Cough hypersensitivity and chronic cough

Abstract

Chronic cough is globally prevalent across all age groups. This disorder is challenging to treat because many pulmonary and extrapulmonary conditions can present with chronic cough, and cough can also be present without any identifiable underlying cause or be refractory to therapies that improve associated conditions. Most patients with chronic cough have cough hypersensitivity, which is characterized by increased neural responsivity to a range of stimuli that affect the airways and lungs, and other tissues innervated by common nerve supplies. Cough hypersensitivity presents as excessive coughing often in response to relatively innocuous stimuli, causing significant psychophysical morbidity and affecting patients' quality of life. Understanding of the mechanisms that contribute to cough hypersensitivity and excessive coughing in different patient populations and across the lifespan is advancing and has contributed to the development of new therapies for chronic cough in adults. Owing to differences in the pathology, the organs involved and individual patient factors, treatment of chronic cough is progressing towards a personalized approach, and, in the future, novel ways to endotype patients with cough may prove valuable in management.

Fig. 1. Global prevalence of chronic cough.

Map showing the results of a meta-analysis of 90 published studies assessing the regional pooled prevalence of chronic cough in adult populations. Reprinted with permission from ref., ERS.

Fig. 2. Neural pathways and mechanisms that contribute to the generation of cough.

(1) Vagal sensory neurons that are involved in cough innervate the larynx, trachea and main bronchi and, possibly, the lung parenchyma (blue and green dashed lines). Vagal Aδ fibres (whose cell bodies reside in the nodose ganglia) are activated by mechanical stimuli (such as inhaled particulate matter, mucus and aspirated gastric contents) and protons whereas vagal C fibres (whose cell bodies reside in the jugular ganglia) are activated by irritant chemicals and inflammatory mediators. (2) Vagal fibres involved in cough express several ion channels and receptors needed for transduction of diverse sensory stimuli and the formation, conduction and regulation of action potentials and (3) project to brainstem nuclei to coordinate cough motor patterning. (4) Distinct networks in the higher brain are involved in the behavioural regulation of cough, encoding of the urge to cough and for cognitive and affective processing. (5) Central mechanisms allow for volitional and cognitive modulation of cough through top-down regulation of brainstem processing (black dashed lines). AITC, allyl isothiocyanate; ASICs, acid sensing ion channel subtypes; B2, bradykinin type 2 receptor; CLC, chloride channel subtypes; H⁺, protons/acid; Nav, voltage-gated sodium channel subtypes; NGF, nerve growth factor; NKCC1, sodium (Na⁺) potassium (K⁺) chloride (Cl⁻) co-transporter; P2X, purinergic receptor subtypes; PG, prostaglandin; PGR, prostaglandin receptor; TrkA, tyrosine receptor kinase A; TRP, transient receptor potential cation channel.

Fig. 3. Peripheral and central processes contributing to cough hypersensitivity.

(1) Preclinical studies have described potential mechanisms that affect vagal sensory nerve fibres that are driven by the inflammatory pathology of the underlying diseases and potentially reversed by disease-specific therapy. (2) Functional synergy may also exist between sensory neurons innervating the various tissues shown. These interactions likely occur at the level of the brainstem, where convergence of vagal and/or trigeminal inputs leads to enhanced cough sensitivity. Peripheral organ pathologies have also been shown to alter synaptic efficacy in the brainstem, indicative of state of central sensitization. Patients with cough hypersensitivity have (3) increased activity in midbrain areas, and (4) a reduced ability to suppress coughing owing to a failure to recruit descending brain networks that subserve cough suppression. (5) Patients with chronic cough have a range of effects in the cognitive domain, suggestive of altered cortical processing of airway sensory information. Drugs that target vagal sensory neurons and inhibit their activity, neuromodulatory drugs that target brain processes involved in maintaining hypersensitive states, and speech and language therapy aimed at improving cough control, are all clinically useful antitussive options for patients with troublesome cough.

Fig. 4. Evaluation and management of chronic cough in adults.

A proposed algorithm for the clinical management of patients with chronic cough, including recommendations for managing difficult-to-treat cough. The algorithm was devised using recommendations contained in existing clinical guidelines and other reference material^,,,,.

Fig. 5. Evaluation and management of chronic cough in children.

A proposed algorithm for the clinical management of paediatric patients with chronic cough. The algorithm was devised using recommendations contained in existing clinical guidelines^,. GERD, gastro-oesophageal reflux disease.