Patients
Nonsmoking patients (age >18 years) with a history of chronic cough
(>8 weeks) during the 6 months prior to screening, without established PND or pulmonary disease, were eligible for enrollment. All eligible patients were previously assessed in the Otolaryngology and Pulmonology Clinics at the Rabin Medical Center to exclude otolaryngeal or pulmonary pathology. Referral of patients for screening was performed by otorhinolaryngologists and gastroenterologists from the Otorhinolaryngology and Gastroenterology outpatient clinics, respectively, at the Rabin Medical Center. Exclusion criteria included gastric or esophageal surgery, active peptic ulcer disease, malignancy, endoscopic evidence for erosive esophagitis, or Barrett's esophagus. In addition, we excluded pregnant patients, active smokers, patients with asthma, chronic bronchitis, or pathologic findings on spirometry or chest X-ray, patients with gastroparesis and those on active treatment with angiotensin-converting enzyme inhibitors. We also excluded patients reluctant or incapable of providing informed consent, unable to fully complete all phases of the study, or with a contraindication to PPI therapy.
Study design
This prospective, interventional open-label trial, was conducted between January 2013 to May 2016, in the Divisions of Otorhinolaryngology and Gastroenterology at the Rabin Medical Center, Israel, and was performed in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice and was approved by the Human Subjects Protection Program of the Rabin Medical Center, Israel on 4th of March 2013 (trial 0125-13).
All patients provided written informed consent before enrollment into the study. All eligible patients who gave informed consent underwent an upper endoscopy (at baseline only) if they had not done so in the past year.
This study adheres to CONSORT guidelines.
Patient screening and enrollment
After initial screening, patients with chronic cough were assessed during a face-to-face interview by one of the two chief investigators (R.D. and U.A.). This was performed to ensure that the inclusion and exclusion criteria were met, to obtain written informed consent, and to prescribe PPI therapy. Treatment comprised esomeprazole 40mg twice daily for a period of 4 months.
Study instruments and measurements
Patients were evaluated by questionnaires and by fiberoptic laryngoscopy at baseline, 2 months and 4 months after initiation of treatment. At each time point, patients were interviewed by chief investigators to obtain numerical responses to the items in the questionnaires.
Demographic questionnaire
The demographic questionnaire included characteristics regarding age, gender, body mass index, ethnicity, level of education, occupation, and marital status.
Reflux symptoms index (RSI)
The RSI is a 9-item self-administered outcome questionnaire designed to evaluate extraesophageal reflux related symptoms and severity. Symptoms include hoarseness, vocal fatigue, excessive throat clearing, dysphagia, chronic cough, and PND. Regurgitation and heartburn are also evaluated. Patients are asked to rate how these 9 symptoms have affected them over the past month on a scale of 0 (none) to 5 (severe), with a maximum total score of 45. A total score of more than 13 is considered suggestive of extraesophageal reflux. The higher the score, the more severe the symptoms experienced by the patient [12].
Leicester cough questionnaire (LCQ)
The LCQ is a validated, self reported quality of life instrument comprising 19 items relating to three main domains: Physical, psychological, and social [13]. Patients are asked to rate the frequency and severity of symptoms on a 7-point Likert scale (ranging from 1 to 7). Scores are calculated as a mean of each domain, and the total score is calculated by adding every domain score. The lower the score, the greater the symptoms experienced by the patient.
Fiberoptic laryngoscopic examination
Fiberoptic laryngoscopic examination was performed at all 3 time points by the study investigators (Y.V. and U.A.) to evaluate the signs suggestive of reflux, and for completion of the Reflux Findings Score (RFS) [14]. If the vocal cords and surrounding structures were not clearly visible with a rigid endoscope, a flexible nasopharyngoscope was used. Participants were instructed to verbalize “ee” in a high-pitched, low-pitched, and regular-pitched tone.
Reflux finding score (RFS)
The RFS is an 8-item index designed to assess clinical severity based on laryngoscopic findings [14]. The 8 items included in the scale are subglottic edema, ventricular obliteration, erythema/hyperemia, vocal fold edema, diffuse laryngeal edema, posterior commissure hypertrophy, granuloma/granulation tissue, and excessive endolaryngeal mucus. Scores range from 0 (normal) to 26 (most severe). A score of 11 or above is suggestive of GERD.
Statistical analysis
A positive response to PPI treatment was defined as an improvement of at least 50% in any score (RSI, LCQ, and RFS) over baseline, as described in previous studies [15]. Patients were stratified into positive and negative response groups. Continuous variables were compared between groups with the nonparametric Mann-Whitney U test because of the small sample size and abnormal distribution of some of the variables. Pearson chi-square test was used to analyze dichotomous variables. A p value of less than 0.05 was considered statistically significant. Data were generated and analyzed with SPSS Version 15.0.