Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough.

BACKGROUND: The differential sensitivity of cough to antitussive therapies implies the existence of heterogeneity in cough hypersensitivity, but how such heterogeneity is expressed across individual patients is poorly understood. We investigated the phenotypes of cough hypersensitivity by examining transient receptor potential ankyrin 1 (TRPA1)- and transient receptor potential vanilloid 1 (TRPV1)-mediated cough sensitivity in patients with chronic refractory cough. METHODS: Using a selective TRPA1 agonist, allyl isothiocyanate (AITC), we established an AITC cough challenge as a measure of TRPA1-mediated cough sensitivity. The AITC cough challenge and the widely used capsaicin (a selective TRPV1 agonist) cough challenge were performed with 250 patients with chronic refractory cough and 56 healthy subjects. The concentration of AITC or capsaicin solution causing at least two (C2) and five coughs (C5) was recorded. Cough sensitivity was expressed as the mean (95% confidence interval) of log C5, and cough hypersensitivity was defined as a log C5 value lower than that of healthy subjects. RESULTS: A distinct concentration-response effect of inhaled AITC was identified both in patients with chronic refractory cough and in healthy subjects. Cough sensitivity to AITC and capsaicin was significantly higher in patients than in healthy subjects (AITC: 2.42 [2.37-2.48] vs 2.72 [2.66-2.78] mM, p = 0.001; capsaicin: 1.87 [1.75-1.98] vs 2.53 [2.36-2.70] µM, p = 0.001) and was higher in females than in males for both healthy subjects and patients (all p < 0.05). Among the 234 patients who completed both challenges, 25 (10.7%) exhibited hypersensitivity to both AITC and capsaicin, 44 (18.8%) showed hypersensitivity to AITC only, 28 (11.9%) showed hypersensitivity to capsaicin only, and 137 (58.6%) exhibited hypersensitivity to neither. Those with TRPA1- and/or TRPV1-mediated hypersensitivity were predominantly female, while those without TRPA1- and TRPV1-mediated hypersensitivity were mainly male. CONCLUSIONS: Four phenotypes of cough hypersensitivity were identified by the activation of TRPV1 and TRPA1 channels, which supports the existence of heterogeneity in cough pathways and provides a new direction for personalized management of chronic refractory cough. TRIAL REGISTRATION: ClinicalTrials.gov NCT02591550 .

Disease burden, comorbidities and antecedents of chronic cough phenotypes in Australian adults.

BACKGROUND AND OBJECTIVES: While adult chronic cough has high burden, its phenotypes, particularly those without aetiologically related underlying conditions, are understudied. We investigated the prevalence, lung function and comorbidities of adult chronic cough phenotypes. METHODS: Data from 3608 participants aged 53 years from the Tasmanian Longitudinal Health Study (TAHS) were included. Chronic cough was defined as cough on most days for >3 months in a year. Chronic cough was classified into "explained cough" if there were any one of four major cough-associated conditions (asthma, COPD, gastroesophageal reflux disease or rhinosinusitis) or "unexplained cough" if none were present. Adjusted regression analyses investigated associations between these chronic cough phenotypes, lung function and non-respiratory comorbidities at 53 years. RESULTS: The prevalence of chronic cough was 10% (95%CI 9.1,11.0%) with 46.4% being "unexplained". Participants with unexplained chronic cough had lower FEV1/FVC (coefficient: -1.2% [95%CI:-2,3, -0.1]) and increased odds of comorbidities including obesity (OR=1.6 [95%CI: 1.2, 2.3]), depression (OR=1.4 [95%CI: 1.0, 2.1]), hypertension (OR=1.7 [95%CI: 1.2, 2.4]) and angina, heart attack or myocardial infarction to a lesser extent, compared to those without chronic cough. Participants with explained chronic cough also had lower lung function than both those with unexplained chronic cough and those without chronic cough. CONCLUSIONS: Chronic cough is prevalent in middle-age and a high proportion is unexplained. Unexplained cough contributes to poor lung function and increased comorbidities. Given unexplained chronic cough is not a symptom of major underlying respiratory conditions it should be targeted for better understanding in both clinical settings and research.

WAO-ARIA consensus on chronic cough - Part II: Phenotypes and mechanisms of abnormal cough presentation - Updates in COVID-19.

BACKGROUND: Chronic cough can be triggered by respiratory and non-respiratory tract illnesses originating mainly from the upper and lower airways, and the GI tract (ie, reflux). Recent findings suggest it can also be a prominent feature in obstructive sleep apnea (OSA), laryngeal hyperresponsiveness, and COVID-19. The classification of chronic cough is constantly updated but lacks clear definition. Epidemiological data on the prevalence of chronic cough are informative but highly variable. The underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR). A current challenge is to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR. OBJECTIVES: The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on classification, epidemiology, presenting features, and mechanistic pathways of chronic cough in airway- and reflux-related cough phenotypes, OSA, and COVID-19. The interplay of cough reflex sensitivity with other pathogenic mechanisms inherent to airway and reflux-related inflammatory conditions was also analyzed. OUTCOMES: Currently, it is difficult to clearly ascertain true prevalence rates in epidemiological studies of chronic cough phenotypes. This is likely due to lack of standardized objective measures needed for cough classification and frequent coexistence of multi-organ cough origins. Notwithstanding, we emphasize the important role of HCR as a mechanistic trigger in airway- and reflux-related cough phenotypes. Other concomitant mechanisms can also modulate HCR, including type2/Th1/Th2 inflammation, presence or absence of deep inspiration-bronchoprotective reflex (lower airways), tissue remodeling, and likely cough plasticity, among others.