Prevalence and disease burden of chronic cough in nine cities of China: an observational study.

BACKGROUND: Chronic cough (CC) is common in the general population of China, creating a difficult-to-ignore public health burden. However, there is a lack of research on the nationwide prevalence and disease burden of CC in the Chinese population. We aim to use an insurance claims database to assess the prevalence and the corresponding economic burden owing to CC in China. METHODS: This was a retrospective observational study based on an administrative medical insurance database in 2015, 2016 and 2017, from nine cities in North, South, East, South-West, and North-West regions of China. The study population was Chinese adults (≥ 18 years old) who had been identified as CC patients. Descriptive data analyses were used in statistical analysis. RESULTS: A total of 44,472, 55,565, and 56,439 patients with mean ages of 53.2 (16.3) years were identified as patients with CC in 2015, 2016, and 2017, respectively. Of these, 55.24% were women. In addition, 8.90%, 9.46%, and 8.37% of all patients in 2015, 2016, and 2017, who had applied for medical insurance, had CC, respectively, with a three-year average probability of 8.88%. The median number of outpatient visits within a calendar year was 27 per year due to any reason during the period of 2015-2017. The median medical cost of each patient per year increased from 935.30 USD to 1191.47 USD from 2015 to 2017. CONCLUSION: CC is common among medical insurance users, with a substantial utilization of medical resources, highlighting the huge burden of CC in China.

Non-allergic eosinophilic inflammation and airway hyperresponsiveness induced by diesel engine exhaust through activating ILCs.

RATIONALE: Diesel engine exhaust (DEE) is associated with the development and exacerbation of asthma. Studies have shown that DEE can aggravate allergen-induced eosinophilic inflammation in lung. However, it remains not clear that whether DEE alone could initiate non-allergic eosinophilic inflammation and airway hyperresponsiveness (AHR) through innate lymphoid cells (ILCs) pathway. OBJECTIVE: This study aims to investigate the airway inflammation and hyperresponsiveness and its relationship with ILC after DEE exposure. METHOD: Non-sensitized BALB/c mice were exposed in the chamber of diesel exhaust or filtered air for 2, 4, and 6 weeks (4 h/day, 6 days/week). Anti-CD4 mAb or anti-Thy1.2 mAb was administered by intraperitoneal injection to inhibit CD4+T or ILCs respectively. AHR、airway inflammation and ILCs were assessed. RESULT: DEE exposure induced significantly elevated level of neutrophils, eosinophils, collagen content at 4, 6 weeks. Importantly, the airway AHR was only significant in the 4weeks-DEE exposure group. No difference of the functional proportions of Th2 cells was found between exposure group and control group. The proportions of IL-5+ILC2, IL-17+ILC significantly increased in 2, 4weeks-DEE exposure group. After depletion of CD4+T cells, both the proportion of IL-5+ILC2 and IL-17A ILCs was higher in the 4weeks-DEE exposure group which induced AHR, neutrophilic and eosinophilic inflammation accompanied by the IL-5, IL-17A levels. CONCLUSION: Diesel engine exhaust alone can imitate asthmatic characteristics in mice model. Lung-resident ILCs are one of the major effectors cells responsible for a mixed Th2/Th17 response and AHR.

Identification of cough-variant asthma phenotypes based on clinical and pathophysiologic data.

BACKGROUND: Cough-variant asthma (CVA) may respond differently to antiasthmatic treatment. There are limited data on the heterogeneity of CVA. OBJECTIVE: We aimed to classify patients with CVA using cluster analysis based on clinicophysiologic parameters and to unveil the underlying molecular pathways of these phenotypes with transcriptomic data of sputum cells. METHODS: We applied k-mean clustering to 342 newly physician-diagnosed patients with CVA from a prospective multicenter observational cohort using 10 prespecified baseline clinical and pathophysiologic variables. The clusters were compared according to clinical features, treatment response, and sputum transcriptomic data. RESULTS: Three stable CVA clusters were identified. Cluster 1 (n = 176) was characterized by female predominance, late onset, normal lung function, and a low proportion of complete resolution of cough (60.8%) after antiasthmatic treatment. Patients in cluster 2 (n = 105) presented with young, nocturnal cough, atopy, high type 2 inflammation, and a high proportion of complete resolution of cough (73.3%) with a highly upregulated coexpression gene network that related to type 2 immunity. Patients in cluster 3 (n = 61) had high body mass index, long disease duration, family history of asthma, low lung function, and low proportion of complete resolution of cough (54.1%). TH17 immunity and type 2 immunity coexpression gene networks were both upregulated in clusters 1 and 3. CONCLUSION: Three clusters of CVA were identified with different clinical, pathophysiologic, and transcriptomic features and responses to antiasthmatics treatment, which may improve our understanding of pathogenesis and help clinicians develop individualized cough treatment in asthma.

Expression of interferon-γ and its effect on cough hypersensitivity in chronic refractory cough patients.

Chronic refractory cough (CRC) is characterised by cough hypersensitivity. Interferon-γ (IFN-γ) has been reported to induce calcium influx, action potentials of vagal neurons in vitro and cough response in guinea pigs. While the effect of IFN-γ in CRC patients remains unknown. Here, via flow-cytometry and inhalation cough challenge, we found CRC patients had significantly increased levels of sputum IFN-γ+CD4+ T cells, IFN-γ+CD8+ T cells as well as supernatant of IFN-γ. The average number of coughs in CRC patients increased as the concentration of inhaled IFN-γ went up in IFN-γ cough challenge. Two or more coughs and five or more coughs elicited by inhaled IFN-γ in CRC patients occurred in 7 of 10 and 2 of 10, respectively. Preinhaled IFN-γ (100 µg/mL) increased the capsaicin cough sensitivity in CRC patients but not healthy volunteers. Targeting IFN-γ may be a potential effective anti-tussive strategy in CRC patients.

Effects of treatment with montelukast alone, budesonide/formoterol alone and a combination of both in cough variant asthma.

BACKGROUND: Whether cysteinyl-leukotriene receptor antagonists (LTRAs) have a similar antitussive effect to inhaled corticosteroids and long-acting ß2-agonist (ICS/LABA), and that LTRA plus ICS/LABA is superior to LTRAs alone or ICS/LABA alone in treating cough variant asthma (CVA) remain unclear. This study aimed to investigate and compare the efficacy of montelukast alone, budesonide/formoterol alone and the combination of both in the treatment of CVA. METHODS: Ninety-nine CVA patients were assigned randomly in a 1:1:1 ratio to receive montelukast (M group: 10 mg, once daily), budesonide/formoterol (BF group: 160/4.5 µg, one puff, twice daily), or montelukast plus budesonide/formoterol (MBF group) for 8 weeks. The primary outcomes were changes in the cough visual analogue scale (VAS) score, daytime cough symptom score (CSS) and night-time CSS, and the secondary outcomes comprised changes in cough reflex sensitivity (CRS), the percentage of sputum eosinophils (sputum Eos%) and fractional exhaled nitric oxide (FeNO). CRS was presented with the lowest concentration of capsaicin that induced at least 5 coughs (C5). The repeated measure was used in data analysis. RESULTS: The median cough VAS score (median from 6.0 to 2.0 in the M group, 5.0 to 1.0 in the BF group and 6.0 to 1.0 in the MBF group, all p < 0.001), daytime CSS (all p < 0.01) and night-time CSS (all p < 0.001) decreased significantly in all three groups after treatment for 8 weeks. Meanwhile, the LogC5 and sputum Eos% improved significantly in all three groups after 8 weeks treatment (all p < 0.05). No significant differences were found in the changes of the VAS score, daytime and night-time CSSs, LogC5 and sputum Eos% among the three groups from baseline to week 8 (all p > 0.05). The BF and MBF groups also showed significant decreases in FeNO after 8 weeks treatment (p = 0.001 and p = 0.008, respectively), while no significant change was found in the M group (p = 0.457). Treatment with MBF for 8 weeks significantly improved the FEV1/FVC as well as the MMEF% pred and decreased the blood Eos% (all p < 0.05). CONCLUSIONS: Montelukast alone, budesonide/formoterol alone and a combination of both were effective in improving cough symptom, decreasing cough reflex sensitivity and alleviating eosinophilic airway inflammation in patients with CVA, and the antitussive effect and anti-eosinophilic airway inflammation were similar. Trial registration ClinicalTrials.gov, number NCT01404013.

Characteristics of different asthma phenotypes associated with cough: a prospective, multicenter survey in China.

BACKGROUND: Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. We compared the clinical and pathophysiological characteristics of cough predominant asthma (CPA), cough variant asthma (CVA) and classic asthma (CA) in order to determine any differential phenotypic traits. METHODS: In 20 clinics across China, a total of 2088 patients were finally recruited, including 327 CVA, 1041 CPA and 720 CA patients. We recorded cough and wheezing visual analogue scale, Leicester cough questionnaire (LCQ) and asthma control test scores. Fractional exhaled nitric oxide (FeNO), induced sputum cell counts, and capsaicin cough challenge were also measured and compared. RESULTS: CPA patients more frequently presented with cough as the initial symptom, and laryngeal symptoms (p < 0.001), had less symptoms related with rhinitis/sinusitis and gastroesophageal reflux (p < 0.05) than CA patients. Comorbidities including rhinitis and gastroesophageal reflux were similar, while the proportion of COPD and bronchiectasis was higher in CA patients. There were no differences in FeNO levels, sputum eosinophil and neutrophil counts, FEV1 (%pred) decreased from CVA to CPA to CA patients (p < 0.001). Cough sensitivity was higher in CVA and CPA compared to CA (p < 0.001), and was positively correlated with LCQ scores. CONCLUSIONS: CVA, CPA and CA can be distinguished by the presence of laryngeal symptoms, cough sensitivity and airflow obstruction. Asthma-associated chronic cough was not associated with airway inflammation or comorbidities in our cohort. Trial registration The Chinese Clinical Trial Registration Center, ChiCTR-POC-17011646, 13 June 2017.

Inhibition of TRPA1 reduces airway inflammation and hyperresponsiveness in mice with allergic rhinitis.

This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.

Aspergillus tracheobronchitis with Birt-Hogg-Dubè syndrome as a rare cause of chronic cough.

BACKGROUND: Aspergillus tracheobronchitis (ATB) is confined as a condition of chronic superficial infection of tracheobronchial tree. Its diagnosis is difficult due to atypical manifestations and low detective rate of Aspergillus thus far. CASE PRESENTATION: Herein, we presented a 45-year-old male patient with a sole chronic productive cough for five years referred to our cough specialist clinic. Chest high-resolution computed tomography showed multiple lung cysts predominantly located in the subpleural lesions and near the mediastinum. Neither bacteria nor fungi were identified by sputum culture. However, metagenomic next-generation sequencing in sputum detected Aspergillus fumigatus DNA. The genetic testing of whole blood suggested the germline mutation of the tumor suppressor gene folliculin, supporting a diagnosis of Birt-Hogg-Dubé (BHD) syndrome. His productive cough symptom significantly improved after receiving itraconazole treatment for 2 months. After discontinuation of antifungal treatment, there was no relapse for four months follow-up. A diagnosis of ATB with BHD syndrome was eventually established in this patient. CONCLUSION: ATB should be considered in any patient with prolonged unexplained productive cough. Next-generation sequencing technologies may be useful to identify ATB which is uncommon and easily ignored in clinical practice.

Prevalence of chronic cough in China: a systematic review and meta-analysis.

BACKGROUND: Individual studies have indicated variable prevalence for chronic cough, but thus far, there has been no systematic report on the prevalence of this condition. METHODS: In this study, we performed a systematic review and meta-analysis by searching databases including PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese biomedical literature service system, Wanfang Database, and VIP database, for studies on chronic cough in China published before December 28, 2020. A random effects model was used to calculate pooled prevalence estimates with 95% confidence interval [95%CI], weighted by study size. RESULTS: Fifteen studies with 141,114 community-based adults were included in the study, showing a prevalence of 6.22% (95% CI 5.03-7.41%). And 21 studies with 164,280 community-based children were included, presenting a prevalence of 7.67% (95% CI 6.24-9.11%). In subgroup meta-analyses, the prevalence in adults was 4.38% (95% CI 2.74-6.02%) in southern China and 8.70% (95% CI 6.52-10.88%) in northern China. In the children population, the prevalence in northern China was also higher than in southern China (northern vs. southern: 7.45% with a 95% CI of 5.50-9.41%, vs. 7.86% with a 95% CI of 5.56-10.16%). CONCLUSIONS: Our population-based study provides relatively reliable data on the prevalence of chronic cough in China and may help the development of global strategies for chronic cough management.

The risk factors for urinary incontinence in female adults with chronic cough.

BACKGROUND: Female patients with chronic cough are more likely to suffer from urinary incontinence (UI). However, there are few data in regard of risks related with UI in female adults with chronic cough. METHOD: We recruited female adult patients with chronic cough from the cough specialist clinic. Demographic information and clinical characteristics including age, BMI, duration of cough, severity of cough, nature and timing of cough, cough triggers, concomitant symptoms, comorbidities and UI condition were collected. The demographics and clinical features of patients with UI and those without UI were compared. RESULT: A total of 700 female patients with the main symptom of chronic cough were included, of whom 351 (50.1%) presented with UI. As compared with patients without UI, patients with UI showed a longer mean age (years) (49.5 vs. 42.4, p < 0.001), a more severe cough symptom (median of cough Visual Analogue Scale: 65 vs. 50, p < 0.001), a higher prevalence of chronic sinusitis (17.6% vs. 8.6%, p = 0.002), and combined with a higher incidence of abdominal muscle pain due to cough (39.6% vs. 18.7%, p < 0.001).In addition, patients in UI group whose cough were more easily triggered by exercise (28.2% vs. 17.2%, p = 0.048). Multivariate logistic regression analysis indicated the above five variables were risk factors for UI in female adult patients with chronic cough. CONCLUSION: Urinary incontinence is a common complication in female patients with chronic cough. Older age, severe cough, combing with a higher proportion of chronic sinusitis and abdominal muscle pain, a cough easily triggered by exercise are identified as risk factors for urinary incontinence. We should pay more attention to female chronic coughers with these risk factors in clinics.

STAT1 participates in the induction of substance P expression in airway epithelial cells by respiratory syncytial virus.

PURPOSE: The regulation effect and mechanism of respiratory syncytial virus (RSV) infection on the expression of tachykinin substance P (SP) in airway epithelial cells was investigated. METHODS: The regulation of SP expression by RSV was investigated in the BEAS-2B airway epithelial cell line. RT-qPCR, immunofluorescence, and ELISA assay were used to examine the expression of the SP encoding gene TAC1, the intracellular SP protein expression, and the extracellular SP secretion. RESULTS: The mRNA expression of TAC1 and the intracellular SP protein level in BEAS-2B cells were significantly enhanced by RSV infection with multiplicity of infection (MOI) values of both 1 and 0.1 at 48 hours post infection. Heat-inactivated and UV-inactivated RSV, but not live RSV, significantly induced SP secretion in both control BEAS-2B cells and CX3CR1 receptor knockout cells without affecting the TAC1 gene expression or cell viability. RSV G protein (2-10 µg/ml) and fractalkine (10-50 ng/ml), both CX3CR1 receptor ligands, did not affect SP secretion in BEAS-2B cells. Inhibition of STAT1 phosphorylation by fludarabine (1 µM) markedly reduced the RSV-induced TAC1 gene expression and antagonized the inhibition of RSV replication by interferon-α in BEAS-2B cells. CONCLUSIONS: STAT1 participates in RSV infection-induced SP expression in airway epithelial cells.

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

BACKGROUND: The clinical characteristics of patients with chronic cough are reported only in single-center survey in China, being significantly different from that in western countries. Here, we performed a multicenter study to describe the clinical characteristics of chronic cough patients. METHODS: A cross-sectional observational survey was conducted in thirteen tertiary hospitals of Guangdong, South China. Relevant data were recorded using a standardized questionnaire and analyzed, including demographics, educational attainment, cough features, and concomitant symptoms. RESULTS: Of 933 patients in this study, the median age was 40.0 (IQR 31.0-52.0) years with a peaked age of 30-39 years. The proportion of females (487, 52.2 %) was comparable to that of males (446, 47.8 %). Up to 81.9 % of the patients were non-smokers. More than two-thirds of the subjects with chronic cough had a low educational level. The median cough duration was 6.0 (IQR 3.0-24.0) months, and 73.0 % of chronic cough patients presented with dry cough. Laryngeal paresthesia was the most common concomitant symptom (704, 75.5 %), followed by rhinitis/sinusitis-related (350, 37.5 %) and respiratory symptoms (322, 34.5 %). Rhinitis/sinusitis-related symptoms more frequently occurred in patients with productive cough than in those with dry cough (49.0 % vs. 33.0 %, P < 0.001). Moreover, female patients displayed an older age and a higher prevalence of nocturnal cough compared to male patients (both P < 0.05). CONCLUSIONS: Our results show an equal gender, young profile and laryngeal paresthesia in patients with chronic cough, and different clinical features between females and males.

ERS guidelines on the diagnosis and treatment of chronic cough in adults and children.

These guidelines incorporate the recent advances in chronic cough pathophysiology, diagnosis and treatment. The concept of cough hypersensitivity has allowed an umbrella term that explains the exquisite sensitivity of patients to external stimuli such a cold air, perfumes, smoke and bleach. Thus, adults with chronic cough now have a firm physical explanation for their symptoms based on vagal afferent hypersensitivity. Different treatable traits exist with cough variant asthma (CVA)/eosinophilic bronchitis responding to anti-inflammatory treatment and non-acid reflux being treated with promotility agents rather the anti-acid drugs. An alternative antitussive strategy is to reduce hypersensitivity by neuromodulation. Low-dose morphine is highly effective in a subset of patients with cough resistant to other treatments. Gabapentin and pregabalin are also advocated, but in clinical experience they are limited by adverse events. Perhaps the most promising future developments in pharmacotherapy are drugs which tackle neuronal hypersensitivity by blocking excitability of afferent nerves by inhibiting targets such as the ATP receptor (P2X3). Finally, cough suppression therapy when performed by competent practitioners can be highly effective. Children are not small adults and a pursuit of an underlying cause for cough is advocated. Thus, in toddlers, inhalation of a foreign body is common. Persistent bacterial bronchitis is a common and previously unrecognised cause of wet cough in children. Antibiotics (drug, dose and duration need to be determined) can be curative. A paediatric-specific algorithm should be used.

Determinants of response to bronchodilator in patients with cough variant asthma- A randomized, single-blinded, placebo-controlled study.

BACKGROUND: Not all patients with cough variant asthma (CVA) show responsiveness to bronchodilators (RB) in clinic. Whether there are specific clinical and pathophysiological features can indicate RB in patients with CVA needs further investigation. Thus, we aimed to investigate the RB in patients with CVA and associated factors. METHODS: Forty-two CVA patients were randomized in a 2:1 ratio to receive oral bambuterol hydrochloride (10 mg, once daily, for 3 days) or matched placebo, 36 patients (24 with bronchodilator and 12 with placebo) completed the study eventually. RB was considered when cough visual analogue scale (VAS) score decreased 30% or more after 3 days treatment. The baseline clinical and pathophysiological characteristics between patients with RB and patients without RB were compared. CRS was presented with the lowest concentration of capsaicin inducing at least 5 coughing (C5). RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (62.5% vs 16.7%, p < 0.01). Patients with RB showed a significant greater mean decline of FEV1% predicted after bronchial provocation (26.7% vs 22.4%, p < 0.05) and higher geometric mean of sputum eosinophils (1.37 vs 0.69, p < 0.05) as compared with these without RB. No significant differences in sputum neutrophil, Log C5 were found between patients with RB and patients without RB. There was a moderate correlation between the decline of FEV1% pred and RB (rs = 0.443, p < 0.05). The regression analysis showed that nocturnal cough was a predictor of RB (OR, 7.33, 95% CI: 1.11-48.26, p = 0.038). No adverse events were reported by all of the patients after the study. CONCLUSION: More than one-third of patients with CVA do not respond to bronchodilator treatment, indicating that the response to bronchodilator should not be a diagnostic requirement of CVA. CVA patients with higher airway responsiveness will more likely respond to bronchodilator. Cough of CVA might be elicited by different mechanisms, which suggests that CVA could be divided into two phenotypes according to the response to bronchodilators.

Current Status and Future Directions of Chronic Cough in China.

Chronic cough is one of the most common complaints for which patients in China seek medical attention. However, there are no nationwide data on the prevalence and socioeconomic burden of chronic cough. Although approximately 50% of Chinese men smoke, the vast majority of patients presenting for evaluation of chronic cough are never smokers. An equal sex distribution and a middle-aged predominance have been observed in the Chinese chronic cough population, despite demonstration of a higher cough reflex sensitivity in females and older patients. The role of air pollution in the distinct age and sex distribution requires further study. In terms of the etiologies of chronic cough in China, cough-variant asthma, upper airway cough syndrome, nonasthmatic eosinophilic bronchitis, and atopic cough are the most common causes, comprising 75.2% to 87.6% of cases across different regions. Chinese Guidelines for Diagnosis and Treatment of Cough were initially published in 2005, and updated in 2009 and 2016. In addition, the China Cough Coalition was established in 2016. Great progress has been made in both cough-related clinical practice and research in recent years, however, there are still challenges ahead. To facilitate optimal management of chronic cough in China, efforts promoting the dissemination and application of published guidelines will be essential, especially in community-based healthcare and in rural regions. As chronic refractory cough has been identified as a huge challenge to clinicians worldwide, continued international cooperation will be essential in optimizing evaluation and management of chronic cough.

Elevated Circulating CD4+CD25+CD127-/low Regulatory T Cells in Patients with Non-asthmatic Eosinophilic Bronchitis.

PURPOSE: Non-asthmatic eosinophilic bronchitis (NAEB) is a common cause of chronic cough. It is characterized by sputum eosinophilia like asthma but lacks airway hyperresponsiveness. Regulatory T cells (Tregs) are recognized as immune suppressors and are involved in the pathogenesis of asthma. However, the relationship between Tregs and NAEB remains unknown. This study aimed to preliminarily explore the role of Tregs in NAEB by comparing circulating Tregs levels to asthma and healthy controls. METHODS: Fractional exhaled nitric oxide (FeNO), spirometry with bronchial provocation test, sputum induction and blood routine test were performed in all subjects. Peripheral blood mononuclear cells were used to detect the Tregs (CD4+CD25+CD127-/low) by flow cytometry. Relationship between the levels of circulating Tregs and clinical indexes was also observed. RESULTS: A total of 15 patients with NAEB, 20 patients with asthma and 11 healthy controls were included. The absolute numbers of circulating Tregs in the NAEB group (49.8 ± 18.9 × 103 cells/ml) and asthma group (53.3 ± 18.7 × 103 cells/ml) were higher than that in healthy control group (32.7 ± 11.6 × 103 cells/ml) (both P < 0.01). In total, the level of circulating Tregs showed positive correlation with FeNO (r = 0.30, P < 0.05). CONCLUSION: Tregs may play a key role not only in asthmatic patients, but also in patients with NAEB, as reflected by the elevated Tregs in peripheral blood.

Cough in hypereosinophilic syndrome: case report and literature review.

BACKGROUND: Cough and airway eosinophilic inflammation has not been highlighted in hypereosinophilic syndrome (HES). CASE PRESENTATION: We report 2 further cases and reviewed the clinical features and treatment of HES present with cough from the literature. Both cases were middle age male, presenting with chronic cough, airway eosinophilic inflammation and hyper eosinophilia who have been previous misdiagnosed as cough-variant asthma and failed anti-asthma treatment. PDGFRA fusion gene was confirmed in one case, but not in the other case. Both had evidence of myeloproliferative features. The tyrosine kinase inhibitor, imatinib, resulted in complete resolution of eosinophilia and cough. By searching PubMed, we found 8 HES cohorts of 411 cases between 1975 and 2013, where the incidence of cough was 23.11%. Sixteen case reports of HES presented with cough as predominant or sole symptom, with nine male patients with positive PDGFRA fusion gene, who responded well to imatinib. Six of seven patients, who tested negative for the PDGFRA, responded to systemic glucocorticoids. CONCLUSIONS: Cough and airway eosinophilic inflammation is common in some HES patients. PDGFRA+ HES patients present with chronic cough respond well to imatinib. Our case reports indicate that PDGFRA negative HES patients may respond to imatinib as well.

A new simple score of chronic cough: cough evaluation test.

BACKGROUND: Chronic cough has an important impact on physical, social and psychological aspects. A simple and effective method to assess different aspects of chronic cough severity is required. We aimed to develop a simple, self-completed test, Cough Evaluation Test (CET), to evaluate cough severity and its impact on health. METHOD: The items of preliminary CET were generated based on literature review and clinical practice. Items reduction was conducted by modified Delphi method. Patients with chronic cough were recruited to complete CET, Cough Visual Analog Scales (VAS), Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC), and Cough Symptom Score (CSS). Reassessments were performed at 1 week apart before treatment, and after more than 2 weeks treatments. Concurrent validation, internal consistency, repeatability, responsiveness and the minimal important difference (MID) were determined. RESULTS: CET consists of five items with a 5-point Likert scale (1-5 scaling of items, 5-25 score range). The Cronbach's alpha values for CET was 0.80. CET showed a stronger correlation with LCQ-MC (r = - 0.74) compared to that between LCQ-MC with VAS (r = - 0.61). CET also showed a stronger correlation with VAS (r = 0.70) compared to that between VAS with other measures. Intraclass correlation coefficients for CET was 0.84. In patients undergoing treatment, CET scores significantly changed (p < 0.0001). The MID of CET was 2. CONCLUSION: Cough Evaluate Test is a reliable, valid and responsive tool to simply evaluate impact of cough on physical, social and psychological aspects.

Traffic-related air pollution induces non-allergic eosinophilic airway inflammation and cough hypersensitivity in guinea-pigs.

BACKGROUND: The pathogenesis and pathophysiology of eosinophilia-related chronic cough such as non-asthmatic eosinophilic bronchitis and cough variant asthma are still not clear. OBJECTIVE: This study is to examine the potential role of traffic-related air pollution (TRAP) in eosinophilic inflammation and cough responses. METHODS: Non-sensitized guinea-pigs were exposed to TRAP in an urban traffic tunnel or kept in a filtered air environment for 7 or 14 days. Reflexive cough was measured using citric acid and allyl isothiocyanate (AITC) challenges, respectively. Spontaneous cough counting was determined using audio recording and a waveform analysis. Airway inflammation was evaluated using differential cells in bronchoalveolar lavage fluid (BALF) and lung histopathology. To further elucidate the relationship between airway inflammation and cough hypersensitivity, a subgroup of those exposed for 14 days received a dexamethasone treatment. RESULTS: Compared to reflexive cough count (mean (95% confidence interval) in 10 minutes) provoked by the AITC challenge for the unexposed animals (3.1 (1.7-4.5)), those were increased significantly following both the 7-day (12.0 (6.8-17.2), P < 0.01) and the 14-day (12.0 (6.4-17.6), P < 0.01) TRAP exposure. The effect provoked by the citric acid challenge was more profound following the 14-day exposure (26.0 (19.5-32.5) vs 3.8 (1.5-6.0) for the control, P < 0.001). TRAP exposures enhanced spontaneous cough events, caused a significant increase of eosinophils and neutrophils in BALF and resulted in a dramatic eosinophilic infiltration in submucosal layer of trachea and bronchus, which can be inhibited significantly by dexamethasone treatment. CONCLUSIONS & CLINICAL RELEVANCE: TRAP exposures induced cough hypersensitivity and non-allergic eosinophilic inflammation of airways in guinea-pigs. This study highlights the potential mechanisms of eosinophilia-related chronic cough that can be induced by traffic-related air pollution.

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 .