The observation that coughs temporally associate with preceding distal oesophageal reflux, supports a neuronal mechanism linking reflux to cough. Neuronal oesophageal-airway crosstalk most likely occurs where vagal afferents converge and synapse within the brainstem in the nucleus tractus solitarius (nTS). This has previously often been described as the “oesophago-bronchial reflex”. Further evidence supporting the presence of such a mechanism comes from studies infusing acid into the distal oesophagus reporting increased cough frequency [
47] and cough reflex sensitivity [
48] in patients with chronic cough and associated GORD. Oesophageal acid infusion has not been found to change cough reflex sensitivity in healthy volunteers [
48], suggesting that this pathway is usually dormant under normal physiological conditions. This might imply that patients exhibiting a positive SAP
R-C have a central sensitisation or neuroplastic change in these pathways permitting oesophageal stimuli to modulate airway responses, which is in keeping with the finding that SAP
R-C positive patients have heightened cough responses to inhaled citric acid compared with negative SAP
R-C subjects. Indeed a difference in cough reflex sensitivity was the only factor that discriminated between these groups, as the number and acidity of reflux events and incidence of oesophagitis at gastroscopy, were no different between groups. Only in one study in patients with suspected GORD presenting with otolaryngology symptoms has cough been suggested to be associated with oesophagitis [
49]
, but identification of such disease appeared to be a poor predictor of treatment response [
50]. Other concomitant conditions potentially contributing to cough, such as nasal disease, asthma, eosinophilic bronchitis and bronchiectasis also had similar prevalence in SAP
R-C positive and negative subjects, suggesting reflux may contribute to coughing independently of other conditions.
Exactly how vagal pathways might become modified to permit oesophageal-airway crosstalk is not known, but there is evidence that similar processes are also present in other conditions. For example, in asthma patients several studies found that oesophageal acid infusion can induce bronchoconstriction [
51‐
54] and also cough reflex hypersensitivity [
55]. However a meta-analysis of studies of PPI in asthma only found a small improvement in peak flow, unlikely to be clinically important [
56]. Experimental oesophageal acid infusion studies such as these have contributed to the expectation that acid suppression therapy should be successful in patients with cough/asthma and GOR, but it should be acknowledged that the responses to oesophageal acid may be a reflection of a more general visceral hypersensitivity of the oesophagus, which may occur in response to a variety of stimuli and therefore does not necessarily implicate oesophageal acid in the pathophysiology.
Sensitization within the nTS of the brain stem may also be responsible for the reverse association i.e. cough induced reflux. Vagal afferents from the proximal stomach are responsible for transient lower oesophageal sphincter relaxation (TLOSR), the main mechanism thought to be responsible for reflux events in both health and disease [
57,
58]. These afferents could conceivably be activated by cough induced diaphragmatic motion, or by changes in vagal tone associated with cough reflex activations to initiate TLOSRs and thus reflux events, even several minutes after cough [
38].