Cough Reflex Sensitivity and Bronchial Hyper-responsiveness

Pilot Studies Evaluating Cough Reflex Sensitivity and Bronchial Hyper-responsiveness: The Road to Cough and Wheeze in Patients With Gastroesophageal Reflux.

The aim of this study is to provide pilot data on the possible gastrointestinal predictors of respiratory hyper-responsiveness and how these relate to the clinical sub-types of gastroesophageal reflux disease (GERD) and visceral acid hypersensitivity.

Study Overview

• Status: Completed
• Conditions: Gastroesophageal Reflux Disease; Chronic Cough; Broncho-hyperreactivity
• Intervention / Treatment: Procedure: Cough Reflex Sensitivity; Procedure: Methacholine Challenge

Detailed Description

This study recruited participants into three groups: reflux patients with non-erosive disease (NERD) with abnormal levels of acid reflux, NERD patients with normal levels of reflux and healthy volunteers. Participants were assessed for cough reflex sensitivity (CRS) to citric acid and bronchial-hyperresponsiveness (BHR) to methacholine challenge, both before (baseline) and after esophageal acid infusion (HCl, 0.15M) or normal saline control (8ml/min). The order of CRS and BHR was randomized, as was the order of the acid/saline infusions.

• Study Type: Observational
• Enrollment (Actual): 24

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

This study will recruit participants into three groups ages 18-60 years: 12 reflux patients with non-erosive disease (NERD) with abnormal levels of acid reflux, 12 NERD patients with normal levels of reflux and 12 healthy volunteers.

Description

Inclusion Criteria:

• symptomatic reflux (i.e., one symptom at least one day a week, with at least 'moderate' severity)
• no evidence of esophagitis
• non-smokers

Exclusion Criteria:

• previous gastrointestinal surgery (excluding minor surgeries, such as cholecystectomy, appendectomy
• active peptic ulcer disease
• Zollinger Ellison Syndrome
• Barrett's esophagus
• eosinophilic esophagitis
• cardiac disease
• diabetes or neurological deficit
• use of tricyclics
• selective serotonin reuptake inhibitors
• narcotics or benzodiazepines
• current use of medications that may affect symptoms of perception,lower esophageal sphincter basal pressure, acid clearance time or acid suppression
• antibiotics within 60 days
• Nursing mothers will be excluded
• allergies to citrus
• asthma
• chronic lung disease
• heart attack or stroke within the last three months
• hypersensitivity to methacholine products
• know aortic aneurysm
• uncontrolled hypertension (defined as systolic pressure greater than 200 or diastolic greater than 100)
• reduced pulmonary function test (forced expiratory volume in one second (FEV1) or the FEV1 to forced vital capacity (FVC) ratio (FEV1/FVC) of less that 70% of predicted value)
• None of the controls will have any GERD symptoms or ever used antireflux treatment.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy Volunteers; Subjects in this arm were healthy volunteers. Subjects underwent both Cough Reflex Sensitivity and the Methacholine Challenge procedures.	Procedure: Cough Reflex Sensitivity; Subjects inhaled increasing concentrations of citric acid, which induces coughing in a dose-dependent, reproducible matter. Following each inhalation, the number of coughs in the subsequent 15 seconds was counted and recorded. The challenge was terminated once the citric acid induced 5 or more coughs and the logarithmic (base 10) concentration provoking 5 coughs was recorded.; Procedure: Methacholine Challenge; A baseline spirometry was used to assess how well the participant's lungs work by measuring how much air was inhale, how much was exhale and how quickly the participant exhaled. If this was normal, the subject inhaled slowly and deeply the methacholine test solution from a nebulizer and was told to hold their breath for 5 seconds. This was repeated until 5 inhalations were performed in no more than two minutes.
Non-erosive reflux disease with reflux; Subjects enrolled in this arm had non-erosive reflux disease with reflux (heartburn) for at least 6 of the preceding 12 months. Subjects underwent both Cough Reflex Sensitivity and the Methacholine Challenge procedures.	Procedure: Cough Reflex Sensitivity; Subjects inhaled increasing concentrations of citric acid, which induces coughing in a dose-dependent, reproducible matter. Following each inhalation, the number of coughs in the subsequent 15 seconds was counted and recorded. The challenge was terminated once the citric acid induced 5 or more coughs and the logarithmic (base 10) concentration provoking 5 coughs was recorded.; Procedure: Methacholine Challenge; A baseline spirometry was used to assess how well the participant's lungs work by measuring how much air was inhale, how much was exhale and how quickly the participant exhaled. If this was normal, the subject inhaled slowly and deeply the methacholine test solution from a nebulizer and was told to hold their breath for 5 seconds. This was repeated until 5 inhalations were performed in no more than two minutes.
Non-erosive reflux disease without reflux; Subjects enrolled in this arm had non-erosive reflux disease with normal levels of reflux (heartburn). Subjects underwent both Cough Reflex Sensitivity and the Methacholine Challenge procedures.	Procedure: Cough Reflex Sensitivity; Subjects inhaled increasing concentrations of citric acid, which induces coughing in a dose-dependent, reproducible matter. Following each inhalation, the number of coughs in the subsequent 15 seconds was counted and recorded. The challenge was terminated once the citric acid induced 5 or more coughs and the logarithmic (base 10) concentration provoking 5 coughs was recorded.; Procedure: Methacholine Challenge; A baseline spirometry was used to assess how well the participant's lungs work by measuring how much air was inhale, how much was exhale and how quickly the participant exhaled. If this was normal, the subject inhaled slowly and deeply the methacholine test solution from a nebulizer and was told to hold their breath for 5 seconds. This was repeated until 5 inhalations were performed in no more than two minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in cough reflex sensitivity (CRS)	baseline, approximately 4 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: University of Manchester
• Investigators: Principal Investigator: Kenneth R. DeVault, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2012
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: January 24, 2013
• First Submitted That Met QC Criteria: January 24, 2013
• First Posted (Estimate): January 29, 2013

Study Record Updates

• Last Update Posted (Actual): February 17, 2017
• Last Update Submitted That Met QC Criteria: February 16, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Respiration Disorders; Gastrointestinal Diseases; Bronchial Diseases; Signs and Symptoms, Respiratory; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Gastroesophageal Reflux; Cough; Bronchial Hyperreactivity; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Cholinergic Agonists; Respiratory System Agents; Miotics; Parasympathomimetics; Bronchoconstrictor Agents; Muscarinic Agonists; Methacholine Chloride
• Other Study ID Numbers: 11-006873

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No