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.

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.

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.

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.

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.

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.

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.

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).

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 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.

Nutrigenetic response to omega-3 fatty acids in obese asthmatics (NOOA): rationale and methods.

Uncontrolled asthma is a major cause of hospitalizations and emergency room visits. Factors including obesity, African ancestry and childhood are associated with increased asthma severity. Considering the high morbidity caused by asthma, relatively few classes of drugs exist to control this common disease. Therefore, new therapeutic strategies may be needed to reduce asthma's impact on public health. Data suggest that a high fat diet that is deficient in omega-3 fatty acids could promote both obesity and excessive inflammation, resulting in greater asthma severity. Small trials with supplemental omega-3 fatty acids have been conducted with encouraging but inconsistent results. The variability in response seen in past trials may be due to the past subjects' genetics (specifically ALOX5 rs59439148) or their particular asthma phenotypes. Therefore, the "Nutrigenetic response to Omega-3 Fatty acids in Obese Asthmatics (NOOA)" trial is currently underway and was designed as a randomized, double-blind, placebo controlled intervention study to determine if supplemental omega-3 fatty acids improves symptoms among obese adolescents and young adults with uncontrolled asthma. Here we report the design and rationale for the NOOA trial. Participants were given either 3.18 g daily of eicosapentaenoic acid and 822 mg daily docosahexaenoic acid, or matched control soy oil, for 24 weeks. Change in the asthma control questionnaire score was the primary outcome. Secondary outcomes included spirometry, impulse oscillometry, exacerbation rate, airway biomarkers, systemic inflammation, leukotriene biosynthesis and T-lymphocyte function. NOOA may lead to a new therapeutic treatment strategy and greater understanding of the mechanistic role of diet in the pathogenesis of asthma.

Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response.

OBJECTIVES: To (i) determine whether montelukast undergoes carrier-mediated uptake; (ii) classify the carrier protein(s) responsible for uptake; (iii) identify specific transporters that mediate transport of montelukast; and (iv) evaluate whether variation in the gene encoding the transport protein(s) influences the pharmacokinetics and pharmacodynamics of montelukast. METHODS: In-vitro permeability studies of montelukast are carried out using Caco-2 cell culture, a standard model of human intestinal drug transport. In-vivo plasma concentrations of montelukast in an asthmatic population are determined by high-performance liquid chromatography, and genotyping of transport proteins is by LightTyper analysis. RESULTS: Permeability of montelukast has an activation energy of 13.7+/-0.7 kcal/mol, consistent with carrier-mediated transport. Permeability is saturable at high concentrations of montelukast and follows Michaelis-Menten kinetics. Permeability is subject to competition by sulfobromophthalein, estrone-3-sulfate, pravastatin, taurocholic acid, and cholic acid (P<0.05, percentage of control: 72+/-7-86+/-7) and is inhibited by 5-10% citrus juice (P<0.05, maximal inhibition percentage of control: 31+/-2). An MDCKII cell line expressing OATP2B1 (coded for by the SLCO2B1 gene) displays significantly increased permeability of montelukast (P<0.05, percentage of control: 140+/-20). A nonsynonymous polymorphism in SLCO2B1, rs12422149; SLCO2B1 {NM_007256.2}:c.935G>A, associates with significantly reduced plasma concentration in patients measured on the morning after an evening dose (P<0.025, square root mean transformed plasma concentration+/-SE; c.[935G>A]+[935G]=3+/-1, c.[935G]+[935G]=7.0+/-0.9) and differential response as assessed by change in baseline Asthma Symptom Utility Index scores after 1 month of therapy (delta mean Asthma Symptom Utility Index; c.[935G>A]+[935G]=0.02+/-0.01, P=1.0; c.[935G]+[935G]=1.0+/-0.3, P<0.0001). CONCLUSION: Altogether, these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast.

Growth factor regulation of human growth plate chondrocyte proliferation in vitro.

Linear growth occurs as the result of growth plate chondrocytes undergoing proliferative and hypertrophic phases. Paracrine feedback loops that regulate the entry of chondrocytes into the hypertrophic phase have been shown and similar pathways likely exist for the proliferative phase. Human long-bone growth plate chondrocytes were cultured in vitro. The proliferative effects of a variety of factors were determined by [3H]thymidine uptake and the gene expression profile of these cells was determined by DNA microarray analysis. Serum, insulin-like growth factor (IGF)-I and -II, transforming growth factor-beta (TGF-beta, fibroblast growth factor (FGF)-1, -2, and -18, and platelet-derived growth factor (PDGF)-BB were potent stimulators of proliferation. FGF-10, testosterone, and bone morphogenetic proteins (BMP)-2, -4, and -6 inhibited proliferation. Microarray analysis showed that the genes for multiple members of the IGF-I, TGF-beta, FGF, and BMP pathways were expressed, suggesting the presence of autocrine/paracrine pathways that regulate the proliferative phase of growth plate-mediated growth.

Mitochondrial ribosomal proteins: candidate genes for mitochondrial disease.

Most of the energy requirement for cell growth, differentiation, and development is met by the mitochondria in the form of ATP produced by the process of oxidative phosphorylation. Human mitochondrial DNA encodes a total of 13 proteins, all of which are essential for oxidative phosphorylation. The mRNAs for these proteins are translated on mitochondrial ribosomes. Recently, the genes for human mitochondrial ribosomal proteins (MRPs) have been identified. In this review, we summarize their refined chromosomal location. It is well known that mutations in the mitochondrial translation system, i.e., ribosomal RNA and transfer RNA cause various pathologies. In this review, we suggest possible associations between clinical conditions and MRPs based on coincidence of genetic map data and chromosomal location. These MRPs may be candidate genes for the clinical condition or may act as modifiers of existing known gene mutations (mt-tRNA, mt-rRNA, etc.).

Using real-time, quantitative PCR for rapid genotyping of the steroid 21-hydroxylase gene in a north Florida population.

The most common cause of congenital adrenal hyperplasia is steroid 21-hydroxylase deficiency. The molecular genetics of this disease are such that genotyping is a potentially useful tool in its diagnosis. An assay was developed using real-time, quantitative PCR to detect deletions of the steroid 21-hydroxylase gene (CYP21A2). This assay was able to detect heterozygous gene deletions with an alpha error rate of less than 5%, with a power greater than 95%. When combined with allele-specific PCR, genotyping for the nine most common mutations can be completed within hours of blood sampling. This technique was used to study subjects with 21-hydroxylase deficiency in North Florida. Twenty-eight subjects with congenital adrenal hyperplasia, seven first-degree relatives and thirteen normal subjects, were characterized. Of 96 chromosomes, 69 abnormal alleles were identified. Among unrelated abnormal alleles, the frequency of specific mutations was 28% for a gene deletion, 24% for the intron 2 splice mutation, 10% for ile172asn, 8% each for val281leu and the exon 6 cluster, and 6% for gln318x mutations. These frequencies, as well as the genotype/phenotype correlation, were similar to those found in comparable populations. The utility of genotyping in the diagnosis of 21-hydroxylase deficiency is increased by the rapidity of the analysis. With quantitative PCR, the need for more expensive and time consuming Southern blot analysis is reduced and limited to the clarification of certain genotypes. Faster results will allow for more timely initiation of appropriate therapy and limit the exposure of potentially unnecessary therapy.