Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non‐acid gastro‐oesophageal reflux

BackgroundChronic cough affects more than 70 percent of patients with Idiopathic Pulmonary Fibrosis and causes significant morbidity. Gastroesophageal reflux is the cause of some cases of chronic cough; and also has a postulated role in the aetiology of Idiopathic Pulmonary Fibrosis. A high prevalence of acid; and more recently non-acid, reflux has been observed in Idiopathic Pulmonary Fibrosis cohorts. Therefore, gastroesophageal reflux may be implicated in the pathogenesis of cough in Idiopathic Pulmonary Fibrosis.MethodsEighteen subjects with Idiopathic Pulmonary Fibrosis underwent 24-hour oesophageal impedance and cough count monitoring after the careful exclusion of causes of chronic cough other than gastroesophageal reflux. All 18 were then treated with high dose acid suppression therapies. Fourteen subjects underwent repeat 24-hour oesophageal impedance and cough count monitoring after eight weeks.ResultsTotal reflux and acid reflux frequencies were within the normal range in the majority of this cohort. The frequencies of non-acid and proximal reflux events were above the normal range. Following high dose acid suppression therapy there was a significant decrease in the number of acid reflux events (p = 0.02), but an increase in the number of non-acid reflux events (p = 0.01). There was no change in cough frequency (p = 0.70).ConclusionsThis study confirms that non-acid reflux is prevalent; and that proximal oesophageal reflux occurs in the majority, of subjects with Idiopathic Pulmonary Fibrosis. It is the first study to investigate the effect of acid suppression therapy on gastroesophageal reflux and cough in patients with Idiopathic Pulmonary Fibrosis. The observation that cough frequency does not improve despite verifiable reductions in oesophageal acid exposure challenges the role of acid reflux in Idiopathic Pulmonary Fibrosis associated cough. The finding that non-acid reflux is increased following the use of acid suppression therapies cautions against the widespread use of acid suppression in patients with Idiopathic Pulmonary Fibrosis given the potential role for non-acid reflux in the pathogenesis of cough and Idiopathic Pulmonary Fibrosis itself.Study registrationThe study was registered with the Cardiff and Vale University Local Health Board Research and Development Committee (09/CMC/4619) and the South East Wales Ethics Committee (09/WSE04/57).

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“…Cough reflex sensitivity to capsaicin is similarly increased in patients with both acid and non-acid reflux [18]. …”

Section: Introductionmentioning

confidence: 99%

Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study

Kilduff

Counter

Thomas

et al. 2014

Cough

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“…Sputum was induced and processed as described previously [19]. Briefly, the subjects continuously inhaled the 4% hypertonic saline solution through an ultrasonic nebulizer (YS9801, Yisheng Corp., Shanghai, China) and were asked to expectorate sputum into a sterile pot every 5 min, after blowing their noses and rinsing their mouths.…”

Section: Methodsmentioning

confidence: 99%

Capsaicin-sensitive cough receptors in lower airway are responsible for cough hypersensitivity in patients with upper airway cough syndrome

Wang

et al. 2013

Med Sci Monit

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BackgroundCough hypersensitivity may be related to the pathogenesis of upper airway cough syndrome (UACS). The purpose of the study was to investigate the role of capsaicin-sensitive cough receptors on the laryngopharynx and lower airway in the cough hypersensitivity of patients with UACS.Material/Methods59 patients with UACS, 33 patients with rhinitis/sinusitis without cough, and 39 healthy volunteers were recruited for the study. Cough threshold C5, defined as the lowest concentration of capsaicin required for the induction of ≥5 coughs upon esposure to capsaicin, were determined at baseline and after laryngopharngeal anesthesia with lidocaine in all the subjects. After induced sputum cytology, the concentrations of histamine, prostaglandin E2 (PGE2), and calcitonin-gene-related peptide (CGPR) in the induced sputum were measured by ELISA. In 15 patients with UACS, sputum cytology and measurement of the above mediators were repeated after successful therapy.ResultsC5 response to capsaicin was significantly lower in the UACS group than in the rhinitis/sinusitis group and healthy control groups [3.9 (0.98, 7.8) μmol/L vs. 7.8 (3.9, 93.75) μmol/L vs. 31.2 (15.6, 62.5) μmol/L, H=40.12, P=0.000]. Laryngopharngeal anesthesia with lidocaine dramatically increased C5 to capsaicin in the subjects of all 3 groups by a similar degree, but the increase in the UACS group was still the lowest, with an increased level of histamine, PGE2, and CGRP in the induced sputum. When cough resolved with the treatment of cetirizine alone or in combination with erythromycin, the levels of CGRP and histamine in the induced sputum decreased significantly in 15 patients with UACS, with no obvious change in cell differential or concentration of PGE2 in the induced sputum.ConclusionsLaryngeal TRPV1 plays an important role in cough sensitivity, but sensitization of capsaicin-sensitive cough receptors in the lower airway may be more responsible for the cough hypersensitivity in patients with UACS.

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“…However, other biomarkers of inflammation such as prostaglandin D2 and histamine were not significantly increased in these samples [16]. Another study on inflammatory markers in 20 GER patients with cough or mild asthma found no elevation in fibrinogen levels in induced sputum, and an elevation in ECP was more associated with asthma than with GER.…”

Section: Biomarkers In Sputummentioning

confidence: 99%

“…In another study patients with GER and chronic cough were shown to have 50–100 times more of the tachykinin substance P in their sputum when compared to GER patients without chronic cough or healthy subjects [16]. Similarly, a cross-sectional study of 32 subjects showed a positive association between GER and the tachykinins substance P and neurokinin A in induced sputum samples, both in asthmatics and nonasthmatics.…”

Section: Biomarkers In Sputummentioning

confidence: 99%

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Biomarkers for Gastroesophageal Reflux in Respiratory Diseases

Emilsson

Gíslason

Olin

et al. 2013

Gastroenterology Research and Practice

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Gastroesophageal reflux (GER) is commonly associated with respiratory symptoms, either through a vagal bronchoconstrictive reflex or through microaspiration of gastric contents. No diagnostic test is available, however, to diagnose when respiratory illnesses are caused by GER and when not, but research in this field has been moving forward. Various biomarkers in different types of biosamples have been studied in this context. The aim of this review is to summarize the present knowledge in this field. GER patients with respiratory diseases seem to have a different biochemical profile from similar patients without GER. Inflammatory biomarkers differ in asthmatics based on GER status, tachykinins are elevated in patients with GER-related cough, and bile acids are elevated in lung transplant patients with GER. However, studies on these biomarkers are often limited by their small size, methods of analysis, and case selections. The two pathogenesis mechanisms are associated with different respiratory illnesses and biochemical profiles. A reliable test to identify GER-induced respiratory disorders needs to be developed. Bronchoalveolar lavage is too invasive to be of use in most patients. Exhaled breath condensate samples need further evaluation and standardization. The newly developed particles in exhaled air measurements remain to be studied further.

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Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non‐acid gastro‐oesophageal reflux

Abstract: Chronic cough due to non-acid reflux may be related to cough reflex hypersensitivity caused by neurogenic airway inflammation and mast cell activation, in which weakly acidic reflux is possibly a major factor.

Cited by 66 publications

References 36 publications

Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study

Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study

Capsaicin-sensitive cough receptors in lower airway are responsible for cough hypersensitivity in patients with upper airway cough syndrome

Biomarkers for Gastroesophageal Reflux in Respiratory Diseases

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