Mechanisms and Rationale for Targeted Therapies in Refractory and Unexplained Chronic Cough

Abstract

Chronic cough, defined as a cough lasting > 8 weeks, is a common medical condition that exerts a substantial physical, mental, and social burden on patients. A subset of patients with chronic cough are troubled with a cough that persists despite optimal treatment of presumed associated common and uncommon conditions (refractory chronic cough; RCC) or in which no diagnosable cause for cough can be identified despite extensive assessment (unexplained chronic cough; UCC). Many of these patients exhibit clinical features of cough hypersensitivity, including laryngeal paresthesia, hypertussia, and allotussia. Over-the-counter cough remedies are ineffective and can lead to intolerable side effects when used for RCC/UCC, and the lack of approved treatments indicated for these conditions reflects a major unmet need. An increased understanding of the anatomy and neurophysiology of protective and pathologic cough has fostered a robust clinical development pipeline of several targeted therapies for RCC/UCC. This manuscript reviews the mechanisms presumed to underly RCC/UCC together with the rationale and clinical evidence for several targeted therapies currently under clinical investigation, including transient receptor potential channel antagonists, P2X3-receptor antagonists, voltage-gated sodium channel blockers, neuromodulators, and neurokinin-1-receptor antagonists. Finally, we provide an overview of targets that have been investigated in preclinical models of cough and other airway diseases that may hold future promise for clinical studies in RCC/UCC. Development of targeted therapies with different sites of action may foster a precision medicine approach to treat this heterogeneous, underserved patient population.

Clinical characteristics of patients with chronic cough in Guangdong, China: a multicenter descriptive study

“…In our study, the median cough duration was 7.0 months, being consistent with those previous reports in general respiratory clinics (average duration 4–12 months) [ 6 , 21 , 22 ]. In clinical practice, some patients frequently complained of their cough for several years [ 11 ]. And many patients visiting specialist cough clinics had a longer duration (around 24 months) than those attending the respiratory clinics [ 8 ].…”

“…An increased sensitivity to the tussigenic agents such as capsaicin, citric acid, and ATP was found in patients with chronic cough in comparison with healthy volunteers [ 10 , 11 ]. Besides, chronic cough was also associated to occupational exposure, cigarette smoking, unhealthy lifestyle as well as ambient air pollution [ 7 , 12 , 13 ].…”

Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses

“…The advice for treating the acute and chronic cough of COVID-19 is based on available treatments and guidelines. 77 , 78 Although many drugs are on the market or in development for the relief of cough, 79 there is no good evidence for their benefits in the treatment of cough associated with acute viral infection or pneumonia. 80 , 81 In the UK National Institute for Health and Care Excellence guidelines for managing acute symptoms of COVID-19, only taking honey or opioid-derived antitussives are recommended for cough.…”

The Changes in Expression of NaV1.7 and NaV1.8 and the Effects of the Inhalation of Their Blockers in Healthy and Ovalbumin-Sensitized Guinea Pig Airways

“…Evans et al [ 25 ] proved the involvement of Na V 1.7 in the cough reflex, which explained benzonatate (a clinically used antitussive)’s mechanism of action in catecholamine A differentiated (CAD) cells, which express TTX-sensitive Na V channels, composed primarily of Na V 1.7 with smaller contributions of Na V 1.1 and Na V 1.3. The selective inhibition of Na V 1.7 via gene silencing in nodose sensory neurons reduces the excitability of these neurons and inhibits mechanically induced and citric-acid-induced coughing in guinea pigs [ 26 ]. Muroi and Undem [ 15 ] describe the upregulation of Na V 1.8 expression and significantly reduced threshold for activation after the exposure of sensory neurons to an inflammatory mediator.…”