Chronic cough: new insights and future prospects

Abstract

Chronic cough is defined in adults as a cough that lasts for ≥8 weeks. When it proves intractable to standard-of-care treatment, it can be referred to as refractory chronic cough (RCC). Chronic cough is now understood to be a condition of neural dysregulation. Chronic cough and RCC result in a serious, often unrecognized, disease burden, which forms the focus of the current review.The estimated global prevalence of chronic cough is 2-18%. Patients with chronic cough and RCC report many physical and psychological effects, which impair their quality of life. Chronic cough also has a significant economic burden for the patient and healthcare systems. RCC diagnosis and treatment are often delayed for many years as potential treatable triggers must be excluded first and a stepwise empirical therapeutic regimen is recommended.Evidence supporting most currently recommended treatments is limited. Many treatments do not address the underlying pathology, are used off-label, have limited efficacy and produce significant side-effects. There is therefore a significant unmet need for alternative therapies for RCC that target the underlying disease mechanisms. Early clinical data suggest that antagonists of the purinergic P2X3 receptor, an important mediator of RCC, are promising, though more evidence is needed.

FIGURE 1

a) Ascending and descending neural pathways involved in the cough reflex. b) Stimulation and activation of airway sensory neurons. Essentially, noxious stimuli or inflammation cause an increase in intracellular calcium which opens the pannexin channel and releases ATP to activate P2X3 channels on sensory nerves. This leads to cell depolarisation potentially triggering the opening of NaVs and generating an action potential which is carried through the vagus nerve to the central nervous system. Mechanisms for the cough reflex still have to be fully established in humans; many other pathways and receptors are probably involved. Ca²⁺: calcium; NaV: voltage-gated sodium channel; Na⁺: sodium; TRPA: transient receptor potential ankyrin; TRPM: transient receptor potential melastatin; TRPV: transient receptor potential vanilloid. Reproduced and modified from [5, 13].