BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) is one of the main causes of chronic cough. We evaluated the role of microaspiration in the pathogenesis of reflux-related cough by determining the amount of lipid-laden macrophages (LLMs) in bronchoalveolar lavage (BAL) specimens. METHODS: A total of 161 cases of chronic cough were evaluated, and 36 patients (average age 48.2 years) were recruited for this single center prospective study. Patients with a history of smoking, angiotensin converting enzyme inhibitor usage, any abnormality on pulmonary function tests, abnormal chest X-rays, occupational or environmental exposures, or upper airway cough syndrome were excluded. GERD was evaluated by 24-hour esophageal impedance-pH monitoring. BAL specimens for LLM determination were obtained from 34 patients by flexible bronchoscopy. RESULTS: Patients with pathological intra-esophageal reflux according to multichannel intraluminal impedance and pH monitoring had higher LLM positivity in BAL specimens than patients without pathological reflux (8/14 in reflux positive group vs 1/22 in reflux negative group; P = 0.004). The BAL cell distribution was not different between the 2 groups (P = 0.574 for macrophages, P = 0.348 for lymphocytes, P = 0.873 for neutrophils and P = 0.450 for eosinophils). CONCLUSIONS: Our results confirm the role of the microaspiration of refluxate in the pathogenetic mechanism of chronic cough. While bronchoscopy is indicated in patients with chronic cough, in addition to the routine airway evaluation, BAL and LLM detection should be performed. LLM can be used to diagnose aspiration in reflux-related chronic cough. Future studies are needed to evaluate the response to anti-reflux medications or surgery in patients with LLM positivity.
Bronchoalveolar Lavage ; Bronchoscopy ; Cough* ; Electric Impedance ; Environmental Exposure ; Gastroesophageal Reflux ; Humans ; Hydrogen-Ion Concentration ; Lymphocytes ; Macrophages ; Neutrophils ; Peptidyl-Dipeptidase A ; Prospective Studies ; Respiratory Function Tests ; Smoke ; Smoking ; Thorax

Background/Aims: Dilated intercellular spaces (DISs) facilitate the diffusion of noxious agents into the deep layers of the esophageal epithelium. The role of DIS in heartburn pathogenesis is still controversial. Therefore, we aim to reinvestigate DIS in an extensively evaluated group of patients and healthy controls (HCs). Methods: We classified 149 subjects into the following groups: 15 HC, 58 mild erosive reflux disease (ERD), 17 severe ERD, 25 nonerosive reflux disease (NERD), 15 reflux hypersensitivity (RH), and 19 functional heartburn (FH). A total of 100 length measurements were performed for each patient’s biopsy. Results: The overall intercellular spaces (ISs) value of gastroesophageal reflux disease (GERD) patients was higher than that of HC (P = 0.020).In phenotypes, mild ERD (vs HC [P = 0.036], NERD [P = 0.004], RH [P = 0.014]) and severe ERD (vs HC [P = 0.002], NERD [P < 0.001], RH [P = 0.001], FH [P = 0.004]) showed significantly higher IS. There was no significant difference between the HC, NERD, RH, and FH groups. The 1.12 μm DIS cutoff value had 63.5% sensitivity and 66.7% specificity in the diagnosis of GERD. There was a weak correlation (r = 0.302) between the IS value and acid exposure time, and a weak correlation (r = −0.359) between the IS value and baseline impedance. A strong correlation was shown between acid exposure time and baseline impedance (r = −0.783). Conclusions Since the IS length measurement had better discrimination power only in erosive groups, it is not feasible to use in daily routine to discriminate other nonerosive phenotypes and FH. The role of DIS in heartburn in nonerosive patients should be reconsidered.

Background/Aims: Gastroesophageal reflux disease is frequently observed and has no definitive treatment. There are 2 main views on the pathogenesis of gastroesophageal reflux disease. The first is that epithelial damage starts from the mucosa by acidic-peptic damage and the inflammatory response of granulocytes. The other view is that T-lymphocytes attract chemoattractants from the basal layer to the mucosa, and granulocytes do not migrate until damage occurs. We aim to investigate the inflammatory processes occurring in the esophageal epithelium of the phenotypes at the molecular level. We also examined the effects of these changes on tissue integrity. Methods: Patients with mild and severe erosive reflux, nonerosive reflux, reflux hypersensitivity, and functional heartburn were included.Inflammatory gene expressions (JAK/STAT Signaling and NFKappaB Primer Libraries), chemokine protein levels, and tissue integrity were examined in the esophageal biopsies. Results: There was chronic inflammation in the severe erosion group, the acute response was also triggered. In the mild erosion group, these 2 processes worked together, but homeostatic cytokines were also secreted. In nonerosive groups, T-lymphocytes were more dominant.In addition, the inflammatory response was highly triggered in the reflux hypersensitivity and functional heartburn groups, and it was associated with physiological reflux exposure and sensitivity. Conclusions “Microinflammation” in physiological acid exposure groups indicates that even a mild trigger is sufficient for the initiation and progression of inflammatory activity. Additionally, the anti-inflammatory cytokines were highly increased. The results may have a potential role in the treatment of heartburn symptoms and healing of the mucosa.