Neuro-pulmonary mechanistic interplay underlying chronic cough.

Chronic cough is a highly prevalent debilitating condition. Chronic cough can be unexplained despite investigations (unexplained chronic cough) or persist despite guideline-based management of treatable traits (refractory chronic cough). Individuals with refractory and unexplained chronic cough (RUCC) often share similar clinical characteristics, including a dry cough, persistent urge-to-cough and throat irritation. Most individuals with RUCC display cough reflex hypersensitivity, coughing in response to chemical, thermal and mechanical triggers. Compared to controls, individuals with RUCC cough at lower concentrations of inhaled stimuli (hypersensitivity) and have increased cough responses across concentrations (hyperresponsiveness). Neuro-pulmonary mechanisms are also supported by treatment responses in RUCC to neuromodulatory medications and behavioural cough control therapy. Mechanisms leading to RUCC are complex but likely involve alterations in the neuro-pulmonary axis in the peripheral and central nervous system. Mechanisms are not fully understood, but RUCC may relate to alterations in airway receptors on vagus nerve terminals, (ATP) release and/or metabolism and plasticity of airway sensory nerves. A wide network of midbrain and higher cortical centres are involved in processing of airway sensations and top-down cough control. Top-down inhibitory control of cough may be altered in RUCC.