Equity and Inclusion in Pediatric Gastroenterology Telehealth: A Study of Demographic, Socioeconomic, and Digital Disparities.

OBJECTIVES: The purpose of our study is to compare in-person and telehealth pediatric care ambulatory visits for gastroenterology (GI) at the Nemours Children's Health System in the Delaware Valley (NCH-DV) based on geospatial, demographic, socioeconomic, and digital disparities. METHODS: Characteristics of 26,565 patient encounters from January 2019 to December 2020 were analyzed. U.S. Census Bureau geographic identifiers were assigned to each participant and aligned with the American Community Survey (2015-2019) socioeconomic and digital outcomes. Reported odds ratios (OR) are telehealth encounter/in-person encounter. RESULTS: GI telehealth usage increased 145-fold in 2020 compared to 2019 for NCH-DV. Comparing telehealth to in-person usage in 2020 revealed that GI patients who required a language translator were 2.2-fold less likely to choose telehealth [individual level adjusted OR (I-OR a ) [95% confidence interval, CI], 0.45 [0.30-0.66], P < 0.001]. Individuals of Hispanic ethnicity or non-Hispanic Black or African American race are 1.3-1.4-fold less likely to utilize telehealth than non-Hispanic Whites (I-OR a [95% CI], 0.73 [0.59-0.89], P = 0.002 and 0.76 [0.60-0.95], P = 0.02, respectively). Households in census block groups (BG) that are more likely to utilize telehealth: have broadband access (BG-OR = 2.51 [1.22-5.31], P = 0.014); are above the poverty level (BG-OR = 4.44 [2.00-10.24], P < 0.001); own their own home (BG-OR = 1.79 [1.25-2.60], P = 0.002); and have a bachelor's degree or higher (BG-OR = 6.55 [3.25-13.80], P < 0.001). CONCLUSIONS: Our study is the largest reported pediatric GI telehealth experience in North America that describes racial, ethnic, socioeconomic, and digital inequities. Advocacy and research for pediatric GI focused on telehealth equity and inclusion is urgently needed.

Medical treatment of eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated eosinophilic inflammatory disease isolated to the esophagus. As a clinicopathologic disorder, a diagnosis of EoE requires a constellation of clinical symptoms of esophageal dysfunction and histologic findings (at least 15 eosinophils/high-powered microscope field (eos/hpf)). Current guidelines no longer require the failure of response to proton pump inhibitor medications to establish a diagnosis of EoE, but continue to suggest the exclusion of other etiologies of esophageal eosinophilia. The treatment goals for EoE are improvement in clinical symptoms, resolution of esophageal eosinophilia and other histologic abnormalities, endoscopic improvement, improved quality of life, improved esophageal function, minimized adverse effects of treatment, and prevention of disease progression and subsequent complications. Currently, there is no cure for EoE, making long-term treatment necessary. Standard treatment modalities include dietary modifications, esophageal dilation, and pharmacologic therapy. Effective pharmacologic therapies include corticosteroids, rapidly emerging biological therapies, and proton pump inhibitor medications. OBJECTIVES: To evaluate the efficacy and safety of medical interventions for people with eosinophilic esophagitis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP to 3 March 2023. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing any medical intervention or food elimination diet for the treatment of eosinophilic esophagitis, either alone or in combination, to any other intervention (including placebo). DATA COLLECTION AND ANALYSIS: Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as a risk ratio (RR) and as the mean or standardized mean difference (MD/SMD) with 95% confidence interval (CI). We assessed the certainty of the evidence using GRADE. Our primary outcomes were: clinical, histological, and endoscopic improvement, and withdrawals due to adverse events. Secondary outcomes were: serious and total adverse events, and quality of life. MAIN RESULTS: We included 41 RCTs with 3253 participants. Eleven studies included pediatric patients while the rest recruited both children and adults. Four studies were in patients with inactive disease while the rest were in patients with active disease. We identified 19 intervention comparisons. In this abstract we present the results of the primary outcomes for the two main comparisons: corticosteroids versus placebo and biologics versus placebo, based on the prespecified outcomes defined of the primary studies. Fourteen studies compared corticosteroids to placebo for induction of remission and the risk of bias for these studies was mostly low. Corticosteroids may lead to slightly better clinical improvement (20% higher), measured dichotomously (risk ratio (RR) 1.74, 95% CI 1.08 to 2.80; 6 studies, 583 participants; number needed to treat for an additional beneficial outcome (NNTB) = 4; low certainty), and may lead to slightly better clinical improvement, measured continuously (standard mean difference (SMD) 0.51, 95% CI 0.17 to 0.85; 5 studies, 475 participants; low certainty). Corticosteroids lead to a large histological improvement (63% higher), measured dichotomously (RR 11.94, 95% CI 6.56 to 21.75; 12 studies, 978 participants; NNTB = 3; high certainty), and may lead to histological improvement, measured continuously (SMD 1.42, 95% CI 1.02 to 1.82; 5 studies, 449 participants; low certainty). Corticosteroids may lead to little to no endoscopic improvement, measured dichotomously (RR 2.60, 95% CI 0.82 to 8.19; 5 studies, 596 participants; low certainty), and may lead to endoscopic improvement, measured continuously (SMD 1.33, 95% CI 0.59 to 2.08; 5 studies, 596 participants; low certainty). Corticosteroids may lead to slightly fewer withdrawals due to adverse events (RR 0.64, 95% CI 0.43 to 0.96; 14 studies, 1032 participants; low certainty). Nine studies compared biologics to placebo for induction of remission. Biologics may result in little to no difference in clinical improvement, measured dichotomously (RR 1.14, 95% CI 0.85 to 1.52; 5 studies, 410 participants; low certainty), and may result in better clinical improvement, measured continuously (SMD 0.50, 95% CI 0.22 to 0.78; 7 studies, 387 participants; moderate certainty). Biologics result in better histological improvement (55% higher), measured dichotomously (RR 6.73, 95% CI 2.58 to 17.52; 8 studies, 925 participants; NNTB = 2; moderate certainty). We could not draw conclusions for this outcome when measured continuously (SMD 1.01, 95% CI 0.36 to 1.66; 6 studies, 370 participants; very low certainty). Biologics may result in little to no difference in endoscopic improvement, measured dichotomously (effect not estimable, low certainty). We cannot draw conclusions for this outcome when measured continuously (SMD 2.79, 95% CI 0.36 to 5.22; 1 study, 11 participants; very low certainty). There may be no difference in withdrawals due to adverse events (RR 1.55, 95% CI 0.88 to 2.74; 8 studies, 792 participants; low certainty). AUTHORS' CONCLUSIONS: Corticosteroids (as compared to placebo) may lead to clinical symptom improvement when reported both as dichotomous and continuous outcomes, from the primary study definitions. Corticosteroids lead to a large increase in histological improvement (dichotomous outcome) and may increase histological improvement (continuous outcome) when compared to placebo. Corticosteroids may or may not increase endoscopic improvement (depending on whether the outcome is measured dichotomously or continuously). Withdrawals due to adverse events (dichotomous outcome) may occur less frequently when corticosteroids are compared to placebo. Biologics (as compared to placebo) may not lead to clinical symptom improvement when reported as a dichotomous outcome and may lead to an increase in clinical symptom improvement (as a continuous outcome), from the primary study definitions. Biologics lead to a large increase in histological improvement when reported as a dichotomous outcome, but this is uncertain when reported as a continuous outcome, as compared to placebo. Biologics may not increase endoscopic improvement (dichotomous outcome), but this is uncertain when measured as a continuous outcome. Withdrawals due to adverse events as a dichotomous outcome may occur as frequently when biologics are compared to placebo.

Comparative Effectiveness of Intravenous Azithromycin Versus Erythromycin Stimulating Antroduodenal Motility in Children.

BACKGROUND: Azithromycin has been shown to improve gastrointestinal motility in adults and may have fewer drug interactions and reduced arrhythmogenic effects than erythromycin. We hypothesized that azithromycin is comparable to erythromycin in eliciting pharmacodynamic outcomes for antral and small bowel motility. OBJECTIVE: To compare the pharmacodynamic effectiveness of azithromycin and erythromycin for eliciting antral and duodenal motility in pediatric patients who underwent antroduodenal manometry for different indications. METHODS: We conducted a retrospective comparison of clinic data and manometric pharmacodynamics outcomes in patients who underwent antroduodenal manometry between 2013 and 2017. RESULTS: Fifty-one patients mean age (± standard deviation) 9.7 (5.4) years, received either azithromycin 3 mg/kg (n = 20) or erythromycin 2 mg/kg (n = 31) during antroduodenal manometry. For patients receiving erythromycin, mean area under the curve (AUC) across all eight pressure ports increased from median [95% confidence interval] 2256 [1585, 2602] to 8742 [5876, 11761] mmHg × s (P < 0.001) and mean motility index increased from 8.63 [7.87, 9.42] to 11.98 [11.20, 12.21] (P < 0.001). For patients receiving azithromycin, mean AUC increased from 2255 [1585, 2602] to 8254 [5649, 10470] mmHg × s (P < 0.001) and motility index increased from 8.63 [7.87,9.42] to 11.79 [11.03, 12.21] (P < 0.001). Neither mean stimulated AUC nor mean motility index was significantly different between azithromycin and erythromycin treatments. There was no significant difference in side effects between groups. CONCLUSIONS: Azithromycin and erythromycin have similar pharmacodynamic effects on antral and small bowel contractility in children. Azithromycin should be considered an acceptable alternative to erythromycin as an upper gastrointestinal tract prokinetic for children and has historically had fewer side effects than erythromycin.

STAT6 Variants Associate With Relapse of Eosinophilic Esophagitis in Patients Receiving Long-term Proton Pump Inhibitor Therapy.

BACKGROUND & AIMS: Based on histologic features, variants in STAT6 are associated with a poor initial response to proton pump inhibitor (PPI) therapy in pediatric patients with eosinophilic esophagitis (EoE). We investigated whether these genetic variants are associated with a poor long-term response in children with EoE who initially responded to PPI therapy. METHODS: We performed a prospective longitudinal cohort study of children ages 2 to 16 years who met the diagnostic criteria for EoE (≥15 eosinophils/high-power field [eos/hpf]), responded to 8 weeks of treatment with 2 mg/kg/d PPI (<15 eos/hpf), and whose dose then was reduced to 1 mg/kg/d PPI (maintenance therapy) for 1 year, at which point biopsy specimens were collected by endoscopy. Genomic DNA was isolated from formalin-fixed paraffin-embedded biopsy tissue and was genotyped for variants of STAT6. Remission of inflammation was assessed at eos/hpf thresholds of <15 and ≤5. RESULTS: Among 73 patients who received 1 mg/kg/d PPI maintenance therapy for 1 year, 13 patients (18%) had 6 to 14 eos/hpf, 36 patients (49%) had 5 or fewer eos/hpf, and 24 patients (33%) relapsed to EoE (≥15 eos/hpf). Carriage of any of 3 STAT6 variants in linkage disequilibrium (r2 ≥0.8; rs324011, rs167769, or rs12368672) was associated with a 2.3- to 2.8-fold increase in the odds of EoE relapse, and with a 2.8- to 4.1-fold increase in the odds of having 6 to 14 eos/hpf. For rs324011, the odds ratio [95% CI] for relapse was 2.77 [1.11, 6.92]; P = .029, and the odds ratio [95% CI] for having 6 to 14 eos/hpf was 3.06 [1.27, 7.36]; P = .012. CONCLUSIONS: Pediatric EoE patients who initially respond to PPI therapy and carry STAT6 variants rs324011, rs167769, or rs12368672 are at increased risk of relapse after 1 year of PPI maintenance therapy.

CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis.

OBJECTIVE: Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19 and STAT6 associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19 and STAT6 influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). METHODS: Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. RESULTS: Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C1917 (P = 0.35). In children who received a PPI dose between ≥1.54 and ≤2.05 mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C1917 associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P = 0.031). Carriage of STAT6 allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P = 0.028), whereas carriage of STAT6 rs324011 synergizes with CYP2C1917 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P = 0.022; CYP2C1917 OR [95% CI] = 8.19[1.42, 50.57], P = 0.023). CONCLUSIONS: Common variants in CYP2C19 and STAT6 associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.

Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment.

When pediatric gastroesophageal reflux disease (GERD) that is refractory to proton pump inhibitor (PPI) medication treatment is identified in clinical practice and anti-reflux surgery (ARS) is being considered, genetic factors related to PPI metabolism by the CYP2C19 enzyme are currently not part of the clinical decision-making process. Our objective was to test the hypothesis that the distribution of the extensive metabolizer (EM) phenotypes among children undergoing ARS after failing PPI therapy would differ compared to controls (children with no history of ARS). We conducted a case-control study between children across the Nemours Health System from 2000 to 2014 who received ARS after failing PPI therapy and a control group comprised of healthy children. Our results demonstrated 2.9% of ARSs vs 20.8% of controls were poor metabolizers (PMs), 55.9% of ARSs vs 49.0% of controls were normal metabolizers (NMs), and 41.2% of ARSs vs 30.2% of controls were EMs; p = 0.035. Next, we performed a multiple-regression model to account for race as a potential confounding variable and the EM group was significantly associated with ARS compared to controls (OR 9.78, CI 1.25-76.55, p < 0.03). CONCLUSION: Among children with medically refractory GERD despite PPI therapy, carriage of CYP2C19*17 allele corresponding to the EM phenotype was associated with ARS. Prospective comparative personalized medicine effectiveness studies are needed to determine if CYP2C19 genotype-guided dosing improves response to PPI therapy without a corresponding increase in adverse effects in children. What is known: • Anti-reflux surgery (ARS) is one of the most common surgical procedures performed in children for the indication of refractory gastroesophageal reflux disease (GERD). What is new: • Individualizing PPI medication dosing based on CYP2C19 diplotype may avoid GERD treatment failures and reduce the need for anti-reflux surgery (ARS).

Free 25(OH)D concentrations are associated with atopy and lung function in children with asthma.

BACKGROUND: Evidence suggests free mono-hydroxyvitamin D (25[OH]D) concentrations are more strongly linked to certain outcomes than total concentrations; however, no studies have examined the relation between free 25(OH)D and respiratory or allergic disease. OBJECTIVE: To examine associations between total and free 25(OH)D concentrations and asthma outcomes. METHODS: We quantified total and free 25(OH)D concentrations in 137 Peruvian children with asthma and 152 children without asthma and examined associations with asthma outcomes. RESULTS: Mean age ± SD was 13 ± 2.5 years, and 50.2% were boys. Mean total and measured free 25(OH)D concentrations were 29 ± 9.5 ng/mL and 5.0 ± 1.3 pg/mL, respectively. Lower free but not total 25(OH)D concentrations were significantly associated with atopy in all children (total, odds ratio [OR] 1.3 per 10-ng/mL decrease, 95% confidence interval [CI] 0.95-1.7, P = .12; vs free, OR 1.3 per 1-pg/mL decrease, 95% CI 1.0-1.6, P = .02) and children with asthma (total, OR 1.1 per 10-ng/mL decrease, 95% CI 0.75-1.7, P = .57; vs free, OR 1.6 per 1-pg/mL decrease, 95% CI 1.0-2.5, P = .04). Free but not total 25(OH)D levels were significantly associated with pre-bronchodilator forced expiratory volume in 1 second (total, 0.11 L, -0.12 to 0.34, P = .34; vs free, 0.20 L, 0.021-0.39, P = .03) and forced vital capacity (total, 0.13 L, -0.12 to 0.37, P = .31; vs free, 0.22 L, 0.026-0.42, P = .03) Z-scores in children with asthma. CONCLUSION: Atopy, forced expiratory volume in 1 second, and forced vital capacity were more strongly linked to free than to total 25(OH)D concentrations, suggesting the free form might be more relevant in modulating allergic disease risk and pulmonary function in children with asthma.

Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children.

OBJECTIVE: To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency. STUDY DESIGN: Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes. RESULTS: The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04). CONCLUSIONS: Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.

Methacholine PC20 in African Americans and whites with asthma with homozygous genotypes at ADRB2 codon 16.

BACKGROUND: African Americans have worse asthma outcomes compared to whites. Adrenoceptor beta 2, surface gene (ADRB2) Gly16Arg genotypes have been associated with ß2-agonist bronchodilator response, asthma exacerbation rate, response to methacholine, and lung function decline but not specifically in African Americans. OBJECTIVE: We sought to compare the provocative concentration of methacholine that causes a 20% fall in FEV1 (PC20) in African Americans and whites with asthma who were ADRB2 homozygous at codon 16 (Arg16Arg or Gly16Gly). METHODS: African Americans and whites whose parents and grandparents were of the same race, aged ≥10 years, with baseline FEV1 of ≥60% predicted, and no upper or lower respiratory tract infection within the previous 2 weeks meeting genotype criteria were enrolled. PC20 was measured after withholding short-acting and long-acting ß2-agonists for 8 and 12 h respectively, montelukast for 24 h, ipratropium bromide and inhaled corticosteroids for 12 h, and antihistamines for 72 h. RESULTS: 423 participants were screened and 88 had a positive challenge. Participants were 32 yrs ± 19 yrs (mean ± SD), 70% female, 51% White (vs. African American), 6% Hispanic. Similar numbers of participants were using inhaled corticosteroids by race and genotype. There were significant differences in log PC20 between race/genotype groups (p = 0.012). African American Arg16Arg participants had a lower log PC20 than White Gly16Gly (p = 0.009) and African American Gly16Gly (p = 0.041) participants. Both race and genotype contributed significantly to the model (p = 0.037 and p = 0.014, respectively) but there was no interaction between race and genotype on log PC20. CONCLUSIONS AND CLINICAL RELEVANCE: Airway hyperresponsiveness is influenced by race and the ADRB2 codon 16 polymorphism. African Americans with the Arg16Arg genotype have increased airway reactivity and may be at risk for worse asthma outcomes. Inclusion of genetic information as an additional clinical tool may aid in the personalization of asthma management decisions. [ClinicalTrials.gov Identifier: NCT00708227].

Proton Pump Inhibitor Therapy for Eosinophilic Esophagitis: History, Mechanisms, Efficacy, and Future Directions.

Over the past decade, the role of proton pump inhibitor (PPI) medication has evolved from a diagnostic tool for Eosinophilic Esophagitis (EoE), by excluding patients with PPI responsive esophageal eosinophilia (PPI-REE), to a therapy for EoE. This transition resulted from the Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the Appraisal of Guidelines for Research and Evaluation II (AGREE) Conference to support PPI therapy for EoE in children and adults. Additional recent advances have suggested a role for genetic variations that might impact response to PPI therapy for EoE. This review article will explore a brief background of EoE, the evolution of PPI therapy for EoE and its proposed mechanisms, efficacy and safety in children and adults, and considerations for future PPI precision medicine in patients with EoE.

Telehealth for Pediatric Gastroenterology Care Now: The Transition to Telehealth and the Impact of Webinar-Based Didactics.

With the coronavirus disease 2019 public health emergency (PHE), telehealth (TH) became essential for continued delivery of care. Members of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) formed the Telehealth for Pediatric Gastrointestinal Care Now (TPGCN) working group and rapidly organized a telemedicine webinar to provide education and guidance. We aim to describe the webinar development and prospectively assess the effectiveness of this webinar-based educational intervention. Methods: NASPGHAN members who registered for the TPGCN webinar received pre- and post-webinar surveys. Outcome measures included a modified Telehealth Acceptance Model (TAM) survey and a Student Evaluation of Educational Quality (SEEQ) standardized instrument. Results: Seven hundred seventy-six NASPGHAN members participated in the webinar, 147 (33%) completed the pre-webinar survey; of these, 25 of 147 (17%) completed a post-webinar survey. Before the PHE, 50.3% of the pre-webinar survey participants had no TH knowledge. Webinar participants trended to have increased acceptance of TH for follow-up visits (pre-webinar, 68% versus post-webinar, 81%; P = 0.15) and chronic disease care (pre-webinar, 57% vs post-webinar, 81%; P = 0.01). The overall acceptance of TH as shown by TAM pre-webinar was 1.74 ± 0.8, which improved to 1.62 ± 0.8 post-webinar (lower scores indicate greater acceptance; P < 0.001). SEEQ results indicate that webinar material was understandable (post-webinar, 95%). Participants found breakout sessions informative and enjoyable (post-webinar, 91%). Conclusion: The TPGCN TH webinar was an effective educational intervention that fostered increased TH usage for follow-up and chronic care visits, improved TAM scores, and was well received by participants as seen by high SEEQ scores. Sustained and expanded pediatric gastrointestinal TH usage beyond the coronavirus disease 2019 PHE is expected.

Pharmacogenomics fail to explain proton pump inhibitor refractory esophagitis in pediatric esophageal atresia.

BACKGROUND: Esophagitis is prevalent in patients with esophageal dysmotility despite acid suppression, likely related to poor esophageal clearance. Esophageal atresia (EA) is a classic model of dysmotility where this observation holds true. In adult non-dysmotility populations, failure of esophagitis to respond to proton pump inhibitors (PPI) has been linked to variants in CYP2C19 that influence the activity of the encoded enzyme. It is unknown if CYP2C19 metabolizer phenotype contributes to PPI-refractory, non-allergic esophagitis in EA. METHODS: We performed a cross-sectional study of 314 children with (N = 188) and without (N = 126) EA who were on PPI therapy at the time of endoscopy to evaluate for possible gastroesophageal reflux disease. Patients with eosinophilic esophagitis and/or fundoplication were excluded. Clinical and histology data were collected. Genomic DNA from biopsy samples was genotyped for polymorphisms in CYP2C19. RESULTS: CYP2C19 metabolizer phenotypes were not associated with presence or severity of esophagitis (P = 0.994). In a multivariate logistic regression adjusted for potential confounders, EA was the strongest and only significant predictor of esophagitis (odds ratio 2.72, P = 0.023). Using negative binomial regression, we found that CYP2C19 phenotype was not a significant predictor of eosinophil count in children with PPI-refractory esophagitis. CONCLUSIONS: Patients with EA are significantly more likely to experience PPI-refractory, non-allergic esophagitis than controls regardless of CYP2C19 metabolizer phenotype, suggesting that factors other than CYP2C19 genetics, including dysmotility, are the primary drivers of esophagitis in EA. CYP2C19 genotype failed to predict PPI-refractory, non-allergic esophagitis in both EA and non-EA children.

Fish Oil Supplementation in Overweight/Obese Patients with Uncontrolled Asthma. A Randomized Trial.

Rationale: Omega-3 fatty acid (n3PUFA) supplementation has been proposed as a promising antiasthma strategy. The rs59439148 ALOX5 polymorphism affects leukotriene production and possibly inflammatory responses to n3PUFA. Objectives: Assess the effects of n3PUFA supplementation and ALOX5 genotype on asthma control in patients with obesity and uncontrolled asthma. Methods: This multicenter trial among 12- to 25-year-olds with overweight/obesity and uncontrolled asthma randomized subjects in a 3:1 allotment to n3PUFA (4 g/d) or soy oil control for 24 weeks. Asthma Control Questionnaire was the primary outcome; secondary outcomes included blood leukocyte n3PUFA levels, urinary leukotriene-E4, spirometry, and asthma-related events. The number of SP1 tandem repeats in rs59439148 determined ALOX5 genotype status. Simple and multivariable generalized linear models assessed effects on outcomes. Results: Ninety-eight participants were randomized (77 to PUFA, 21 to control), and more than 86% completed all visits. Asthma and demographic characteristics were similar among treatment groups. n3PUFA treatment increased the n3-to-n6 PUFA ratio in circulating granulocytes (P = 0.029) and monocytes (P = 0.004) but did not affect mean Asthma Control Questionnaire change at 6 months (n3PUFA: mean, -0.09; 95% confidence interval [CI], 0.09 to 0.10; vs. control: mean, -0.18; 95% CI, -0.42 to 0.06; P = 0.58). Changes in urinary leukotriene-E4 (P = 0.24), forced expiratory volume in 1 second % predicted (P = 0.88), and exacerbations (relative risk [RR], 0.92; 95% CI, 0.30-2.89) at 6 months were similar in both groups. n3PUFA treatment was associated with reduced asthma-related phone contacts (RR, 0.34; 95% CI, 0.13-0.86; P = 0.02). ALOX5 genotype did not affect n3PUFA treatment responses. Conclusions: We did not find evidence that n3PUFA use improves most asthma-related outcomes and cannot recommend it as a prevention strategy for overweight/obese patients with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT01027143).

Genotype tailored treatment of mild symptomatic acid reflux in children with uncontrolled asthma (GenARA): Rationale and methods.

Asthma causes enormous suffering and cost for children in the US and around the world [1-3]. Co-morbid gastroesophageal reflux disease (GERD) makes asthma management more difficult due to increased symptoms. Proton pump inhibitor (PPI) drugs are effective at improving to GERD symptoms, however they have demonstrated only modest and variable effects on asthma control in the setting of co-morbid GERD. Importantly, PPI metabolism and efficacy depend on CYP2C19 genotype. The Genotype Tailored Treatment of Symptomatic Acid Reflux in Children with Uncontrolled Asthma (GenARA) study is a randomized, double-blind, placebo-controlled trial to determine if genotype-tailored PPI dosing improves asthma symptoms among children with inadequately controlled asthma and GERD symptoms. This study has an innovative design to both assess the efficacy of genotype-tailored PPI dosing and perform pharmacokinetic modeling of the oral PPI Lansoprazole. Children ages 6-17 years old with clinician-diagnosed asthma and mild GERD symptoms will submit a saliva sample for CYP2C19 genotyping. Participants will undergo a two-step randomization to: (1) genotype-tailored versus conventional dosing of open-label oral lansoprazole for pharmacokinetic modeling, and (2) genotype-tailored lansoprazole daily versus placebo for 24 weeks to determine the effect of genotype-tailored PPI dosing on asthma control. Measures of asthma control, spirometry, and nasal washes during acute illnesses will be collected at 8-week intervals throughout the study. GenARA will better define the effects of CYP2C19 genotype on the dose response of lansoprazole in children and adolescents and assess if a novel dosing regimen improves GERD and asthma control.

Novel Implementation of Genotype-Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial.

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype-guided pediatric dosing of PPI medications. Children aged 5-17 years old with gastric-acid-related conditions were randomized to receive either conventional dosing of a PPI or genotype-guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype-guided dosing arm (P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype-guided dosing arm. The number of participants who reported an infection was marginally lower in genotype-guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype-guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype-guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI-associated infections. A future large scale randomized clinical trial of CYP2C19 genotype-guided pediatric dosing of PPI medications in children is warranted.

Association Between CYP2C19*17 Alleles and pH Probe Testing Outcomes in Children With Symptomatic Gastroesophageal Reflux.

Esophageal pH monitoring remains a primary diagnostic tool for detecting gastroesophageal reflux disease (GERD). GERD that is refractory to proton pump inhibitor (PPI) medications may be related to CYP2C19 variants. Current PPI dosing practices in children do not take into account CYP2C19 allelic variants, which may lead to underdosing and subsequently to a misperception of PPI therapy failure. We hypothesized that pH probe acid exposure outcomes associate with CYP2C19*17 alleles among children with clinical concern for GERD. We identified a retrospective cohort of 74 children (age range 0.71-17.1 years, mean 8.5, SD 4.6) with stored endoscopic tissue samples and who had also undergone esophageal pH testing while on PPI therapy. These individuals were genotyped for common CYP2C19 alleles and were dichotomized to either CYP2C19*17 allelic carriers without corresponding loss of function alleles as cases vs controls. Associations between pH probe acid exposure outcomes and CYP2C19*17 alleles were investigated. Compared to controls, children who carry CYP2C19*17 alleles without corresponding loss-of-function alleles demonstrated statistically significant longer times with pH < 4 (76.46 vs 33.47 minutes, P = .03); and higher percent of time with pH < 4.0 (5.71 vs 2.67 minutes, P = .04). These findings remained statistically significant using multiple-regression modeling with test duration, PPI dose, and race as confounding variables. PPI therapy in children with *17 alleles may be better optimized with CYP2C19 genotype-guided dosing prior to pH probe testing.

Serum folate concentrations, asthma, atopy, and asthma control in Peruvian children.

BACKGROUND: The relationship between folate status and asthma-related outcomes has not been carefully examined in low- and middle-income countries where folate deficiency is common. METHODS: Ancillary analysis of an unmatched case-control study in which we analyzed serum folate concentrations in 412 children with asthma and 342 controls living in peri-urban communities in Lima, Peru. We examined baseline associations between folate and asthma, atopy, total serum IgE, pulmonary function, and fractional exhaled nitric oxide. We then followed children with asthma longitudinally for 6-9 months and assessed associations between folate and odds of uncontrolled asthma (defined as Asthma Control Test score ≤ 19) and of ≥1 emergency visits during follow-up. RESULTS: A 10 ng/mL decrease in serum folate was associated with 45% higher adjusted odds of asthma (OR = 1.45, 95% CI 1.05-2.02). The folate-asthma relationship differed by atopic status: a 10 ng/mL decrease in serum folate was associated with a 2.4-fold higher odds of asthma among children without atopy (2.38, 1.20-4.72) and 23% higher odds of asthma in children with atopy (1.23, 0.85-1.80). Among children with asthma, a 10 ng/mL decrease in serum folate was associated with 62% higher odds of uncontrolled asthma (1.62, 1.02-2.56) and 73% higher odds of ≥1 emergency visits during follow-up (1.73, 1.05-2.85). CONCLUSIONS: Serum folate concentrations were inversely associated with asthma, but this effect was stronger in children without atopy. Among children with asthma, lower serum folate concentrations were associated with higher risk of uncontrolled asthma.

Associations between serum 25(OH)D concentrations and prevalent asthma among children living in communities with differing levels of urbanization: a cross-sectional study.

BACKGROUND: Prior evidence suggests that vitamin D deficiency may increase the risk of asthma and atopy and impair pulmonary function in children. METHODS: In this cross-sectional analysis nested in a case-control study, we analyzed serum 25(OH)D concentrations in 413 children with asthma and 471 children without asthma living in two geographically adjacent study communities (Pampas and Villa El Salvador). We measured total and antigen-specific IgE levels, pulmonary function, asthma control, and exhaled nitric oxide. RESULTS: Mean 25(OH)D concentrations were 25.2 ng/mL (SD 10.1) in children with asthma and 26.1 ng/mL (SD 13.7) in children without asthma (p = 0.28). Vitamin D deficiency (25(OH)D < 20 ng/ml) was more common in Pampas than in Villa El Salvador (52.7% vs. 10.5%; p < 0.001). In the overall study population, a 10 ng/ml decrease in serum 25(OH)D concentrations was not significantly associated with odds of asthma (OR 1.09, 95% CI: 0.94 to 1.25). However, vitamin D deficiency was associated with a 1.6-fold increase in odds of asthma in the overall cohort (95% CI: 1.14 to 2.25). After stratifying by site, a 10 ng/mL decrease in serum 25(OH)D concentrations was associated with 18% higher odds of having asthma in Pampas (OR = 1.18, 95% CI 1.02 to 1.38), whereas there was no significant association between 25(OH)D concentrations and asthma in Villa El Salvador (OR = 0.95, 95% CI 0.87 to 1.05). Combined data from these geographically adjacent populations suggests a possible threshold for the relationship between 25(OH)D levels and asthma at approximately 27.5 ng/ml. Serum 25(OH)D concentrations were not clearly associated with asthma control, total serum IgE, atopy, or airway inflammation. CONCLUSION: Serum 25(OH)D concentrations were inversely associated with asthma in one study community with a high prevalence of deficiency. Studies are needed to investigate a possible threshold 25(OH)D concentration after which higher vitamin D levels show no further benefit for asthma.

Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype.

RATIONALE: Gastric acid blockade in children with asymptomatic acid reflux has not improved asthma control in published studies. There is substantial population variability regarding metabolism of and response to proton pump inhibitors based on metabolizer phenotype. How metabolizer phenotype affects asthma responses to acid blockage is not known. OBJECTIVES: To determine how metabolizer phenotype based on genetic analysis of CYP2C19 affects asthma control among children treated with a proton pump inhibitor. METHODS: Asthma control as measured by the Asthma Control Questionnaire (ACQ) and other questionnaires from a 6-month clinical trial of lansoprazole in children with asthma was analyzed for associations with surrogates of lansoprazole exposure (based on treatment assignment and metabolizer phenotype). Groups included placebo-treated children; lansoprazole-treated extensive metabolizers (EMs); and lansoprazole-treated poor metabolizers (PMs). Metabolizer phenotypes were based on CYP2C19 haplotypes. Carriers of the CYP2C19*2, *3, *8, *9, or *10 allele were PMs; carriers of two wild-type alleles were extensive metabolizers (EMs). MEASUREMENTS AND MAIN RESULTS: Asthma control through most of the treatment period was unaffected by lansoprazole exposure or metabolizer phenotype. At 6 months, PMs displayed significantly worsened asthma control compared with EMs (+0.16 vs. -0.13; P = 0.02) and placebo-treated children (+0.16 vs. -0.23; P < 0.01). Differences in asthma control were not associated with changes in gastroesophageal reflux symptoms. Recent upper respiratory infection worsened asthma control, and this upper respiratory infection effect may be more pronounced among lansoprazole-treated PMs. CONCLUSIONS: Children with the PM phenotype developed worse asthma control after 6 months of lansoprazole treatment for poorly controlled asthma. Increased exposure to proton pump inhibitor may worsen asthma control by altering responses to respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00604851).

Association Between Serum 25-Hydroxy Vitamin D Levels and Blood Pressure Among Adolescents in Two Resource-Limited Settings in Peru.

INTRODUCTION: Serum 25-hydroxyvitamin D (25OHD) deficiency (<50 nmol/l or 20 ng/ml) has been associated with increased blood pressure (BP) in observational studies. A paucity of data on this relationship is available in Latin American or child populations. This study investigates the association between 25OHD levels and BP in adolescents at risk for vitamin D deficiency in 2 Peruvian settings. METHODS: In a population-based study of 1,441 Peruvian adolescents aged 13-15 years, 1,074 (75%) provided a serum blood sample for 25OHD analysis and BP measurements. Relationships between 25OHD and BP metrics were assessed using multiple linear regressions, adjusted for anthropometrics and sociodemographic factors. RESULTS: 25OHD deficiency was associated with an elevated diastolic BP (DBP) (1.09 mm Hg increase, 95% confidence interval: 0.04 to 2.14; P = 0.04) compared to nondeficient adolescents. Systolic BP (SBP) trended to increase with vitamin D deficiency (1.30 mm Hg increase, 95% confidence interval: -0.13 to 2.72; P = 0.08). Mean arterial pressure (MAP) was also greater in adolescents with 25OHD (1.16 mm Hg increase, 95% confidence interval: 0.10 to 2.22; P = 0.03). SBP was found to demonstrate a U-shaped relationship with 25OHD, while DBP and MAP demonstrated inverse J-shaped relationships with serum 25OHD status. The association between 25OHD deficiency and BP was not different across study sites (all P ≥ 0.19). DISCUSSION: Adolescents deficient in 25OHD demonstrated increased DBP and MAP and a trend toward increased SBP, when compared to nondeficient subjects. 25OHD deficiency early in life was associated with elevated BP metrics, which may predispose risk of hypertension later in adulthood.