Effect of anti-reflux treatment on gastroesophageal reflux-associated chronic cough: Implications of neurogenic and neutrophilic inflammation

Abstract

Objective: Gastroesophageal reflux disease (GERD) is an important cause of chronic cough. Substance P (SP) has been implicated in the pathophysiology of cough. Proton pump inhibitors (PPIs) and prokinetic agents are the current treatment for GER-associated cough. The aim was to evaluate the effects of anti-reflux treatment and its associations with cellular and neurogenic inflammation.

Methods: Thirty-seven patients with GER-associated cough suspected based on characteristic symptoms such as heartburn and worsening of cough by phonation and rising were recruited. A PPI, rabeprazole 20 mg daily, and a prokinetic agent, itopride 50 mg t.i.d., were administered for 4 weeks in a prospective, observational manner. Before and after treatment, subjective cough measures [visual analog scale (VAS) and the Japanese version of the Leicester Cough Questionnaire (J-LCQ)], the modified frequency scale for the symptoms of GERD [FSSG, consisting of 2 domains: acid-reflux (AR) and functional dyspepsia symptoms], sputum and plasma SP levels, and sputum cell differentials were examined. Patients with good response to treatment [Δ (decrease of) VAS >15 mm; n = 21) were compared with poor responders (ΔVAS ≤15 mm).

Results: Anti-reflux treatment significantly improved the cough VAS, J-LCQ, and AR symptoms, and ΔVAS and ΔAR were significantly correlated. Decreases of plasma and sputum SP levels and sputum neutrophil counts were significantly greater in responders than in poor responders. Both baseline values and post-treatment changes of plasma SP and sputum neutrophils were significantly correlated for all patients.

Conclusions: Successful treatment of GER-associated cough may be associated with the attenuation of neurogenic and neutrophilic inflammation.

Keywords:

• cough
• gastroesophageal reflux disease
• substance P
• neurogenic inflammation
• neutrophil

Disclosure statement

MT has received pharmaceutical company grant monies from Daiichi-Sankyo and Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (JSPS). AN has received research pharmaceutical company grant monies from Kyowa-Medex, Boehringer Ingelheim, Takeda Pharmaceutical, Kyorin Pharmaceutical, Teijin Pharmaceutical and Novartis, and lecture fee from AstraZeneca, Boehringer Ingelhim, Novartis, MSD, Taiho Pharmaceutical, Teijin Pharmaceutical, Shionogi Pharmaceutical, Takeda Pharmaceutical, and Kyorin Pharmaceutical. The rest of the authors have no declaration of interest.

Additional information

Funding

The study was supported in part by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government (23591117, 26461165 and 17K09621).