BACKGROUND:MG-K10 is a long-acting, humanised monoclonal antibody against interleukin-4 receptor alpha (IL-4Rα), which inhibits IL-4 and IL-13-mediated signalling to reduce type 2 inflammation in asthma. OBJECTIVE:This Phase Ib/II study aimed to evaluate the preliminary efficacy, safety and pharmacodynamic characteristics of MG-K10 in Chinese patients with asthma. METHODS:This study included an initial phase Ib to evaluate safety and tolerability, followed by a phase II study in which eligible patients with moderate-to-severe asthma were randomised 1:1:1 to receive MG-K10 300 mg every 2 weeks (Q2W), MG-K10 300 mg every 4 weeks (Q4W), or a matched placebo (2 mL) Q2W subcutaneously for 24 weeks. The primary endpoint was the absolute change from baseline in the prebronchodilator forced expiratory volume in 1 s (FEV1) at week 12. Secondary efficacy endpoints, including asthma control, the rate of severe exacerbations and safety, were assessed. This trial is registered with ClinicalTrials.gov (NCT05382910). RESULTS:A total of 64, 60 and 63 patients were randomised to the MG-K10 Q2W, MG-K10 Q4W and placebo groups respectively. At week 12, the least squares mean improvements in prebronchodilator FEV1 were significantly greater in both MG-K10 groups than in the placebo group [Q2W vs. placebo: 0.35 L (95% CI, 0.208-0.490), Q4W vs. placebo: 0.30 L (95% CI, 0.156 to 0.441), both p < 0.0001]. Greater FEV1 improvements were observed in patients with baseline blood eosinophils ≥ 0.3 × 109/L. The incidence of adverse events was similar across groups [MG-K10 300 mg, Q2W (79.7%), MG-K10 300 mg Q4W (85.0%) and placebo groups (79.4%)]. MG-K10 was safe and well-tolerated, and consistent with the known safety signals. CONCLUSIONS:MG-K10 was superior to placebo in improving lung function, enhancing asthma control and reducing severe exacerbations in patients with asthma. The once-every-4-week regimen offers extended dosing intervals that may enhance medication adherence.

There are few data regarding the duration, long-term prognosis of persistent cough post coronavirus disease 2019 (COVID-19). The break of COVID-19 Omicron mutant infection provides an opportunity to investigate the long-term outcome of postinfectious cough and its risk factors. In this multicenter prospective study, we recruited patients aged ≥ 18 years with cough duration ≥ 3 weeks after COVID-19 infection during early stage of 2023 in respiratory clinics, cough assessments and laboratory investigations were conducted. Patients underwent two follow-up visits at 12 weeks and 52 weeks. A total of 1650 patients were enrolled, with an average age of 42.2 ± 14.4 years and 63.3

Background:There is limited information available on patients with asthma in hospitals in China. We investigated their clinical and phenotypic characteristics and management. Methods:The China Asthma Data Registry Project (CHART) study is a multicentre, hospital-based, prospective, observational study in which patients were recruited from outpatient clinics. This analysis used baseline cross-sectional data from patients with asthma (≥12 years) enrolled at 58 tertiary hospitals in China between 25 March 2018 and 11 July 2019. Results:A total of 20 683 patients with asthma (56.2% female, 15.0% patients with active tobacco use) were enrolled. Overall, 22.8% had uncontrolled asthma, 39.5% had partially controlled asthma. Furthermore, 45.3% experienced ≥1 exacerbation annually, including 31.7% who required hospitalisation, with only 21.4% having previously used inhaled corticosteroids (ICSs) in the past year. Cough (80.0%) was the most common symptom, followed by wheezing (70.7%), with 14.6% having cough-predominant asthma and 11.4% having cough-variant asthma. Multivariate logistic regression revealed that cough severity independently predicted poor control, irrespective of airflow limitation or inflammatory status. The association was stronger in ICS users than in nonusers across all cough severity metrics: a visual analogue scale (VAS) score ≥40 (aOR 3.88-5.47 versus 2.49-2.94), a cough evaluation test (CET) score ≥12 (aOR 11.15-20.91 versus 3.97-5.55), and a Leicester Cough Questionnaire (LCQ) score <15 (aOR 6.15-13.66 versus 2.45-3.18). Conclusions:We found significant suboptimal control, a high prevalence of cough-related phenotypes, frequent exacerbations and hospital admissions in patients with asthma attending hospitals. This underscores the need to prioritise the assessment and treatment of cough in asthma.

Rationale:Asthmatic cough may not respond well to corticosteroids. The underlying mechanisms and heterogeneity of cough variant asthma (CVA) remain poorly understood. The objectives of the present study were to explore airway immunological mechanisms and identify molecular endotypes in CVA by analysing sputum transcriptomics, clinical and pathophysiological characteristics. Methods:RNA sequencing and cytokine measurement were performed on sputum samples from newly diagnosed patients with CVA (n=72), classic asthma (CA) (n=28) and healthy controls (HC) (n=28). Patients with CVA were treated and followed-up for 6 months. Results:The majority of differentially expressed genes in CVA versus HC overlapped with those identified in CA versus HC. However, the type 2 immunity co-expression network in CVA was lower than that in CA. Based on sputum transcriptomics profiles, two endotypes of CVA were identified: mixed-inflammatory CVA (n=40) and pauci-inflammatory CVA (n=32). Mixed-inflammatory CVA showed higher inflammation-related gene set signatures compared to both pauci-inflammatory CVA and HC. Mixed-inflammatory CVA also showed elevated levels of eosinophils, neutrophils, type 2, type 1 and type 3 cytokines in sputum compared to HC. Conversely, pauci-inflammatory CVA had slightly elevated sputum eosinophils, but no significant gene signatures and cytokine differences compared to HC. During 6 months' follow-up, pauci-inflammatory CVA showed a trend of less complete resolution in cough (56.2% versus 80.0%, p=0.0553) compared to mixed-inflammatory CVA. Kaplan-Meier analysis found significantly higher cough persistence in pauci-inflammatory versus mixed-inflammatory CVA. Conclusions:CVA exhibits overlapping but distinct airway transcriptomics profiles compared to CA. Two distinct molecular endotypes are identified in CVA, presenting different clinical and pathophysiological features.

BackgroundCough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19. ObjectiveThe aim of this study was to investigate the prevalence, severity, and associated risk factors of severe and persistent cough in individuals with COVID-19 during the latest wave of the Omicron variant in China. MethodsIn this nationwide cross-sectional study, we collected information of the characteristics of cough from individuals with infection of the SARS-CoV-2 Omicron variant using an online questionnaire sent between December 31, 2022, and January 11, 2023. ResultsThere were 11,718 (n=7978, 68.1% female) nonhospitalized responders, with a median age of 37 (IQR 30-47) years who responded at a median of 16 (IQR 12-20) days from infection onset to the time of the survey. Cough was the most common symptom, occurring in 91.7% of participants, followed by fever, fatigue, and nasal congestion (68.8%-87.4%). The median cough visual analog scale (VAS) score was 70 (IQR 50-80) mm. Being female (odds ratio [OR] 1.31, 95% CI 1.20-1.43), having a COVID-19 vaccination history (OR 1.71, 95% CI 1.37-2.12), current smoking (OR 0.48, 95% CI 0.41-0.58), chronic cough (OR 2.04, 95% CI 1.69-2.45), coronary heart disease (OR 1.71, 95% CI 1.17-2.52), asthma (OR 1.22, 95% CI 1.02-1.46), and gastroesophageal reflux disease (GERD) (OR 1.21, 95% CI 1.01-1.45) were independent factors for severe cough (VAS>70, 37.4%). Among all respondents, 35.0% indicated having a productive cough, which was associated with risk factors of being female (OR 1.44, 95% CI 1.31-1.57), having asthma (OR 1.84, 95% CI 1.52-2.22), chronic cough (OR 1.44, 95% CI 1.19-1.74), and GERD (OR 1.22, 95% CI 1.01-1.47). Persistent cough (>3 weeks) occurred in 13.0% of individuals, which was associated with the risk factors of having diabetes (OR 2.24, 95% CI 1.30-3.85), asthma (OR 1.70, 95% CI 1.11-2.62), and chronic cough (OR 1.97, 95% CI 1.32-2.94). ConclusionsCough is the most common symptom in nonhospitalized individuals with Omicron SARS-CoV-2 variant infection. Being female, having asthma, chronic cough, GERD, coronary heart disease, diabetes, and a COVID-19 vaccination history emerged as independent factors associated with severe cough, productive cough, and persistent cough.

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.

Background Chronic cough is a troublesome clinical problem with long-term impacts at the patient level. However, the burden of chronic cough in China is largely unknown. Thus, we performed a multicenter cross-sectional survey on the current status of chronic cough and its impact on quality of life in Guangdong, south China. Methods Using a standardized questionnaire, we extracted and analyzed the relevant data on demographics, number of visits to a doctor, previous diagnosis, previous medications used and initial diagnosis. Cough-specific quality of life was measured by the Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC). Results Of 933 patients from 13 tertiary medical centers in Guangdong, 52.2% were female, the median age was 40.0 [interquartile range (IQR), 31.0–52.0] years, and the median duration of chronic cough was 6.0 (IQR, 3.0–24.0) months. Over half (n=452, 54.0%) of the patients had visited physicians ≥3 times for cough. In terms of previous diagnosis, bronchitis (n=432, 46.5%) had been most frequently diagnosed, followed by pharyngitis (n=246, 26.5%) and asthmatic cough (n=98, 10.5%). A majority of patients with chronic cough had used antitussive agents (n=539, 58.5%), antibiotics (n=374, 40.6%) and traditional Chinese medicine (TCM) (n=294, 31.9%). Among the three subscales of the LCQ-MC, we observed lower scores in the mental health domain than in the physical and social domains (both P<0.001). Additionally, lower LCQ-MC scores were found in females and patients who saw the doctor >3 times for both the total and three subscale scores (all P<0.05). Conclusions Misdiagnosis and inappropriate treatment are prevalent in patients with chronic cough and lead to considerable antibiotic abuse. Chronic cough markedly affects suffers’ quality of life, especially for women.

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

BACKGROUND:The AtyPical Asthma in China (APAC) cohort is a multi-center prospective, observational cohort set-up to investigate the clinical, pathophysiological features, prognosis, and mechanisms of cough variant asthma (CVA). OBJECTIVES:To present the characteristics of newly physician-diagnosed adults with CVA (n = 328) compared to mild-moderate classic asthma (CA, n = 206). METHODS AND MAIN RESULTS:CVA subjects showed a higher proportion of female (67.1 vs. 55.3%, P = 0.0084), abnormal laryngopharyngeal sensations (71 vs. 51%, p < 0.0001) than CA, but presented with near normal spirometry and higher methacholine PD20-FEV1 values [4.2 (1, 8.6) vs. 0.8 (0.4, 4.7), P < 0.0001]. Lower fractional exhaled nitric oxide (FENO) levels [38.5 (19.8, 72.5) vs. 53. (28.5, 92.2), P = 0.0019], blood eosinophil counts [0.2 (0.1, 0.4) vs. 0.3 (0.2, 0.5), P = 0.0014], and sputum eosinophils [2.3 (0.3, 8.0) vs. 12.2 (2, 34.5), p < 0.0001] were found in CVA. Despite lower total serum IgE levels in CVA, there was similar proportion of atopy in both groups. The prevalence of cough in CA was 86.4%, while CVA reported more severe cough on Visual Analog Scale, Cough Evaluation Test, and Leicester Cough Questionnaire, similar anxiety and depression scores but better asthma control scores as reflected by Asthma Control Test compared to CA. No correlation was found between cough assessment outcomes and sputum eosinophil count, blood eosinophil count, FENO, spirometry variables, or PD20-FEV1. CONCLUSION:Cough variant asthma is distinctive from classic asthma in regard to clinical features, lung function, and airway inflammation. Quality of life is badly impaired as well in spite of better asthma control scores.

Background Cough variant asthma (CVA) is one of the special populations of asthma. The aim of the study was to compare small airways, the degree of bronchial hyperresponsiveness (BHR) and airway inflammatory subtypes between CVA and classic asthma (CA), and investigate the relationship between these markers to determine the accuracy as indicators of CVA. Methods A total of 825 asthmatic patients participated in the study and 614 were included. 614 patients underwent spirometry and a bronchial challenge with methacholine and 459 patients performed induction sputum cell test. Results The number of CVA patients showed less small airway dysfunction than those of CA patients ( p < 0.005). The degree of small airways dysfunction was higher in the CA group compared with the CVA group ( p < 0.001). Small airways dysfunction was severer in the eosinophilic airway inflammatory subtype compared with other subtypes ( p < 0.05).The area under curve of MMEF, FEF 50 and FEF 75 (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD 20 and 4.7% of sputum eosinophils was the best diagnostic value for CVA with an AUC of 0.582 and 0.575 ( p = 0.001 and p = 0.005, respectively). Conclusions The eosinophilic airway inflammatory subtype may be increased small airway dysfunction. The value of small airways, BHR and induction sputum cells in CVA prediction, which reflected significant, but not enough to be clinically useful.

BACKGROUND:Cough variant asthma (CVA) is one kind of atypical asthma. The study was to compare spirometric parameters of small airways and the degree of bronchial hyper-responsiveness (BHR) between CVA and classic asthma (CA), and examine the relationship between BHR and small airways to determine the accuracy of these markers as indicators of CVA.METHODS:A total of 825 asthmatic patients were screened for the study, and 614 were included. All patients performed spirometry and underwent a bronchial challenge with methacholine.RESULTS:The number of small airways dysfunctions in the CVA group was less than those of the CA group with MMEF% predicted (70% vs 80.91%, P=0.002) and FEF50% predicted (62.71% vs 73.5%, P=0.004). The degree of small airways dysfunction was less in the CVA group compared with the CA group (P<0.001). Significant positive correlations were observed between the FEV1 level below 20% of the baseline value (PD20) and MMEF% predicted (r=0.282, P<0.001), FEF50% predicted (r=0.2522, P<0.001), and FEF75% predicted (r=0.2504, P<0.001) in patients with CVA. The area under curve (AUC) of MMEF, FEF50, and FEF75 (% predicted) was 0.615, 0.621, and 0.606, respectively. In addition, 0.17 mcg of PD20 was the best diagnostic value for CVA, with an AUC of 0.582 (P=0.001).CONCLUSION:Small airway dysfunction is milder in CVA. The value of BHR combined with small airways in CVA prediction, which was significant, but not enough to be clinically useful.

BACKGROUND:Measurement of sputum is used to define airway inflammatory phenotypes. Cough variant asthma (CVA) is considered to be the initial stage of classic asthma (CA). The aim of this study was to describe the association between the different subtypes of CVA and CA.METHODS:A total of 459 patients with CVA and CA were screened for the study. All included patients performed spirometry, underwent a bronchial challenge with methacholine and induced sputum according to the guidelines.RESULTS:A higher frequency of female patients were found with CVA and the eosinophilic airway inflammation of CVA than in CA and the noneosinophilic airway inflammation of CA (p=0.004 and p=0.024, respectively). Bronchial hyper-responsiveness (BHR) was lower in eosinophilic CVA and CA (p=0.006), while no difference was found in noneosinophilic CVA and CA. Association between the percentage of sputum eosinophils and the FEV1 level fell below 20% of the baseline value (PD20) in CVA and CA (r= -0.1245, p=0.0357 and r= -0.2148, p=0.0014, respectively).CONCLUSION:Eosinophilia may be associated with more severe disease, yet there was no difference in spirometry between the eosinophilic and noneosinophilic groups, and the BHR difference was not dramatic.

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.

Clinical features of cough variant asthma (CVA) in Chinese adults are largely uncertain. A total of 303 patients newly diagnosed as uncontrolled asthma (symptom control and future risk of adverse outcomes), including 175 CVA and 128 classic asthma (CA), were enrolled in this retrospective survey. Clinical features including basic characteristics, pulmonary function, airway hyperresponsiveness (AHR) and cell counts of induced sputum, were compared retrospectively. All patients were classified into four inflammatory subtypes based on the counts of induced sputum eosinophils and neutrophils as eosinophilic (E), neutrophilic (N), mixed granulocytic (M), and paucigranulocytic (P) subtypes. Inflammatory subtype distribution was also compared. Compared with CA patients, CVA patients were younger (P = 0.009), had a higher prevalence of female patients (P = 0.001), higher parameter values of baseline pulmonary function (P ≤ 0.01 for all), shorter duration of disease (P = 0.002), lower AHR (P = 0.001) and lower sputum eosinophil% (P = 0.009). There was a difference in the AHR distribution as the percentage of moderate and severe AHR in CVA was significantly lower than in CA (41.72% VS 64.70%, P = 0.001). The inflammatory subtype distribution was different as the proportion of E and M subtypes in CVA was lower than in CA (56.0% vs 67.19%, P = 0.049). The proportion of subtype P was the lowest and subtype M was the highest in both CVA and CA patients. There was a similar negative correlation of sputum eosinophil% with AHR in CVA and CA (r = − 0.337, P < 0.0001 and r = − 0.27, P = 0.026, respectively), and a positive correlation between sputum eosinophil% and improvement rate of FEV1 after inhalation of bronchodilator (ΔFEV1%) (r = 0.33, P = 0.01). CVA patients showed a better pulmonary function and lower airway inflammation in contrast to CA patients, which may participate in the pathogenesis of chronic cough in CVA.

The fractional exhaled nitric oxide (FeNO) and blood eosinophils are biomarkers of eosinophilic airway inflammation used in the diagnosis and management of asthma, although induced sputum is the gold standard test for phenotypic asthma. Nevertheless, the clinical application of the correlation between sputum eosinophils, FeNO and blood eosinophils is controversial.

Introduction: Measurements of eosinophils in induced sputum and fractional exhaled nitric oxide (FeNO) are noninvasive biomarkers for assessing airway inflammation phenotypes in chronic obstructive pulmonary disease (COPD). Nevertheless, the clinical application of the correlation between FeNO levels and sputum eosinophilia is controversial. The study aimed to investigate the correlation and predictive relationship between FeNO levels and sputum eosinophils in patients with COPD exacerbation. It also examined the relationship between FeNO levels and blood eosinophil percentage.Methods: A total of 163 patients with COPD exacerbation were included in the cross-sectional study. All patients underwent the following on the same day: FeNO test, spirometry, bronchodilator reversibility test, induced sputum, and routine blood test. They were classified as eosinophilic group or noneosinophilic group based on sputum eosinophilic percentage (>= 2.5%)/FeNO levels (>= 32 parts per billion [ppb]).Results: FeNO levels and blood eosinophilic percentage were higher in patients with sputum eosinophilia (n=62) compared to those without (31.35 ppb versus 21.43 ppb, P=0.015; 2.71% versus 0.98%, P<0.0001, respectively). Sputum eosinophilic percentage was higher with raised FeNO (n=34) compared to those with FeNO <32 ppb (5.12% versus 3.12%, P=0.007). Eosinophils in induced sputum correlated with both FeNO levels (rho=0.221, P=0.005) and blood eosinophilic percentage (rho=0.399, P < 0.001). There was no relationship between FeNO and blood eosinophilic percentage. Blood eosinophilic percentage was predictive of sputum eosinophilia (95% confidence interval [CI] =0.65-0.81, P. 0.001) at a cutoff point of 0.65% (sensitivity =73%, specificity = 61.3%). FeNO levels were predictive of sputum eosinophilia (95% CI =0.53-3,071, P=0.012) at a cutoff point of 17.5 ppb (sensitivity =65.1%, specificity =56.4%).Conclusion: The clinical relevance of this study provides evidence that inflammatory biomarkers, including sputum eosinophilic percentage, FeNO level, and blood eosinophilic percentage, can be used to positively diagnose eosinophilic COPD. The FeNO level and blood eosinophilic counts/percentage, which determine an optimal cutoff for sputum eosinophilia, need more studies.