studied retrospectively. Response was defined as <5 eos/hpf on repeat EMB. Characteristics of responders and nonresponders were analyzed. RESULTS Of 326 patients (ages 1 through 18 years) diagnosed with SEE over a 7-year period, 43 (mean age, 8.5 years; 67% males) met inclusion criteria. After PPI therapy, 17 patients (40%) were responders. There were no significant differences in demographics, presenting symptoms, endoscopic, or histological findings between responders and nonresponders. Among patients with 15 to 20 eos/hpf on EMB, 50% were responders; among patients with >20 eos/hpf on EMB, 29% were responders. Seven of 17 (41%) patients with abnormal pH monitoring and 5 of 11 (45%) patients with normal monitoring were responders. CONCLUSIONS Forty percent of patients with SEE demonstrated histological response to PPI therapy. None of the clinical characteristics evaluated predicted response, and response was not dependent on results of pH study. The role of PPI therapy in treating SEE warrants further prospective investigation.

Exploring potential noninvasive biomarkers in eosinophilic esophagitis in children

Background and Aims: Eosinophilic esophagitis (EE) continues to present clinical challenges, including a need for noninvasive tools to manage the disease. To identify a marker able to assess disease status in lieu of repeated endoscopies, we examined 3 noninvasive biomarkers, serum interleukin (IL)-5, serum eosinophil-derived neurotoxin (EDN), and stool EDN, and examined possible correlations of these with disease phenotype and activity (symptoms and histology) in a longitudinal study of children with EE. Subjects and Methods: Children with EE were studied for up to 24 weeks (12 weeks on 1 of 2 corticosteroid therapies and 12 weeks off therapy). Twenty children with normal esophagogastroduodenoscopies with biopsies were enrolled as controls. Serum IL-5, serum EDN, and stool EDN were measured at weeks 0, 4, 12, 18, and 24 in children with EE, and at baseline alone for controls. Primary and secondary statistical analyses (excluding and including outlier values of the biomarkers, respectively) were performed. Results: Sixty subjects with EE (46 [75%] boys, mean age 7.5 ± 4.4 years) and 20 normal controls (10 [50%] boys, mean age 6.7 ± 4.1 years) were included. Significant changes in serum EDN (significant decrease from baseline to week 4, and then rebound from week 4 to week 12) occurred. Serum EDN levels were stable after week 12. Serum IL-5 and stool EDN levels in subjects with EE were not statistically different from those of the control subjects when each time point for the cases was compared with the controls’ 1-time measurement. Conclusions: Serum EDN levels were significantly higher in subjects with EE than in controls, and the results suggest a possible role, after additional future studies, for serum EDN in establishing EE diagnosis, assessing response to therapy, and/or monitoring for relapse or quiescence.

Progression of Lung Disease in Preschool Patients with Cystic Fibrosis

Rationale: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. Objectives: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. Methods: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age‐matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed‐effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. Measurements and Main Results: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. Conclusions: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.

Utility of fecal lactoferrin in identifying Crohn disease activity in children.

Objectives: Fecal lactoferrin (FL) is a noninvasive biomarker that is elevated in Crohn disease (CD) compared to irritable bowel syndrome. The purpose of this study was to evaluate FL in identifying children with active versus inactive CD. Patients and Methods: Fresh stool samples were collected from children with CD scheduled for endoscopy or a clinic visit, and from new outpatients who were scheduled for colonoscopy. FL was determined using a polyclonal antibody-based enzyme-linked immunosorbent assay. Physical global assessment, endoscopic findings, erythrocyte sedimentation rate (ESR), and the Pediatric CD Activity Index (PCDAI) were recorded for patients with CD. The PCDAI scores symptoms, laboratory parameters, physical examination, and extraintestinal manifestations. A score of ≤10 is inactive disease, 11 to 30 is mild active, and ≤31 is moderate to severe active. Results: Of 101 study patients (4- to 20-year-old, 66 boys), 31 had active CD, 23 had inactive CD, and 37 had noninflammatory bowel disease (non-IBD) conditions. Four patients with ulcerative colitis and 6 patients with polyposis were excluded from analysis. FL was significantly elevated in CD versus non-IBD (P < 0.001) and in active versus inactive CD (P < 0.001). The PCDAI and ESR were higher in active CD than in inactive CD (both P < 0.001). Using an FL cutoff of 7.25 μg/g, FL has 100% sensitivity and 100% negative predictive value in detecting active CD. Using an FL cutoff level of 60 μg/g, FL had 84% sensitivity, 74% specificity, 81% positive predictive value, and 77% negative predictive value for detecting active CD. Conclusions: FL is a promising biomarker of active CD and may be more practical to use when it is not feasible to obtain all of the necessary clinical information for the PCDAI.

Association of Antibiotics, Airway Microbiome, and Inflammation in Infants with Cystic Fibrosis

Rationale: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation. Objectives: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF. Methods: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid. Results: Thirty‐two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count. Conclusions: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.

Esophageal pH monitoring with the BRAVO capsule: Experience in a single tertiary medical center

Aim: The aim of the present study was to report the global experience with placement, complication rate, and recording of esophageal pH using the BRAVO capsule at our institution. Patients and Methods: We recorded the rate of any technical problems and complications during placement in all of the patients (ages 4–22 years) who received this device during a 2-year period. All of the patients undergoing esophagogastroduodenoscopy with the placement of BRAVO pH capsule were included in this analysis. We also examined the pH data recorded on days 1 and 2 for significant day-to-day variability during 2 days of pH monitoring. Results: Two hundred eighty-nine BRAVO pH probes were placed from January 1, 2006 to December 31, 2008. At least 1 day of data was obtained in 278 patients (96.2%). Two days of data were obtained in 274 patients (94.8%). Of all of the reported complications, 1% occurred before deployment of the capsule, 4% occurred during deployment of the capsule, and 9% occurred after successful deployment of the capsule. One patient experienced a superficial esophageal tear that was associated with failure of the capsule to release from the delivery system. No patient requested removal of the capsule and all of the capsules detached within 14 days. In 9.12% of our patients, reflux index was normal on day 1 and abnormal on day 2. There was no statistically significant difference between reflux index recorded on day 1 versus day 2 (P = 0.686). Conclusions: The BRAVO pH capsule is easy to place, safe, and well tolerated by children. Performing a 48-hour study detected abnormal reflux in an additional 9% of our patients.

Multiple-breath washout outcomes are sensitive to inflammation and infection in children with cystic fibrosis

Rationale: The lung clearance index is a measure of ventilation distribution derived from the multiple‐breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. Objectives: We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. Methods: Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3‐6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple‐breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. Results: Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. Conclusions: These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.

The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials

The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3–6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible. Two multiple-breath washout test trials are sufficient to determine lung clearance index in early CF lung disease http://ow.ly/YHxu30hnrl2