What’s Going On in Patients with Reflux Who Fail Proton Pump Inhibitors

A recent prospective study (J Abdallah et al. Clin Gastroenterol Hepatol 2019; 17: 1073-80) examined adults patients with documented reflux at baseline.  Patients who reported heartburn and/or regurgitation at least twice a week for 3 months (n=16) despite proton pump inhibitor (PPI) therapy were considered PPI failures. Those (n=13) who responded to standard dose PPI for at least 4 weeks were in the “PPI success” group.

Standard PPI dosing in this study:

  • Omeprazole 20 mg per day
  • Esomeprazole 40 mg per day
  • Pantoprazole 40 mg per day

Methods: Both groups (PPI Failure group, PPI Success group) underwent EGD and pH-MII studies. Abnormal acid exposure was considered if pH <4 was present for >4.2%.

Key findings:

  • 12 patients (75%) in the PPI failure group had either functional heartburn or reflux hypersensitivity
  • 4 patients in both groups had abnormal pH test result.
  • There was no statistically significant differences in the number of reflux events, acid exposure or nonacid reflux parameters between patients who failed or those who were successfully treated with PPIs.
  • In the PPI failure group: 25% had persistent GERD, 12.% had overlap with reflux hypersensitivity, and 62.5% had overlap with functional heartburn

My take: The difference between PPI failure and PPI success largely is due to the overlapping presence of functional esophageal disorders.

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How Many Kids with Reflux Actually Have Reflux?

A terrific recent retrospective study (LB Mahoney, S Nurko, R Rosen. J Pediatr 2017; 189: 86-91) examined how often children with reflux symptoms actually have reflux.

This study reviewed 45 children ≥5 years (mean age 11.8 years) who had undergone both upper endoscopy and impedance pH study (off PPI therapy). Inclusion criteria: no erosive esophagitis. Common symptoms included heartburn, abdominal pain, chest pain, and regurgitation.


  • Nonerosive reflux disease –had abnormal esophageal acid exposure
  • Reflux hypersensitivity -had normal acid exposure but had a positive symptom association to acid or nonacid reflux
  • Functional heartburn -had normal acid exposure and negative symptom association

Key findings:

  • 44% had functional heartburn, 29% with reflux hypersensitivity (27% acid, 2% nonacid), 27% had nonerosive reflux disease (NERD)
  • Response to a proton pump inhibitor (PPI) was not predictive of reflux phenotype: 58% with NERD, 67% with reflux hypersensitivity, and 55% with functional heartburn. Response to PPI was stated as “at least some symptomatic improvement with PPI use.”  There was not a difference in PPI response among those who received a dose <1 mg/kg and those ≥1 mg/kg.
  • Microscopic esophagitis was present in 17% in NERD, 25% with reflux hypersensitivity, and in 20% of functional heartburn

While this study has limitations, including referral bias, it is likely that these patients are typical for many pediatric gastroenterologists. The authors note that typical patients were “patients who underwent a PPI trial but continued to have persistent symptoms.”

My take: In a pediatric gastroenterology setting, the most common reason for “reflux” is actually functional heartburn.  Thus, in those with persistent symptoms, evaluation with endoscopy and pH probe is worthwhile, especially as there has been more attention to potential risks of PPI therapy.

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