Kian Fan Chung

Mitochondria are key metabolic hubs involved in cellular energy production and biosynthesis. ATP is generated primarily by glucose and fatty acid oxidation through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in the mitochondria. During OXPHOS there is also production of reactive oxygen species (ROS), which are involved in the regulation of cellular function. Mitochondria are also central in the regulating cell survival and death, particularly in the intrinsic apoptosis pathway. Severe asthma is a heterogeneous disease driven by various immune mechanisms. Severe eosinophilic asthma entails a type 2 inflammatory response and peripheral and lung eosinophilia, associated with severe airflow obstruction, frequent exacerbations and poor response to treatment. Mitochondrial dysfunction and altered metabolism have been observed in airway epithelial and smooth muscle cells from patients with asthma. However, the role of mitochondria in the development of eosinophilia and eosinophil-mediated inflammation in severe asthma is unknown. In this review, we discuss the currently limited literature on the role of mitochondria in eosinophil function and how it is regulated by asthma-relevant cytokines, including interleukin (IL)-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), as well as by corticosteroid drugs. Moreover, we summarise the evidence on the role of mitochondria in the regulation of eosinophils apoptosis and eosinophil extracellular trap formation. Finally, we discuss the possible role of altered mitochondrial function in eosinophil dysfunction in severe asthma and suggest possible …

BackgroundElectronic noses (eNOSE) provide a non-invasive point-of-care tool that can phenotype chronic respiratory diseases. Their use in the U-BIOPRED study allowed asthma to be phenotyped into atopic and non-atopic disease, in a supervised manner. eNOSE technology has yet to be used for the breath prints of severe asthmatics, longitudinal after anti-IL5/5R therapy to characterise and identify a positive response. MethodsThe breathprint of 38 severe asthmatics were taken at baseline (visit 1), 1 month (visit 2) and 6 months (visit 3) via SpiroNose (a cloud-based eNOSE device) as part of the prospective, longitudinal, observational study–PRISM. 38 subjects were treated with either benralizumab or mepolizumab. Unsupervised clustering was performed using the Gaussian mixture model method, and consensus clustering via ‘NbClust’was used to determine the optimal number of clusters at each visit. The …

Studies of asthma and allergy are generating increasing volumes of omics data for analysis and interpretation. The National Institute of Allergy and Infectious Diseases (NIAID) assembled a workshop comprising investigators studying asthma and allergic diseases using omics approaches, omics investigators from outside the field, and NIAID medical and scientific officers to discuss the following areas in asthma and allergy research: genomics, epigenomics, transcriptomics, microbiomics, metabolomics, proteomics, lipidomics, integrative omics, systems biology, and causal inference. Current states of the art, present challenges, novel and emerging strategies, and priorities for progress were presented and discussed for each area. This workshop report summarizes the major points and conclusions from this NIAID workshop. As a group, the investigators underscored the imperatives for rigorous analytic frameworks …

Background: Cough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19.Objective: The 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.Methods: In 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.Results: There 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 …

Influence of Staphylococcal enterotoxin-specific IgE sensitization on therapeutic efficacy of omalizumab therapy in severe asthma Influence of Staphylococcal enterotoxin-specific IgE sensitization on therapeutic efficacy of omalizumab therapy in severe asthma Respirology. 2024 Mar;29(3):252-255. doi: 10.1111/resp.14663. Epub 2024 Jan 31. Authors Chih-Ming Weng 1 2 , Wei-Ciao Wu 2 , Meng-Jung Lee 2 , Mei-Chuan Chen 2 3 , Chun-Liang Chou 2 3 , Chun-Yu Lin 4 , Kian Fan Chung 5 6 7 , Han-Pin Kuo 2 3 Affiliations 1 School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan. 2 Center of Thoracic Medicine, Taipei Medical University, Taipei, Taiwan. 3 Department of Thoracic Medicine, Taipei Medical University Hospital, Taipei, Taiwan. 4 Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan. 5 Airway Disease Section, National Heart and Lung …

RATIONALE Club cell secretory protein (CC16) is secreted by non-ciliated epithelial cells in the airway. To date, we have demonstrated that the protein levels in BAL and serum and the airway gene expression of CC16 are negatively associated with both type 2 and non-type 2 asthma and their phenotypes (Guerra, et al. JACI 2016; Li, et al. AJRCCM 2022; Kimura, et al. ATS 2023). However, the role of CC16 in these phenotypes is not completely understood. In this study, we investigated the multi-omics data from samples from the airway, blood, and urine in the UBIOPRED adult cohort to identify the molecular signatures associated with CC16. METHODS 243 participants, with 54 non-asthmatic controls, 48 with mild-to-moderate asthma, 104 non-smokers with severe asthma, and 37 smokers with severe asthma were studied. The association with CC16 mRNA expression in the airway (sputum, nasal brushing …

BackgroundThe determinants linked to the short- and long-term improvement in lung function in patients with severe eosinophilic asthma (SEA) on biological treatment (BioT) remain elusive.ObjectiveWe sought to identify the predictors of early and late lung function improvement in patients with SEA after BioT.Methods140 adult patients with SEA who received mepolizumab, dupilumab, or reslizumab were followed up for 6 months to evaluate improvement in forced expiratory volume in one second (FEV1). Logistic regression was used to determine the association between potential prognostic factors and improved lung function at 1 and 6 months of treatment.ResultsMore than a third of patients with SEA using BioT showed early and sustained improvements in FEV1 after 1 month. A significant association was found between low baseline FEV1 and high blood eosinophil count and sustained FEV1 improvement after …

Introduction The impact of climate change on ambient temperatures threatens to worsen pediatric pneumonia-related outcomes considerably. This study examined the associations of temperature variation and extreme temperature with pediatric pneumonia-related events using a meta-analysis. Methods We systematically searched PubMed, Medline, Embase, and Web of Science databases for relevant literature, and the quality of evidence was assessed. Fixed and random-effects meta-analyses were performed to calculate the pooled relative risks (RRs) of the associations with pneumonia-related events. Results We observed that a 1°C temperature variation increased the RR of pneumonia events by 1.06-fold (95% confidence interval (CI): 1.03–1.10). A 1°C temperature variation increased the RR by 1.10-fold of the pediatric pneumonia hospital admissions (95% CI: 1.00–1.21) and 1.06-fold of the pediatric pneumonia emergency department visits (95% CI: 1.01-1.10). Extreme cold increased the RR by 1.25-fold of the pediatric pneumonia events (95% CI: 1.07–1.45). A 1°C temperature variation increased the RR of pneumonia events in children by 1.19-fold (95% CI: 1.08–1.32), girls by 1.03-fold (95% CI: 1.02–1.05), and in temperate climate zones by 1.07-fold (95% CI: 1.03–1.11). Moreover, an increase in extreme cold increased the RR of pneumonia events in children by 2.43-fold (95% CI: 1.72–3.43), girls by 1.96-fold (95% CI: 1.29–2.98) and in temperate climate zones by 2.76-fold (95% CI: 1.71–4.47). Conclusion Our study demonstrated that pediatric pneumonia events are more prevalent among children, particularly girls, and individuals …

PurposeCodeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice.MethodsData from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment.ResultsOf 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one …

The EAACI Guidelines on the impact of short‐term exposure to outdoor pollutants on asthma‐related outcomes provide recommendations for prevention, patient care and mitigation in a framework supporting rational decisions for healthcare professionals and patients to individualize and improve asthma management and for policymakers and regulators as an evidence‐informed reference to help setting legally binding standards and goals for outdoor air quality at international, national and local levels. The Guideline was developed using the GRADE approach and evaluated outdoor pollutants referenced in the current Air Quality Guideline of the World Health Organization as single or mixed pollutants and outdoor pesticides. Short‐term exposure to all pollutants evaluated increases the risk of asthma‐related adverse outcomes, especially hospital admissions and emergency department visits (moderate certainty of …

BackgroundEosinophilic and neutrophilic asthma defined by high levels of blood and sputum eosinophils and neutrophils exemplifies the inflammatory heterogeneity of asthma, particularly severe asthma. We analysed the serum and sputum proteome to identify biomarkers jointly associated with these different phenotypes.MethodsProteomic profiles (N = 1129 proteins) were assayed in sputum (n = 182) and serum (n = 574) from two cohorts (U-BIOPRED and ADEPT) of mild-moderate and severe asthma by SOMAscan. Using least absolute shrinkage and selection operator (LASSO)-penalised logistic regression in a stability selection framework, we sought sparse sets of proteins associated with either eosinophilic or neutrophilic asthma with and without adjustment for established clinical factors including oral corticosteroid use and forced expiratory volume.FindingsWe identified 13 serum proteins associated with …

BackgroundChronic cough is a prevalent and difficult to treat condition often accompanied by cough hypersensitivity, characterised by cough triggered from exposure to low level sensory stimuli. The mechanisms underlying cough hypersensitivity may involve alterations in airway sensory nerve responsivity to tussive stimuli which would be accompanied by alterations in stimulus-induced brainstem activation, measurable with functional magnetic resonance imaging (fMRI).MethodsWe investigated brainstem responses during inhalation of capsaicin and adenosine triphosphate (ATP) in 29 participants with chronic cough and 29 age- and sex-matched controls. Psychophysical testing was performed to evaluate individual sensitivities to inhaled stimuli and fMRI was used to compare neural activation in participants with cough and control participants while inhaling stimulus concentrations that evoked equivalent levels …

Background Maternal smoking during pregnancy (MSDP) is a known risk factor for offspring developing chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. Objective This study aimed to explore whether the increased COPD risk associated with MSDP could be attributed to tobacco dependence (TD). Methods This case-control study used data from the nationwide cross-sectional China Pulmonary Health study, with controls matched for age, sex, and smoking status. TD was defined as smoking within 30 minutes of waking, and the severity of TD was assessed using the Fagerstrom Test for Nicotine Dependence. COPD was diagnosed when the ratio of forced expiratory volume in 1 second to forced vital capacity was <0.7 in a postbronchodilator pulmonary function test according to the 2017 Global Initiative for Chronic Obstructive Lung Disease criteria. Logistic regression was used to examine the correlation between MSDP and COPD, adjusting for age, sex, BMI, educational attainment, place of residence, ethnic background, occupation, childhood passive smoking, residential fine particulate matter, history of childhood pneumonia or bronchitis, average annual household income, and medical history (coronary heart disease, hypertension, and diabetes). Mediation analysis examined TD as a potential mediator in the link between MSDP and COPD risk. The significance of the indirect effect was assessed through 1000 iterations of the “bootstrap” method. Results The study included 5943 participants (2991 with COPD and 2952 …

BackgroundAlthough various monoclonal antibodies have been used as add-on therapy for severe eosinophilic asthma (SEA), to the best of our knowledge, no direct head-to-head comparative study has evaluated their efficacy.ObjectiveTo compare the efficacy of reslizumab, mepolizumab, and dupilumab in patients with SEA.MethodsThis was a multicenter, prospective observational study in patients with SEA who had received 1 of these biologic agents for at least 6 months. Cox proportional hazard models were used to compare the risk of the first exacerbation event, adjusting for sputum or blood eosinophils and common asthma-related covariates. The annual exacerbation rate was analyzed using a negative binomial model, and a mixed-effect model was used to analyze changes in forced expiratory volume in 1 second and asthma control test score over time.ResultsA total of 141 patients with SEA were …

Chronic cough is characterized by a state of cough hypersensitivity. We analyze the process of transpiration, by which water appears to evaporate from laryngeal and tracheal mucus as from the surface of a leaf, as a potential cause of cough hypersensitivity. In this process, osmotic pressure differences form across mucus, pulling water toward the air, and preventing mucus dehydration. Recent research suggests that these osmotic differences grow on encounter with dry and dirty air, amplifying pressure on upper airway epithelia and initiating a cascade of biophysical events that potentially elevate levels of ATP, promote inflammation and acidity, threaten water condensation, and diminish mucus water permeability. Among consequences of this inflammatory cascade is tendency to cough. Studies of isotonic, hypotonic, and hypertonic aerosols targeted to the upper airways give insights to the nature of mucus …

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed …

Background and objective Nicotine metabolic ratio (NMR) has been associated with nicotine metabolism and smoking characteristics. However, there are few studies on the potential association between NMR and smoking cessation efficacy in smokers with chronic obstructive pulmonary disease (COPD) in China or elsewhere. Methods This study was a stratified block randomized controlled trial for smoking cessation in Chinese smokers with COPD. NMR was used as a stratification factor; slow metabolizers were defined as those with NMR <0.31, and normal metabolizers as those with NMR ≥0.31. Participants were randomly assigned to the varenicline or bupropion group. Follow‐up visits were conducted at 1, 2, 4, 6, 9, 12 and 24 weeks. Results Two hundred twenty‐four participants were recruited and analysed from February 2019 to June 2022. In normal metabolizers, the 9–12 weeks continuous …

RationaleSevere eosinophilic asthma (SEA) is associated with high numbers of eosinophils in the blood and sputum. In SEA, patients have high serum levels of the cytokine IL-5 that is involved in the maturation and activation of eosinophils resulting in increased release into the circulation. During inflammation, blood eosinophils tether and become attached to the activated endothelium and cause extravasation mediated by integrins. Mepolizumab, an anti-IL5 biologic therapy, used to treat SEA patients, removes 80% circulating blood eosinophils, however, little is known about the biology of the remaining eosinophils. AimDetermine the adhesion characteristics of eosinophils from severe asthmatics not currently receiving anti-IL5 Mepolizumab, and from severe asthmatics established on the anti-IL5 Mepolizumab. MethodsEosinophils were isolated from whole blood via Percoll density centrifugation and magnetic …

Cough is one of the most frequent and predominant symptoms of many respiratory and some nonrespiratory conditions, and medical practitioners are often confronted with the management of people with persistent cough. Assessment of the duration, severity, and pattern of cough, the presence of sputum production, the physical and psychological effects of cough, potential causes of cough, and associated comorbidities are part of the evaluation of persistent cough in the clinic. 1 A semantics of cough has been developed2 that forms an initial basis for addressing the heterogeneity of different presentations of cough. Using these cough parameters, different classes of cough have been described according to severity, associated causes, triggers, and effects on quality of life. 3–5 However, there is currently little understanding and appreciation of the importance of the different types of cough, which has been proposed …

BackgroundTransient receptor potential (TRP) ankyrin 1 (TRPA1) could mediate ozone-induced lung injury. Optic Atrophy 1 (OPA1) is one of the significant mitochondrial fusion proteins. Impaired mitochondrial fusion, resulting in mitochondrial dysfunction and ferroptosis, may drive the onset and progression of lung injury. In this study, we examined whether TRPA1 mediated ozone-induced bronchial epithelial cell and lung injury by activating PI3K/Akt with the involvement of OPA1, leading to ferroptosis.MethodsWild-type, TRPA1-knockout (KO) mice (C57BL/6 J background) and ferrostatin-1 (Fer-1)-pretreated mice were exposed to 2.5 ppm ozone for 3 h. Human bronchial epithelial (BEAS-2B) cells were treated with 1 ppm ozone for 3 h in the presence of TRPA1 inhibitor A967079 or TRPA1-knockdown (KD) as well as pharmacological modulators of PI3K/Akt-OPA1-ferroptosis. Transcriptome was used to …