Publications by Year: 2023


Leung R, Lo WK, Sharma NS, Goldberg HJ, Chan WW. Esophageal Function and Reflux Evaluations in Lung Transplantation: A Nationwide Survey of UNOS-Accredited Transplant Centers in the United States. Clinical and translational gastroenterology. 2023;14(12):e00641. doi:10.14309/ctg.0000000000000641

INTRODUCTION: Gastroesophageal reflux disease has been associated with worse lung transplant outcomes. We aimed to assess local practices for esophageal function testing (EFT) across transplant centers.

METHODS: This was a survey study of all United Network for Organ Sharing-accredited adult lung transplant centers regarding local EFT practice.

RESULTS: Among 39/63 (60%) responded centers, 38.5% required any EFT (35.9% esophageal manometry, 15.4% pH monitoring, and 28.2% pH impedance), while another 28.2% may consider EFT based on symptoms. Five-year transplant volume was higher among centers requiring EFT (253 vs 159, P = 0.04).

DISCUSSION: Only a minority of lung transplant centers routinely obtained EFT, supporting the need for guidelines for standardized reflux/esophageal assessment.

Zamani M, Alizadeh-Tabari S, Chan WW, Talley NJ. Association Between Anxiety/Depression and Gastroesophageal Reflux: A Systematic Review and Meta-Analysis. The American journal of gastroenterology. 2023;118(12):2133-2143. doi:10.14309/ajg.0000000000002411

INTRODUCTION: An association between gastroesophageal reflux disease (GERD) and common psychiatric conditions, most notably anxiety and depression, has been reported. However, the magnitude of this association is poorly understood. Therefore, we aimed to systematically assess this issue.

METHODS: We comprehensively searched multiple bibliographic databases (Embase, PubMed, Scopus, and Web of Science) from inception to May 15, 2023. We retrieved observational studies that reported the prevalence of anxiety and/or depressive symptoms diagnosed by validated questionnaires in ≥100 adults (aged 18 years or older) with GERD. We also included cohort studies that explored the risk of incident GERD in subjects with anxiety/depression vice versa scenario. Finally, we included Mendelian randomization studies that assessed the cause-and-effect relationship between anxiety/depression and GERD. The extracted data were combined using a random-effects model.

RESULTS: In total, 36 eligible studies were included. The pooled prevalences of anxiety and depressive symptoms were 34.4% (95% confidence interval [CI] 24.7-44.2; I2 = 99.4%) and 24.2% (95% CI 19.9-28.5; I2 = 98.8%) in subjects with GERD based on 30 studies, respectively. Both anxiety and depressive symptoms were more common in subjects with GERD compared with those in healthy controls (odds ratio = 4.46 [95% CI 1.94-10.25] and odds ratio = 2.56 [95% CI 1.11-5.87], respectively). According to 3 cohort studies, subjects with GERD were at an increased risk of developing anxiety/depression and vice versa. Finally, 3 Mendelian randomization studies showed that genetic liability to these mood disorders is linked to an increased risk of developing GERD and vice versa.

DISCUSSION: Up to 1 in 3 subjects with GERD experience anxiety and depression. There is likely a bidirectional causal relationship between anxiety/depression and GERD.

Bailey ME, Borges LF, Goldberg HJ, et al. Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis. Journal of gastroenterology and hepatology. 2023;38(11):1998-2005. doi:10.1111/jgh.16325

BACKGROUND AND AIM: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients.

METHODS: This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3 years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan-Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes.

RESULTS: One hundred twenty-four subjects (mean age = 61.7 ± 8 years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value = 0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25-8.09), P = 0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37-63.9), P = 0.025] over 3 years.

CONCLUSIONS: Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Wechsler E V, Chan W, Shah ED. Reply. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023;21(11):2987-2988. doi:10.1016/j.cgh.2023.03.011
Shah ED, Chan WW, Jodorkovsky D, et al. Optimizing the management algorithm for heartburn in general gastroenterology: Cost-effectiveness and cost-minimization analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Published online 2023. doi:10.1016/j.cgh.2023.08.026

BACKGROUND AND AIMS: Heartburn is the most common symptom seen in gastroenterology practice. We aimed to optimize cost-effective evaluation and management of heartburn.

METHODS: We developed a decision analytic model from insurer and patient perspectives comparing four strategies for patients failing empiric proton pump inhibitors (PPI): (1) PPI optimization without testing, (2) Endoscopy with PPI optimization for all patients, (3) Endoscopy with PPI discontinuation when erosive findings are absent, (4) Endoscopy/ambulatory reflux monitoring with PPI discontinuation as appropriate for phenotypic management. Health outcomes were respectively defined on systematic reviews of clinical trials. Cost outcomes were defined on Centers for Medicare and Medicaid Services databases and commercial multipliers for direct healthcare costs, and national observational studies evaluating healthcare utilization. The time horizon was one year. All testing was performed OFF-PPI.

RESULTS: PPI optimization without testing cost $3,784/year to insurers and $3,128 to patients due to lower work-productivity and suboptimal symptom relief. Endoscopy with PPI optimization lowered insurer costs by $1,020/year and added 11 healthy days/year by identifying erosive reflux disease. Endoscopy with PPI discontinuation added 11 additional healthy days/year by identifying patients without erosive reflux disease that did not need PPI. By optimizing phenotype-guided treatment, endoscopy/ambulatory reflux monitoring with a trial of PPI discontinuation was the most effective of all strategies (gaining 22 healthy days/year) and saved $2,183 to insurers and $2,396 to patients.

CONCLUSION: Among patients with heartburn, endoscopy with ambulatory reflux monitoring (OFF-PPI) optimizes cost-effective management by matching treatment to phenotype. When erosive findings are absent, trialing PPI discontinuation is more cost-effective than optimizing PPI.

Wechsler E V, Ahuja NK, Brenner D, et al. Up-Front Endoscopy Maximizes Cost-Effectiveness and Cost-Satisfaction in Uninvestigated Dyspepsia. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023;21(9):2378-2388.e28. doi:10.1016/j.cgh.2023.01.003

BACKGROUND & AIMS: Practice guidelines promote a routine noninvasive, non-endoscopic initial approach to investigating dyspepsia without alarm features in young patients, yet many patients undergo prompt upper endoscopy. We aimed to assess tradeoffs among costs, patient satisfaction, and clinical outcomes to inform discrepancy between guidelines and practice.

METHODS: We constructed a decision-analytic model and performed cost-effectiveness/cost-satisfaction analysis over a 1-year time horizon on patients with uninvestigated dyspepsia without alarm features referred to gastroenterology. A RAND/UCLA expert panel informed model design. Four competing diagnostic/management strategies were evaluated: prompt endoscopy, testing for Helicobacter pylori and eradicating if present (test-and-treat), testing for H pylori and performing endoscopy if present (test-and-scope), and empiric acid suppression. Outcomes were derived from systematic reviews of clinical trials. Costs were informed by prospective observational cohort studies and national commercial/federal cost databases. Health gains were represented using quality-adjusted life years.

RESULTS: From the patient perspective, costs and outcomes were similar for all strategies (maximum out-of-pocket difference of $30 and <0.01 quality-adjusted life years gained/year regardless of strategy). Prompt endoscopy maximized cost-satisfaction and health system reimbursement. Test-and-scope maximized cost-effectiveness from insurer and patient perspectives. Results remained robust on multiple one-way sensitivity analyses on model inputs and across most willingness-to-pay thresholds.

CONCLUSIONS: Noninvasive management strategies appear to result in inferior cost-effectiveness and patient satisfaction outcomes compared with strategies promoting up-front endoscopy. Therefore, additional studies are needed to evaluate the drivers of patient satisfaction to facilitate inclusion in value-based healthcare transformation efforts.

Goldin AH, Muftah M, Mangla S, et al. Assessment of the clinical and allergy profiles of PPI responsive and non-responsive eosinophilic esophagitis. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. 2023;36(7). doi:10.1093/dote/doac098

A subset of patients with eosinophilic esophagitis (EoE) respond to proton-pump inhibitor (PPI) therapy, however they cannot be distinguished prior to PPI trial and the mechanism of PPI response remains unclear. Improved understanding of the distinct patient phenotypes in PPI-responsive EoE (PPI-r-EoE), PPI-non-responsive EoE (PPI-nr-EoE) and erosive esophagitis (EE) may help guide management. The aim of this paper is to compare the clinical and allergy profiles of PPI-r-EoE versus PPI-nr-EoE and EE. This was a retrospective case-control study of EoE patients (>15 eos/hpf on esophageal biopsies) at a tertiary center. EE controls were identified from the pathology database. EoE patients were classified as PPI-r-EoE or PPI-nr-EoE based on histologic response to twice-daily PPI for ≥8 weeks. Patient demographics, comorbidities, symptoms, allergy history and endoscopic findings were recorded. Univariate analyses were performed using the Fisher-exact test or t-test. Multivariable analyses were performed using logistic regression. In all, 104 EoE (57 PPI-r-EoE/47 PPI-nr-EoE) and 80 EE subjects were included. On multivariable analyses, allergic conditions (aOR 20.1, P < 0.0001) and rings (aOR 108.3, P = 0.001) were independent predictors for PPI-r-EoE versus EE, whereas allergic conditions (aOR 4.8, P = 0.03), rings (aOR 27.5, P = 0.002) and furrows (aOR 17.1, P = 0.04) were independent predictors for PPI-nr-EoE versus EE. Esophageal rings was the only significant predictor found in PPI-nr-EoE versus PPI-r-EoE (OR 2.5, P = 0.03). Allergic conditions and esophageal rings are significantly more prevalent in PPI-r-EoE and PPI-nr-EoE compared with EE. PPI-r-EoE appears clinically similar to PPI-nr-EoE and significantly different from EE. Further studies are needed to delineate the underlying pathophysiology of PPI-r-EoE versus PPI-nr-EoE.

Lo WK, Flanagan R, Sharma N, Goldberg HJ, Chan WW. Pre-Lung transplant reflux testing demonstrates high prevalence of gastroesophageal reflux in cystic fibrosis and reduces chronic rejection risk. World journal of transplantation. 2023;13(4):138-146. doi:10.5500/wjt.v13.i4.138

BACKGROUND: Gastroesophageal reflux (GER) has been associated with poor outcomes after lung transplantation for chronic lung disease, including increased risk of chronic rejection. GER is common in cystic fibrosis (CF), but factors influencing the likelihood of pre-transplant pH testing, and the impact of testing on clinical management and transplant outcomes in patients with CF are unknown.

AIM: To evaluate the role of pre-transplant reflux testing in the evaluation of lung transplant candidates with CF.

METHODS: This was a retrospective study from 2007-2019 at a tertiary medical center that included all patients with CF undergoing lung transplant. Patients with pre-transplant anti-reflux surgery were excluded. Baseline characteristics (age at transplantation, gender, race, body mass index), self-reported GER symptoms prior to transplantation, and pre-transplant cardiopulmonary testing results, were recorded. Reflux testing consisted of either 24-h pH- or combined multichannel intraluminal impedance and pH monitoring. Post-transplant care included a standard immunosuppressive regimen, and regular surveillance bronchoscopy and pulmonary spirometry in accordance with institutional practice as well as in symptomatic patients. The primary outcome of chronic lung allograft dysfunction (CLAD) was defined clinically and histologically per International Society of Heart and Lung Transplantation criteria. Statistical analysis was performed with Fisher's exact test to assess differences between cohorts, and time-to-event Cox proportional hazards modeling.

RESULTS: After applying inclusion and exclusion criteria, a total of 60 patients were included in the study. Among all CF patients, 41 (68.3%) completed reflux monitoring as part of pre-lung transplant evaluation. Objective evidence of pathologic reflux, defined as acid exposure time > 4%, was found in 24 subjects, representing 58% of the tested group. CF patients with pre-transplant reflux testing were older (35.8 vs 30.1 years, P = 0.01) and more commonly reported typical esophageal reflux symptoms (53.7% vs 26.3%, P = 0.06) compared to those without reflux testing. Other patient demographics and baseline cardiopulmonary function did not significantly differ between CF subjects with and without pre-transplant reflux testing. Patients with CF were less likely to undergo pre-transplant reflux testing compared to other pulmonary diagnoses (68% vs 85%, P = 0.003). There was a decreased risk of CLAD in patients with CF who underwent reflux testing compared to those who did not, after controlling for confounders (Cox Hazard Ratio 0.26; 95%CI: 0.08-0.92).

CONCLUSION: Pre-transplant reflux testing revealed high prevalence of pathologic reflux in CF patients and was associated with decreased risk of CLAD. Systematic reflux testing may enhance outcomes in this patient population.

Lo WK, Hiramoto B, Goldberg HJ, Sharma N, Chan WW. Ineffective esophageal motility is associated with acute rejection after lung transplantation independent of gastroesophageal reflux. World journal of gastroenterology. 2023;29(21):3292-3301. doi:10.3748/wjg.v29.i21.3292

BACKGROUND: Gastroesophageal reflux is associated with poorer outcomes after lung transplant, likely through recurrent aspiration and allograft injury. Although prior studies have demonstrated a relationship between impedance-pH results and transplant outcomes, the role of esophageal manometry in the assessment of lung transplant patients remains debated, and the impact of esophageal dysmotility on transplant outcomes is unclear. Of particular interest is ineffective esophageal motility (IEM) and its associated impact on esophageal clearance.

AIM: To assess the relationship between pre-transplant IEM diagnosis and acute rejection after lung transplantation.

METHODS: This was a retrospective cohort study of lung transplant recipients at a tertiary care center between 2007 and 2018. Patients with pre-transplant anti-reflux surgery were excluded. Manometric and reflux diagnoses were recorded from pre-transplant esophageal function testing. Time-to-event analysis using Cox proportional hazards model was applied to evaluate outcome of first episode of acute cellular rejection, defined histologically per International Society of Heart and Lung Transplantation guidelines. Subjects not meeting this endpoint were censored at time of post-transplant anti-reflux surgery, last clinic visit, or death. Fisher's exact test for binary variables and student's t-test for continuous variables were performed to assess for differences between groups.

RESULTS: Of 184 subjects (54% men, mean age: 58, follow-up: 443 person-years) met criteria for inclusion. Interstitial pulmonary fibrosis represented the predominant pulmonary diagnosis (41%). During the follow-up period, 60 subjects (33.5%) developed acute rejection. The all-cause mortality was 16.3%. Time-to-event univariate analyses demonstrated significant association between IEM and acute rejection [hazard ratio (HR): 1.984, 95%CI: 1.03-3.30, P = 0.04], confirmed on Kaplan-Meier curve. On multivariable analysis, IEM remained independently associated with acute rejection, even after controlling for potential confounders such as the presence of acid and nonacid reflux (HR: 2.20, 95%CI: 1.18-4.11, P = 0.01). Nonacid reflux was also independently associated with acute rejection on both univariate (HR: 2.16, 95%CI: 1.26-3.72, P = 0.005) and multivariable analyses (HR: 2.10, 95%CI: 1.21-3.64, P = 0.009), adjusting for the presence of IEM.

CONCLUSION: Pre-transplant IEM was associated with acute rejection after transplantation, even after controlling for acid and nonacid reflux. Esophageal motility testing may be considered in lung transplant to predict outcomes.