Rationale: Capsaicin cough reflex sensitivity (C-CS) is associated with poorly controlled asthma, although its association with severe asthma remains unknown. Objectives: To determine the clinical impact of C-CS on severe asthma. Methods: We prospectively enrolled 157 patients with asthma (including 122 patients with severe asthma who were in step 4 or 5 according to the Global Initiative for Asthma 2015 guidelines) between November 2016 and October 2019. A capsaicin cough challenge was performed along with spirometry and assessment of biomarkers. The concentration required to induce at least five coughs by capsaicin was adopted as an index of C-CS. An Asthma Control Test and comorbidities were also evaluated. Associations of biomarkers with four clinical features of severe asthma made by the European Respiratory Society/American Thoracic Society guidelines (poor control [Asthma Control Test < 20; n = 58], frequent exacerbations [≥2/yr; n = 28], admissions [≥1/yr; n = 17], and airflow limitation [FEV1% predicted < 80%; n = 30]) were assessed. Measurements and Main Results: Heightened C-CS was associated with poor asthma control, frequent exacerbations, and admissions, particularly in patients without atopy (n = 54). Meanwhile, C-CS was not related to airflow limitation. Multivariate regression analysis has revealed that heightened C-CS (at least five coughs by capsaicin ≤ 2.44 μM) was a significant risk for poor asthma control and frequent exacerbations. Regarding general factors and comorbidities, ex-smoking status, diabetes mellitus, and chronic rhinosinusitis were associated with clinical features of severe asthma (all P < 0.05). Conclusions: Heightened C-CS is a risk factor for severe asthma. The present study suggests the association of airway neuronal dysfunction with the pathophysiology of non–type 2 severe asthma.

While gastroesophageal reflux disease (GERD) is one of the commonest causes of subacute/chronic cough along with cough-variant asthma (CVA) and rhinosinusitis, its clinical impact remains unknown. Therefore, we sought to investigate the impact of GERD in patients with subacute/chronic cough. Between April 2012 and March 2018, a total of 312 patients presenting subacute or chronic cough lasting for ≥3 weeks [median cough duration, 4.9 (0.7-434) months] underwent diagnostic tests. GERD symptoms and cough-specific QoL were evaluated through the Frequency Scale for Symptoms of Gastroesophageal reflux (FSSG) and the Japanese version of the Leicester Cough Questionnaire (J-LCQ). According to the FSSG domains, patients with GERD were arbitrarily categorized into 3 groups; acid-reflux predominant, dysmotility predominant, and pauci-symptoms groups, respectively. The average scores of J-LCQ was 12.5 (SD3.7). One hundred-forty three were diagnosed as having GERD-related cough based on classical reflux symptoms including heartburn and characteristic triggers of cough such as phonation, rinsing, lying, and eating. Most of them (89.8%) had other causative diseases including CVA. Cough lasted longer (p = 0.019) and required a longer time until alleviation (p = 0.003) in patients with GERD than in those without GERD. They also scored lower J-LCQ than counterpart group (p < 0.0001). In terms of symptom stratification, dysmotility predominant group showed significant more response to specific GERD treatments than the remnants (p = 0.002). These results indicate that GERD is associated with the aggravation of other causes including CVA. Particularly, dysmotility symptoms may be potential therapeutic target for GERD-related cough.

Patients with asthma show a steeper age-related decline in pulmonary function than healthy subjects, which is often alleviated after the initiation of treatment with inhaled corticosteroids (ICS). However, there still are patients who develop irreversible airflow limitations despite receiving adequate ICS treatment. The identification of the characteristics of such patients and biomarkers of progression for airflow limitation, a functional consequence of airway remodeling, is considered important in the management of asthma. A variety of biomarkers are associated with the forced expiratory volume in 1s (FEV1) in asthma in a cross-sectional fashion. However, few biomarkers are known to reflect the decline in pulmonary function, particularly in patients with asthma who receive ICS treatment. Recently periostin, a matricellular protein that prolongs Th2/eosinophilic inflammation and reflects airway remodeling, was reported to be detected in serum. In a Kinki Hokuriku Airway disease Conference multicenter cohort study, we demonstrated that among several serum markers, high serum periostin level, particularly ≥95ng/mL, was the only marker associated with a greater annual decline in FEV1 and a decline in FEV1 of ≥30mL·yr-1. A variant (rs9603226) of the POSTN gene that encodes periostin was also involved in the frequency of a decline in FEV1 of ≥30mL·yr-1. Our results suggest that the serum periostin level is a useful marker reflecting pulmonary function decline in patients with asthma receiving ICS.