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Introduction: Neutrophilic asthma has been suggested to be a clinically distinct phenotype characterised by more severe airflow obstruction and higher exacerbation risk. However, this has only been assessed in few and smaller studies, using different cut-offs to define neutrophilia, and with conflicting results. We used data from ATLANTIS, an observational longitudinal study including a large number of patients with asthma and healthy controls. The aim of the present study was to examine whether neutrophilic inflammation, either in sputum or blood, is more prevalent in asthma and whether it correlates with disease severity., Methods: ATLANTIS included 773 asthma patients, with blood collected from 767 (99%) and sputum from 228 patients (30%). Data were available from 244 healthy controls, all providing blood and 126 (52%) providing sputum. Asthma patients were characterised, including parameters of large and small airways disease at baseline and after 6 and 12 months of follow-up. Sputum and blood neutrophilia were defined as values exceeding the upper quartile in asthma patients., Results: The prevalence of sputum neutrophilia did not differ between asthma patients and healthy controls. Asthma patients with sputum neutrophilia did not display more severe symptoms, large or small airways disease or more frequent exacerbations. Blood neutrophilia was more common in asthma and was associated with higher body mass index, female sex, current smoking and systemic corticosteroid use. Patients with blood neutrophilia had a statistically significant, but small, increase in residual volume/total lung capacity. Blood neutrophilia was not associated with large or small airways disease or exacerbation risk., Conclusion: Sputum and blood neutrophilia do not define a distinct clinical phenotype in asthma., Competing Interests: Conflict of interest: P.J.M. Kuks reports support for the present study from the Dutch Ministry of Economic Affairs and Climate Policy by means of the public–private partnership programme. Conflict of interest: T.M. Kole reports support for the present study from the Dutch Ministry of Economic Affairs and Climate Policy by means of the public–private partnership programme. Conflict of interest: M. Kraft reports grants or contacts from the National Institutes of Health, American Lung Association, Synairgen, Janssen, AstraZeneca (AZ) and Sanofi (funds paid to the University of Arizona until June 2022 and currently to the Icahn School of Medicine at Mount Sinai, all pharmaceutical industry studies now completed); consulting fees from AZ, Sanofi, Chiesi, GSK, Kinaset and Genentech (funds paid to M. Kraft); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesis (funds paid to M. Kraft); support from the European Respiratory Society (ERS) to attend the ERS Congress in 2023 (partial support paid to M. Kraft); that they are a cofounder and chief medical officer of RaeSedo Inc. (one patent issued and two files for the development of therapeutics for inflammatory lung disease); participation on the ALung data safety monitoring board (DSMB) (funds paid to M. Kraft); leadership or fiduciary roles on the National Heart, Lung and Blood Advisory Council (completed in 2022, funds paid to M. Kraft) and the Association of Professors of Medicine (no compensation); equity ownership in RaeSedo Inc. (company is developing therapeutics for asthma in the preclinical phase, no human trials or IND); and that they are a Section Editor of UpToDate (funds paid to M. Kraft), all in the past 36 months. Conflict of interest: S. Siddiqui reports consulting fees from CSL Behring, AZ, GSK, Areteia Therapeutics and Novartis; speaker fees from Chiesi for presenting ATLANTIS data; support from the ERS to attend ERS Science Council meetings; and being a member of the ATLANTIS scientific steering group, all in the past 36 months. Conflict of interest: L.M. Fabbri reports consulting fees from Chiesi, GSK, AZ, Novartis, Verona Pharma and ICON; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi and GSK; and participation on a DSMB or advisory board for Novartis and Chiesi, all in the past 36 months. Conflict of interest: K.F. Rabe reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AZ, Boehringer Ingelheim, Chiesi, Novartis, Sanofi Regeneron, GSK, Berlin Chemie and Roche Pharma (payments made to K.F. Rabe); participation on a DSMB or advisory board for AZ, Boehringer Ingelheim and Sanofi Regeneron; and leadership or fiduciary roles in the German Center for Lung Research, German Chest Society and American Thoracic Society, all in the past 36 months. Conflict of interest: A. Papi reports that the ATLANTIS study was supported by Chiesi. They also report grants to their institution from Chiesi, AZ, GSK and Sanofi; consulting fees from Chiesi, AZ, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals, Moderna and Roche (to A. Papi); payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chiesi, AZ, GSK, Menarini, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, Avillion, Sanofi and Regeneron (to A. Papi); participation on advisory boards for Chiesi, AZ, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals and Moderna (to A. Papi); and receipt of equipment, materials, drugs, medical writing, gifts or other services from Consorzio Futuro in Ricerca, all in the past 36 months. Conflict of interest: C. Brightling reports support for the ATLANTIS study from a grant from Chiesi and for the Leicester National Institute for Health and Care Research (NIHR) Biomedical Research Centre from the NIHR; and grants and consultancy fees from 4D Pharma, Areteia, AZ, Chiesi, Genentech, GSL, Mologic, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi (paid to their institution), in the past 36 months. Conflict of interest: D. Singh reports consulting fees from Aerogen, AZ, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GSK, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance Biopharma and Verona Pharma, in the past 36 months. Conflict of interest: T. van der Molen reports that Chiesi funded the present study through their department; and Chiesi funded presentations, and GSK funded presentations and travel (to their company), in the past 36 months. Conflict of interest: J.W.W.H. Kocks reports grants or contracts from AZ, Boehringer Ingelheim, Chiesis, GSK and Valneva; consulting fees from AZ, Boehringer Ingelheim, Chiesi, GSK, Teva, MSD, COVIS Pharma and Janssen (payments made to their institution); and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Mundi Pharma and ALK-Bello (payments made to their institution); that they are an ERS group chair, President and a board member of the International Primary Care Respiratory Group, a member of the CAHAG scientific committee, and a board member of the Inhalation Institute Netherlands; and that they are Director of and hold stocks in the General Practitioners Research Institute, and hold <5% stocks in Lothar Medtec, all in the past 36 months. Conflict of interest: K.F. Chung reports a Medical Research Council (MRC) grant on precision medicine for severe asthma, an Engineering and Physical Sciences Research Council (EPSRC) on air pollution and asthma, a GSK grant on mepolizumab and eosinophils in asthma, a Merck grant on the effects of ATP on cough hypersensitivity, and a National Institute of Environmental Health Sciences grant on air pollution and lipid metabolites in asthma (all to their institution); speaking engagements for GSK, Novartis and AZ (payments to K.F. Chung); and advisory board meetings for GSK, AZ, Novartis, Roche, Merck, Trevi, Rickett-Beckinson, Nocion and Shionogi on asthma, COPD and chronic cough, and the Scientific Advisory Board of the Clean Breathing Institute supported by Haleon (all payments to K.F. Chung), all in the past 36 months. Conflict of interest: I.M. Adcock reports European Union Innovative Medicines Initiative funding for the U-BIOPRED project. They also report grants to their institution from GSK, MRC, EPSRC and Sanofi; consulting fees from GSK, Sanofi and Kinaset (all for advisory boards); and lecture fees from AZ and Sanofi, all in the past 36 months. Conflict of interest: P.K. Bhavsar is an associate editor of this journal. Conflict of interest: N.Z. Kermani has nothing to disclose. Conflict of interest: I.H. Heijink reports research grants from NWO, Longfonds and Health∼Holland outside the scope of the present study, in the past 36 months. Conflict of interest: S.D. Pouwels has nothing to disclose. Conflict of interest: H.A.M. Kerstjens reports support for the present study from Chiesi. They also report unrestricted research grants from Boehringer Ingelheim, GSK and Novartis; and participation on a DSMB or advisory board for GSK, AZ, Novartis and Teva (all payments to their institution), in the past 36 months. Conflict of interest: D-J. Slebos reports support for the ATLANTIS consortium from Chiesi. Conflict of interest: M. van den Berge reports research grants paid to their institution from GSK, Chiesi, AZ, Novartis, Genentech and Roche, in the past 36 months., (Copyright ©The authors 2025.)

Allergic asthma is a significant international concern in respiratory health, which can be exacerbated by the increasing levels of non-allergenic pollutants. This rise in airborne pollutants is a primary driver behind the growing prevalence of asthma, posing a health emergency. Additionally, climatic risk factors can contribute to the onset and progression of asthma. Understanding the complex interplay between pollution, climate, and asthma induction is crucial to elucidate how environmental changes intensify asthma. In this study, we investigated the proteomic and metabolomic changes in the lungs of a mouse asthma model following co-exposure to carbon black nanoparticles and high humidity, which represent airborne and climatic factors, respectively. An asthma model was established using ovalbumin, and mice were intratracheally instilled with 15 or 30 μg/kg of carbon black and simultaneously exposed to either 70% or 90% relative humidity. Protein and metabolite profiles from the lung were used to analyze the most significantly changed clusters, and potential biomarkers and enriched pathways were identified to dissect the adverse effects of the two risk factors. The lung proteome and metabolome are significantly altered by the co-exposure, with the effects modulated by carbon black concentration and humidity level. This study proposes 10 proteins and 18 metabolites as candidate biomarkers. The significantly enriched KEGG pathways include one protein pathway (primary immunodeficiency) and six metabolic pathways (ABC transporters, nucleotide metabolism, Parkinson's disease, purine metabolism, choline metabolism in cancer, and biosynthesis of cofactors). A joint proteomic and metabolomic analysis identifies five common pathways across both omics, namely, ABC transporters, central carbon metabolism in cancer, EGFR tyrosine kinase inhibitor resistance, glioma, and NF-kappa B signaling pathway, disturbed by the co-exposure. We provide a multi-omic basis for the health risk assessment and management of co-exposures to environmental risk factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

COPD has many hallmarks of autoimmune dysfunction. Driving this autoimmune response are self-antigens, such as highly abundant structural proteins and cellular proteins, which can lead to the production of auto-antibodies. However, controversy surrounds the detection of some of these auto-antibodies as they have often been screened against native, unmodified proteins. Autoantigens arise as a result of a conformational change in the native protein exposing hidden epitopes or by the creation of neo-epitopes through chemical or enzymatic modifications, often caused by oxidative/carbonyl stress. In this study, we screened for auto-antibodies targeting key structural proteins modified by oxidative/carbonyl stress in peripheral blood from stable COPD patients versus control subjects using ELISA. We found an auto-antibody response against unmodified, carbonyl-modified and citrinylated vimentin, with the highest response observed against carbonyl-modified vimentin. Both the IgG and IgM antibody titres against carbonyl-modified were significantly increased in COPD patients compared to healthy non-smokers. Smokers also displayed increased antibody levels against carbonyl-modified vimentin, but only for the IgG isotype. Selectivity analysis indicated that 70% and 63% of COPD patients had higher IgM and IgG titres, respectively, compared to non-smokers. In contrast only 26% and 48% of smokers had higher IgM and IgG titres, respectively, than non-smokers. ROC analysis gave AUC values of 0.78 (p < 0.01) and 0.84 (p < 0.001) for IgM and IgG, respectively, for COPD versus non-smokers, which fell to 0.70 (p < 0.01) and 0.64 (NS), respectively, when asymptomatic smokers were included. No significant increase in antibody titre against carbonyl-modified elastin or collagen was observed in COPD patients or asymptomatic smokers. We conclude that IgM autoantibody responses against carbonyl modified vimentin could serve as a simple blood-based biomarker for COPD, reflecting the disease's pathophysiology, and could help in patient stratification and diagnosis., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was provided by all subjects and the study approved by the institutional local ethics committee at Ferrara University and Imperial College London. Consent for publication: All authors consent to the publication of this manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Particulate matter less than 2.5 microns in aerodynamic diameter (PM 2.5 ) is a significant air pollutant known to adversely affect respiratory health and increase the incidence of chronic obstructive pulmonary disease (COPD). Furthermore, climate change exacerbates these impacts, as extreme temperatures and relative humidity (RH) levels can intensify the effects of PM 2.5 . This study aims to examine the joint effects of PM 2.5 , temperature, and RH on the risk of COPD., Methods: A case-control study was conducted among 1,828 participants from 2017 to 2022 (995 COPD patients and 833 controls). The radial basis function interpolation was utilized to estimate participants' individual mean and differences in PM 2.5 , temperature, and RH in 1-day, 7-day, and 1-month periods. Logistic regression models examined the associations of environmental exposures with the risk of COPD adjusting for confounders. Joint effects of PM 2.5 by quartiles of temperature and RH were also examined., Results: We observed that a 1 µg/m 3 increase in PM 2.5 7-day and 1-month mean was associated with a 1.05-fold and 1.06-fold increase in OR of COPD (p < 0.05). For temperature and RH, we observed U-shaped effects on OR for COPD with optimal temperatures identified as 21.2 °C, 23.8 °C, and 23.8 °C for 1-day, 7-day, and 1-month mean temperature, respectively, and optimal RH levels identified as 73.8%, 76.7%, and 75.4% for 1-day, 7-day, and 1-month mean RH, respectively (p < 0.05). The joint effect models show that high temperatures (> 23.5 °C) and both extremely low (69.3%) and high (80.9%) RH levels generally exacerbate the effects of PM 2.5 on OR for COPD, especially over longer exposure durations., Conclusion: The joint effects of PM 2.5 , temperature, and RH on the risk of COPD underscore the importance of air pollution control and comprehensive research to mitigate COPD risk in the context of climate change., Competing Interests: Declarations. Ethics approval and consent to participate: The study was undertaken in accordance with the Declaration of Helsinki. Informed consent was obtained from all study participants before the research. This study adheres to the ethical standards, with all necessary approvals obtained from the Taipei Medical University-Joint Institution Review Board (TMU-JIRB no. N202302060). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Cigarette smoking has been reported to be associated with SARS-CoV-2 negative conversion, while little is known about the effect of its dual use with e-cigarettes. This study aimed to investigate whether tobacco product use patterns including e-cigarette use were linked with delayed negative conversion of SARS-CoV-2., Methods: An online national survey was conducted from January 28 through February 21, 2023, targeting a community-based population in mainland of China after peak waves of the coronavirus disease 2019 (COVID-19). Participants were followed from the onset of COVID-19 symptoms until the negative conversion day or the day of answering the questionnaire as the endpoint of the study. Multi-variable adjusted Cox proportional hazard models were used to compare the negative conversion time of SARS-CoV-2 across different cigarette and e-cigarette use patterns., Results: A total of 66,537 participants infected with COVID-19 were enrolled and 13,294 were included in the analyses. During the median duration of 7 days (interquartile range 5 to 10 days), a total of 11,587 (87.2%) had a negative conversion. Compared with never users, current exclusive smokers (multi-variable adjusted HR 0.59, 95% CI 0.48-0.71), current dual users (HR 0.31, 95% CI 0.22-0.44), and previous smokers (HR 0.56, 95% CI 0.37-0.83) took longer to turn negative after 10 days of follow-up., Conclusions: Both current exclusive cigarette use and dual use of cigarettes and e-cigarettes were associated with the delayed negative conversion of SARS-CoV-2, which strengthens the importance of smoking and vaping cessation messaging and community-based tobacco control strategies during pandemics like COVID-19 next time., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Clinical Research Ethics Committee of China-Japan Friendship Hospital (2022-KY-183-1) and conducted in accordance with the Declaration of Helsinki. All the participants provided online informed consent before enrolment. Consent for publication: All the authors have agreed to submit the manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Eosinophils are crucial in allergic inflammation, and their correlation with asthma severity has made them a focal point in predicting treatment outcomes. Blood eosinophil count is a commonly utilized marker. However, its limitations have prompted alternative biomarker exploration, such as eosinophil-derived neurotoxin (EDN)., Objective: This research was conducted over 24 weeks on 56 patients with severe asthma treated with mepolizumab, reslizumab, and dupilumab. We aimed to evaluate the clinical significance of blood eosinophil count and their potential, including those of blood EDN levels and urine EDN values as biomarkers for predicting treatment response., Methods: The analysis encompassed examining correlations between biomarkers and clinical features, including exacerbation rates and lung function, through ELISA assays and subsequent statistical analyses. The study protocol is registered at ClinicalTrials.gov (NCT05164939)., Results: The findings underscore strong correlations between serum EDN levels, blood eosinophil counts, and treatment responses, with EDN demonstrating comparable predictive capabilities to blood eosinophil counts to determine treatment responses. Different biologics exhibited varying efficacy regarding baseline eosinophil counts and EDN levels., Conclusions: Blood eosinophil counts and EDN levels show potential as predictive markers for treatment responses in patients with severe asthma undergoing biologic therapies. However, further comprehensive studies are warranted to enhance the reliability and applicability of EDN as an effective asthma treatment biomarker., Competing Interests: None. This document is provided for informational purposes only and does not contain any conflicts of interest related to its contents. All authors declare no competing interests., (© 2024 The Author(s).)

Rationale: Knowledge about the clinical importance of patient-reported outcome measures (PROMs) in severe asthma is limited., Objectives: To assess whether and to what extent asthma exacerbations affect changes in PROMS over time and asthma-specific PROMs can predict exacerbations in adult patients with severe asthma in usual care., Methods: Data of 421 patients with severe asthma (62% female; mean age 51.9 ± 13.4 years; mean FEV 1 67.5 ± 21.3%pred) from the U-BIOPRED cohort were analyzed. The included PROMs were: Asthma Control Questionnaire (ACQ5); Asthma Quality of Life Questionnaire (AQLQ); Hospital Anxiety and Depression scale (HADS); Epworth Sleepiness Scale (ESS); Medication Adherence Report Scale (MARS); Sino-Nasal Outcomes Test (SNOT20). Participants were assessed at baseline and after 12-18 months of usual care., Results: PROMs showed very weak to weak correlations with clinical characteristics such as age, body mass index, FEV 1 , FeNO and eosinophilic cell count. Patients presenting no exacerbations during follow-up showed a statistically significant improvement in all PROMs (except for MARS), whereas individuals experiencing > 2 exacerbations showed a deterioration. Baseline ACQ5 was a predictor of exacerbations with an AUC of 0.590 (95%CI 0.514-0.666)., Conclusions: The association of PROMs with clinical measures was poor in severe asthmatics. Moreover, PROMs were prone to changes in usual care, with exacerbations playing a key role. PROMs need to be systematically evaluated in severe asthma to improve clinical care based on specific patient's needs., Competing Interests: Declarations. Ethics approval and consent to participate: The medical ethics committee of each participating center of the U-BIOPRED study approved this study. All participants gave written and signed informed consent. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Beta-2 agonists play an important role in the management of asthma. Inhaled long-acting beta-2 agonists (LABAs) and short-acting beta-2 agonists (SABAs) cause bronchodilation by stimulating adrenoceptors. These receptors are also present in cardiac cells and, as a side effect, could also be stimulated by inhaled beta-2 agonists., Objective: This study aims to assess the effect of beta-2 agonists on heart rate (HR)., Methods: The data were retrieved from an observational study, the myAirCoach Quantification Campaign. Beta-2 agonist use was registered by self-reported monthly questionnaires and by smart inhalers. HR was monitored continuously with the Fitbit Charge HR tracker (Fitbit Inc). Patients (aged 18 years and older) were recruited if they had uncontrolled asthma and used inhalation medication. Our primary outcome was the difference in HR between LABA and non-LABA users. Secondary outcomes were the difference in HR on days SABAs were used compared to days SABAs were not used and an assessment of the timing of inhaler use during the day., Results: Patients using LABA did not have a clinically relevant higher HR (average 0.8 beats per minute difference) during the day. Around the moment of SABA inhalation itself, the HR does increase steeply, and it takes 138 minutes before it returns to the normal range., Conclusions: This study indicates that LABAs do not have a clinically relevant effect on HR. SABAs are instead associated with a short-term HR increase., Trial Registration: ClinicalTrials.gov NCT02774772; https://clinicaltrials.gov/study/NCT02774772., (©Rishi Jayant Khusial, Jacob K Sont, Omar S Usmani, Matteo Bonini, Kian Fan Chung, Stephen James Fowler, Persijn J Honkoop. Originally published in JMIR Cardio (https://cardio.jmir.org), 11.12.2024.)

Background: Chronic Obstructive Pulmonary Disease (COPD) remains a significant public health challenge due to its high morbidity and mortality rates. Emerging research has identified eosinophilic inflammation as a crucial factor in the pathogenesis and exacerbation of COPD, warranting a detailed exploration of its underlying mechanisms and therapeutic implications., Objective: This review aims to elucidate the role of eosinophils in COPD, focusing on their contribution to airway remodeling, exacerbation frequency, and the inflammatory cascade., Methods: We conducted a comprehensive literature review of recent studies that discuss the pathophysiological role of eosinophils in COPD and the clinical outcomes associated with modulating eosinophilic activity., Results: Eosinophils contribute to COPD progression by releasing cytotoxic proteins and cytokines that intensify the inflammatory response and airway alterations. Targeting specific eosinophil-related cytokines with monoclonal antibodies or receptor antagonists may potentially reduce eosinophil counts, mitigate exacerbations, and improve patient outcomes., Conclusion: Understanding eosinophilic involvement in COPD can facilitate the development of precision medicine approaches, offering more tailored and effective treatment options. Future research should continue to focus on the integration of eosinophil biomarkers in clinical practice to enhance therapeutic decisions and management strategies for COPD patients.

Patients with severe eosinophilic asthma often require systemic medication, including corticosteroids and anti-type 2 (T2) cytokine biologics, to control the disease. While anti-IL5 and anti-IL4Rα antibodies suppress the effects of IL-4, IL-5 and IL-13, the molecular pathways modified by these biologics that are associated with clinical improvement remain unclear. Therefore, we aimed to describe the effects of T2-targeting biologics on the gene expression of blood immune cells. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from eight patients with severe eosinophilic asthma treated with mepolizumab, reslizumab, or dupilumab. PBMCs were obtained before the initiation of biologics and at 1- and 6-month timepoints after the initiation of treatment to elucidate treatment-induced changes. During treatment, the proportions of T cells/natural killer (NK) cells, myeloid cells, and B cells did not change. However, the composition of classical monocytes (CMs) changed: IL1B + CMs were reduced, and S100A + CMs were increased. The subsets of T cells also changed, and significant downregulation of the NF-κB pathway was observed. The genes related to the NF-κB pathway were suppressed across T/NK, myeloid, and B cells. The transcriptional landscape did not significantly change after the first month of treatment, but marked changes occurred at six-month intervals. In conclusion, regardless of the type of biologics used, suppression of T2-mediated pathways ultimately reduces the expression of genes related to NF-κB signaling in circulating immune cells. Further studies are warranted to identify potential biomarkers related to treatment response and long-term outcomes.Clinical trial registration number: NCT05164939., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Limited understanding exists regarding the progression trajectory of severe eosinophilic asthma (SEA) patients on type 2 biologics therapies., Objective: We aim to explore distinct longitudinal phenotypes of these patients based on crucial asthma biomarkers., Methods: We enrolled 101 adult patients with SEA. Of these, 51 were treated with anti-IL5/IL5Rα or anti-IL5/IL5RαR antibody, and 50 with anti-IL-4Rα antibody. Multi-trajectory analysis, an extension of univariate group-based trajectory modeling, was used to categorize patients based on their trajectories of forced expiratory volume in 1 s (FEV 1 ), blood eosinophil counts (BEC), and fractional exhaled nitric oxide (FeNO) levels at baseline, and after 1, 6, and 12 months of treatment. Associations between trajectory-based clusters and clinical parameters were examined., Results: Among anti-IL5/IL5Rα antibody-treated patients, 2 clusters were identified. The cluster characterized by higher baseline BEC and lower FEV 1 showed a better response, with improvements in FEV 1 and reductions in BEC over time. Among anti-IL-4Rα antibody-treated, 3 clusters were identified. Clusters with moderate BEC and FeNO at baseline demonstrated better improvements in FEV 1 and reductions in FeNO, despite increased BEC during follow-up. Conversely, individuals with extremely low FeNO and high BEC at baseline were more likely to experience poorer progression, demonstrating an increase in FeNO and a reduction in FEV 1 ., Conclusion: To optimally monitor treatment response in SEA patients on type 2 biologics, integrating longitudinal biomarker features is essential., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s).)

Background: IL-17C has been described in a variety of inflammatory diseases driven by neutrophils. However, the role of IL-17C in neutrophilic asthma has not been completely characterized., Methods: The level of IL-17C in asthmatic patients and mice was assessed. Il-17c-deficient mice or mice treated with exogenous rmIL-17C were performed for OVA/CFA-induced asthmatic mice model. Pulmonary inflammation was evaluated by histological analysis, flow cytometry and cytokine analysis. Il-17re-overexpressed Raw264.7 were used in vitro to investigate the role of IL-17C in macrophage polarization., Results: Here, we show IL-17C were increased in serum or plasma from asthmatic patients and OVA/CFA-induced asthma mice. In the OVA/CFA-induced model, exogenous rmIL-17C aggravated neutrophil- and Type 17-dominated inflammation and promoted M1 macrophage differentiation, whereas deficiency of Il-17c reversed the pro-inflammatory phenotypes and inhibited the expansion of M1 macrophages. In vitro, IL-17C in synergy with IFN-γ induced STAT1 activation in Il-17re overexpressed Raw264.7 to upregulate M1-related genes expression, and promoted pro-inflammatory M1 polymerization, whereas IL-17C in contrast to the effect of IL-4 inhibited STAT6 activation, to reduce Raw264.7 differentiation to M2 macrophage and functional M2-related genes expression., Conclusions: IL-17C promotes allergic inflammation via M1 polarization of pulmonary macrophages in neutrophilic asthma. Modulation of the IL-17C/IL-17RE axis represents a novel therapeutic target in neutrophilic asthma., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The concept of cough hypersensitivity suggests that central sensitization plays a role in the pathophysiology of chronic cough. However, it remains unclear which traits are associated with central sensitization features in patients with chronic cough. A cohort of 317 Korean patients with newly referred chronic cough underwent clinical evaluations. The Central Sensitization Inventory (CSI), a questionnaire originally developed as a screening tool to identify patients with Central Sensitization Syndrome, was also administered. Other patient-reported outcomes (PROs), such as the cough severity visual analogue scale, Leicester Cough Questionnaire (LCQ), Cough Hypersensitivity Questionnaire (CHQ), and the Center for Epidemiological Studies Depression (CES-D) scale, were also administered. Follow-up assessments were conducted one month later. At baseline, the presence of CSI scores of ≥ 40 was associated with being female (89.6% vs. 63.4%; P < 0.001), older age, concomitant symptoms, and cough-related complications. CSI scores correlated with PRO scores, including LCQ ( r = -0.424, P < 0.001), CHQ ( r = 0.373, P < 0.001), and CES-D ( r = -0.660, P < 0.001). Their patterns of correlations were similar in the 1-month longitudinal follow-up data analysis. In conclusion, CSI scores in patients with chronic cough correlated with cough-specific and depression-related PROs, suggesting the potential relevance of central sensitization in certain phenotypes of chronic cough., Competing Interests: Kian Fan Chung has received honoraria for participating in Advisory Board meetings of Roche, Merck, Novartis, GSK, Nocion, Shionogi and Rickett-Beckinson and has also been renumerated for speaking engagements for Novartis and AZ. Woo-Jung Song declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi, and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi, and Novartis. Other authors declare that they have no competing interests., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: Treatment of chronic cough remains a challenge. We hypothesised that inhaled alkaline hypertonic divalent salts (alkaline HDS) might provide relief for refractory chronic cough by laryngeal and tracheal hydration., Methods: We conducted an exploratory, single-blinded, nasal saline-controlled study in 12 refractory chronic cough patients to examine cough suppression efficacy of an alkaline HDS composition (SC001) at pH 8 or pH 9 administered by nasal inhalation. As control, we used nasal saline with the same hand-held pump spray aerosol device. Each subject was monitored continuously using a digital cough monitor watch for 1 week of baseline, 1 week of control treatment and 1 week of active treatment., Results: Baseline daily cough rates ranged from 4 to 34 coughs·h -1 with mean visual analogue score 65±17 pre- and post-baseline testing. Control-adjusted efficacy of cough rate reduction ranged from 15% (p=0.015) (from Day 1) to 23% (p=0.002) (from Day 3). Control-adjusted efficacy was highest with SC001 pH 9 (n=5), ranging from 25% (p=0.03) (from Day 1) to 35% (p=0.02) (from Day 3), and lowest for SC001 pH 8 (n=7), ranging from 9% (p=0.08) (from Day 1) to 16% (p=0.02) (from Day 3). Hourly cough counts and visual analogue score correlated for baseline (r=0.254, p=0.02) and control (r=0.299, p=0.007) monitoring weeks. Treatment improved this correlation (r=0.434, p=0.00006). No adverse events were reported., Conclusions: Alkaline (pH 9) HDS aerosol is a promising treatment for refractory chronic cough and should be further evaluated., Competing Interests: Conflict of interest: H. Abubakar-Waziri has no conflicts to report. Conflict of interest: D.A. Edwards and D.B. Bhatta are founders and employees of Sensory Cloud Inc., the manufacturer of SC001. Conflict of interest: J.H. Hull is an associate editor of this journal. Conflict of interest: M. Rudd and P. Small are consultants to and employees of Hyfe Inc., the manufacturer of the digital cough monitor watch. Conflict of interest: K.F. Chung has received honoraria for participating in advisory board meetings of Roche, Merck, Shionogi and Rickett-Benckiser, and has been renumerated for speaking engagements for Novartis and AZ. K.F. Chung is also Scientific Adviser to Hyfe Inc. and Sensory Cloud Inc., (Copyright ©The authors 2024.)

Background: Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome., Methods: Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α-diversity of mild-moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS)., Findings: Fifty-one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n = 16), followed by Actinobacillus unclassified (n = 10), Veillonella unclassified (n = 9), Haemophilus aegyptius (n = 9), Streptococcus pseudopneumoniae (n = 7), Propionibacterium acnes (n = 5), Moraxella catarrhalis (n = 5) and Tropheryma whipplei (n = 5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n = 9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF-κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6-transignalling signature and neutrophil activation., Conclusion: We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Background: Anti-type 2 (T2) biologic therapies (biologics) improve exacerbation rates, lung function, and asthma-related quality of life (QoL) in patients with severe T2 asthma. However, studies comparing different biologics are lacking. We evaluated the QoL in patients with severe asthma comprehensively and compare the efficacy of different T2-directed biologics using QoL questionnaires., Methods: We compared the QoL between severe and mild-to-moderate asthma and between severe asthma with and without biologics treatment. Data of mild-to-moderate were extracted from the Cohort for Reality and Evolution of Adult Asthma in Korea, and data of severe asthma were collected from the Precision Medicine Intervention in Severe Asthma. We included 183 patients with severe asthma treated with T2 biologics or conventional therapy between April 2020 and May 2021 and assessed QoL of them using the Questionnaire for Adult Korean Asthmatics (QLQAKA), Severe Asthma Questionnaire (SAQ), and EuroQoL-5Dimensions (EQ-5D) at baseline and 6 months., Results: The EQ-5D index (0.803) of severe asthma was lower than that of other chronic diseases representing a worse QoL. The scores for all questions of QLQAKA, except "cough," were lower (less control) in the severe asthma group than in the mild-to-moderate asthma group at baseline and 6 months ( P  < 0.05). The total scores and subscores of all domains of the QLQAKA, SAQ, and EQ-5D improved significantly 6 months after biologic therapy but not after conventional therapy. The total QLQAKA, SAQ, and EQ-5D scores improved after 6 months in the anti-IL-5 ( P  < 0.05) and anti-IL-4/IL-13 ( P  < 0.05) treatment groups with no significant difference between groups ( P  > 0.05)., Conclusion: QoL was worse in severe asthma than in mild-to-moderate asthma and other chronic diseases. T2 biologics equally improved QoL in patients with severe asthma., Competing Interests: The authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Background: Clustering approaches using single omics platforms are increasingly used to characterise molecular phenotypes of eosinophilic and neutrophilic asthma. Effective integration of multi-omics platforms should lead towards greater refinement of asthma endotypes across molecular dimensions and indicate key targets for intervention or biomarker development., Objectives: To determine whether multi-omics integration of sputum leads to improved granularity of the molecular classification of severe asthma., Methods: We analyzed six -omics data blocks-microarray transcriptomics, gene set variation analysis of microarray transcriptomics, SomaSCAN proteomics assay, shotgun proteomics, 16S microbiome sequencing, and shotgun metagenomic sequencing-from induced sputum samples of 57 severe asthma patients, 15 mild-moderate asthma patients, and 13 healthy volunteers in the U-BIOPRED European cohort. We used Monti consensus clustering algorithm for aggregation of clustering results and Similarity Network Fusion to integrate the 6 multi-omics datasets of the 72 asthmatics., Results: Five stable omics-associated clusters were identified (OACs). OAC1 had the best lung function with the least number of severe asthmatics with sputum paucigranulocytic inflammation. OAC5 also had fewer severe asthma patients but the highest incidence of atopy and allergic rhinitis, with paucigranulocytic inflammation. OAC3 comprised only severe asthmatics with the highest sputum eosinophilia. OAC2 had the highest sputum neutrophilia followed by OAC4 with both clusters consisting of mostly severe asthma but with more ex/current smokers in OAC4. Compared to OAC4, there was higher incidence of nasal polyps, allergic rhinitis, and eczema in OAC2. OAC2 had microbial dysbiosis with abundant Moraxella catarrhalis and Haemophilus influenzae. OAC4 was associated with pathways linked to IL-22 cytokine activation, with the prediction of therapeutic response to anti-IL22 antibody therapy., Conclusion: Multi-omics analysis of sputum in asthma has defined with greater granularity the asthma endotypes linked to neutrophilic and eosinophilic inflammation. Modelling diverse types of high-dimensional interactions will contribute to a more comprehensive understanding of complex endotypes., Key Points: Unsupervised clustering on sputum multi-omics of asthma subjects identified 3 out of 5 clusters with predominantly severe asthma. One severe asthma cluster was linked to type 2 inflammation and sputum eosinophilia while the other 2 clusters to sputum neutrophilia. One severe neutrophilic asthma cluster was linked to Moraxella catarrhalis and to a lesser extent Haemophilus influenzae while the second cluster to activation of IL-22., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Purpose: Asthma is a clinical syndrome with various underlying pathomechanisms and clinical phenotypes. Genetic, ethnic, and geographic factors may influence the differences in clinical presentation, severity, and prognosis. We compared the characteristics of asthma based on the geographical background by analyzing representative cohorts from the United States, Europe, South America, and Asia using the Severe Asthma Research Program (SARP), Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED), Program for Control of Asthma in Bahia (ProAR), and Cohort for Reality and Evolution of Adult Asthma in Korea (COREA), respectively., Methods: The clinical characteristics and medications for the SARP (n = 669), U-BIOPRED (n = 509), ProAR (n = 996), and COREA (n = 3,748) were analyzed. Subgroup analysis was performed for severe asthma., Results: The mean age was highest and lowest in the COREA and SARP, respectively. The asthma onset age was lowest in the ProAR. The mean body mass index was highest and lowest in the SARP and COREA, respectively. Baseline pulmonary function was lowest and highest in the U-BIOPRED and COREA, respectively. The number of patients with acute exacerbation in the previous year was highest in U-BIOPRED. The mean blood eosinophil count was highest in COREA. The total immunoglobulin E was highest in the ProAR. The frequency of atopy was highest in the SARP. The principal component analysis plot revealed differences among all cohorts., Conclusions: The cohorts from 4 different continents exhibited different clinical and physiological characteristics, probably resulting from the interplay between genetic susceptibility and geographical factors., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2024 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Background: The impact of cigarette smoke (CS) on lung diseases and the role of microbiome dysbiosis in chronic obstructive pulmonary disease (COPD) have been previously reported; however, the relationships remain unclear., Methods: Our research examined the effects of 20-week cigarette smoke (CS) exposure on the lung and intestinal microbiomes in C57BL/6JNarl mice, alongside a comparison with COPD patients' intestinal microbiome data from a public dataset., Results: The study found that CS exposure significantly decreased forced vital capacity (FVC), thickened airway walls, and induced emphysema. Increased lung damage was observed along with higher lung keratinocyte chemoattractant (KC) levels by CS exposure. Lung microbiome analysis revealed a rise in Actinobacteriota, while intestinal microbiome showed significant diversity changes, indicating dysbiosis. Principal coordinate analysis highlighted distinct intestinal microbiome compositions between control and CS-exposed groups. In the intestinal microbiome, notable decreases in Patescibacteria, Campilobacterota, Defferibacterota, Actinobacteriota, and Desulfobacterota were observed. We also identified correlations between lung function and dysbiosis in both lung and intestinal microbiomes. Lung interleukins, interferon-ɣ, KC, and 8-isoprostane levels were linked to lung microbiome dysbiosis. Notably, dysbiosis patterns in CS-exposed mice were similar to those in COPD patients, particularly of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 patients. This suggests a systemic impact of CS exposure., Conclusion: In summary, CS exposure induces significant dysbiosis in lung and intestinal microbiomes, correlating with lung function decline and injury. These results align with changes in COPD patients, underscoring the important role of microbiome in smoke-related lung diseases., (© 2024. The Author(s).)

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 research avenues in order to better understand their role in disease pathogenesis, and identify novel therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Koranteng, Chung, Michaeloudes and Bhavsar.)

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 controls). Mothers of the COPD group had higher pregnancy smoking rates (COPD: n=305, 10.20%; controls: n=211, 7.10%; P<.001). TD was more prevalent in the COPD group (COPD: n=582, 40.40%; controls: n=478, 33.90%; P<.001). After adjusting for covariates, MSDP had a significant effect on COPD (β=.097; P<.001). There was an association between MSDP and TD (β=.074; P<.001) as well as between TD and COPD (β=.048; P=.007). Mediation analysis of TD in the MSDP-COPD association showed significant direct and indirect effects (direct: β=.094; P<.001 and indirect: β=.004; P=.03). The indirect effect remains present in the smoking population (direct: β=.120; P<.001 and indirect: β=.002; P=.03)., Conclusions: This study highlighted the potential association between MSDP and the risk of COPD in offspring, revealing the mediating role of TD in this association. These findings contribute to a deeper understanding of the impact of prenatal tobacco exposure on lung health, laying the groundwork for the development of relevant prevention and treatment strategies., (©Jinxuan Li, Jianying Xu, Lan Yang, Yongjian Xu, Xiangyan Zhang, Chunxue Bai, Jian Kang, Pixin Ran, Huahao Shen, Fuqiang Wen, Kewu Huang, Wanzhen Yao, Tieying Sun, Guangliang Shan, Ting Yang, Yingxiang Lin, Jianguo Zhu, Ruiying Wang, Zhihong Shi, Jianping Zhao, Xianwei Ye, Yuanlin Song, Qiuyue Wang, Gang Hou, Yumin Zhou, Wen Li, Liren Ding, Hao Wang, Yahong Chen, Yanfei Guo, Fei Xiao, Yong Lu, Xiaoxia Peng, Biao Zhang, Zuomin Wang, Hong Zhang, Xiaoning Bu, Xiaolei Zhang, Li An, Shu Zhang, Zhixin Cao, Qingyuan Zhan, Yuanhua Yang, Lirong Liang, Bin Cao, Huaping Dai, Kian Fan Chung, Zhengming Chen, Jiang He, Sinan Wu, Dan Xiao, Chen Wang, China Pulmonary Health Study Group. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 22.02.2024.)

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 late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance., (© 2024. The Author(s).)

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), 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)., Conclusions: Cough 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., (©Tingting Xu, Yuehan Chen, Wenzhi Zhan, Kian Fan Chung, Zhongmin Qiu, Kewu Huang, Ruchong Chen, Jiaxing Xie, Gang Wang, Min Zhang, Xuefen Wang, Hongmei Yao, Xiuqing Liao, Yunhui Zhang, Guojun Zhang, Wei Zhang, Dejun Sun, Jia Zhu, Shujuan Jiang, Juntao Feng, Jianping Zhao, Gengyun Sun, Huaqiong Huang, Jianyong Zhang, Lingwei Wang, Feng Wu, Suyun Li, Pusheng Xu, Chunhua Chi, Ping Chen, Mei Jiang, Wen He, Lianrong Huang, Wei Luo, Shiyue Li, Nanshan Zhong, Kefang Lai, China Cough Coalition. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 05.02.2024.)

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 residing in temperate climate zones. Climate change represents an emergent public health threat, affecting pediatric pneumonia treatment and prevention.., Systematic Review Registration: PROSPERO (CRD42022378610)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Makrufardi, Triasih, Nurnaningsih, Chung, Lin and Chuang.)

Background: Chronic 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)., Methods: We 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 of urge-to-cough sensation., Findings: Participants with chronic cough were significantly more sensitive to inhaled capsaicin and ATP and showed a change in relationship between urge-to-cough perception and cough induction. When urge-to-cough levels were matched, participants with chronic cough displayed significantly less neural activation in medullary regions known to integrate airway sensory inputs. By contrast, neural activations did not differ significantly between the two groups in cortical brain regions known to encode cough sensations whereas activation in a midbrain region of participants with chronic cough was significantly increased compared to controls., Interpretation: Cough hypersensitivity in some patients may occur in brain circuits above the level of the medulla, perhaps involving midbrain regions that amplify ascending sensory signals or change the efficacy of central inhibitory control systems that ordinarily serve to filter sensory inputs., Funding: Supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Pty Ltd. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme (Australia) Pty Ltd., Competing Interests: Declaration of interests SBM reports receiving grants from the National Health and Medical Research Council (NHMRC) of Australia and the Australian Research Council (ARC), Merck, Bellus Health and Reckitt Benkiser, and remuneration for consultancy from Merck, Trevi Therapeutics, Reckitt Benkiser and Nerre Therapeutics, has served on advisory committees for Reckitt Benkiser and has received payment from Reckitt Benkiser for assistance with manuscript writing. KFC reports research grants from Merck and GSK, remuneration for lectures from Novartis and AstraZeneca; has served on advisory boards for Roche, Merck, Reckitt Benckiser, and Shionogi & Co., Ltd., and a Data Safety Monitoring Board for Nocion. LMG reports research grants from Bayer AG, Bellus Health, Chiesi, Merck, and Shionogi, remuneration for lectures from Bayer AG, Bellus Health, Chiesi, GlaxoSmithKline, Merck, and Shionogi, remuneration for consultancy from Bayer AG, Bellus Health, Chiesi, Merck, NeRRe Therapeutics, Nocion Therapeutics, and Shionogi, and has served on advisory committees for Applied Clinical Intelligence, Bayer AG, Bellus Health, Chiesi, Merck, NeRRe Therapeutics, Nocion Therapeutics, and Shionogi and on a Data and Safety Monitoring Board for Bayer AG. All other authors declare no relevant conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The Ryukyu Islands of Japan are a biodiversity hotspot due to geographical and historical factors. Tricyrtis formosana is a perennial herbaceous plant that commonly found in Taiwan. But only a few populations have been identified in a limited habitat on Iriomote Island, while populations of unknown origin occur near human settlements in an area on the main island of Okinawa. To better understand these populations of the phylogenetic uniqueness and intrinsic vulnerability, we conducted comparative analyses including (1) phylogeny and population structure with MIG-seq data, (2) photosynthesis-related traits of plants grown under common conditions and (3) transcriptome analysis to detect deleterious variations. Results revealed that T. formosana was split into two clades by the congeners and that Iriomote and Okinawa populations independently derived from ancestral Taiwanese populations in each clade. Photosynthetic efficiency was lowest in the Iriomote population, followed by Okinawa and Taiwan. Transcriptome analysis showed that the Iriomote population accumulated more deleterious variations, suggesting intrinsic vulnerability. These results indicate that each T. formosana population in Japan is phylogenetically unique and has been independently dispersed from Taiwan, and that the Iriomote population presents a high conservation difficulty with a unique photosynthesis-related characteristic and a larger amount of deleterious variations., (© 2024. The Author(s).)

Background: Eosinophilic 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., Methods: Proteomic 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., Findings: We identified 13 serum proteins associated with eosinophilic asthma, including 7 (PAPP-A, TARC/CCL17, ALT/GPT, IgE, CCL28, CO8A1, and IL5-Rα) that were stably selected while adjusting for clinical factors yielding an AUC of 0.84 (95% CI: 0.83-0.84) compared to 0.62 (95% CI: 0.61-0.63) for clinical factors only. Sputum protein analysis selected only PAPP-A (AUC = 0.81 [95% CI: 0.80-0.81]). 12 serum proteins were associated with neutrophilic asthma, of which 5 (MMP-9, EDAR, GIIE/PLA2G2E, IL-1-R4/IL1RL1, and Elafin) complemented clinical factors increasing the AUC from 0.63 (95% CI: 0.58-0.67) for the model with clinical factors only to 0.89 (95% CI: 0.89-0.90). Our model did not select any sputum proteins associated with neutrophilic status., Interpretation: Targeted serum proteomic profiles are a non-invasive and scalable approach for subtyping of neutrophilic and eosinophilic asthma and for future functional understanding of these phenotypes., Funding: U-BIOPRED has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013), and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contributions (www.imi.europa.eu). ADEPT was funded by Johnson & Johnson/Janssen pharmaceutical Company., Competing Interests: Declaration of interests Prof M Chadeau-Hyam holds shares in the O-SMOSE company; consulting activities conducted by the company are independent of the present work. Prof Adcock reports consulting fees from GSK, Sanofi, Chiesi and Kinaset; speaker fees from AZ, Sanofi, Eurodrug and Sunovion; travel support from AZ; grants from GSK, MRC, EPSRC, Sanofi and NIEHS, which were independent of the present work. Dr. Dahlén reports consulting fees from Affiboby, AZ, Cayman Chemicals, GSK and Regeneron, and speaker fees from AZ, GSK and Sanofi, outside the submitted work. Prof Chung has received speaker fees from Novartis, AZ and Merck; honoraria for participating in Advisory Board meetings of GSK, Novartis, Roche, Merck, Trevi, Rickett-Beckinson, Nocion and Shionogi; and has received grants from MRC, EPSRC and GSK. Prof Chung is a member of the Scientific Advisory Board of the Clean Breathing Institute supported by Haleon. Dr Djukanovic declares consulting fees from Synairgen plc and lecture fees from GSK, ZenasBio and Celltrion. He holds shares from Synairgen and is Chair of the European Respiratory Society's Clinical collaboration on severe asthma (SHARP). The other authors have no conflict of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Older adults with asthma have the greatest burden and worst outcomes, and there is increasing evidence that chronic cough (CC) is associated with asthma severity and poor prognosis. However, the clinical characteristics of older adult patients with both asthma and CC remain largely unknown., Methods: Participants with stable asthma underwent two cough assessments within 3 months to define the presence of CC. Patients were divided into four groups based on CC and age (cut-off ≥60 years). Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to investigate asthma exacerbations. Logistic regression models were used to explore the interaction effect of CC and age on asthma control and exacerbations., Results: In total, 310 adult patients were prospectively recruited and divided into four groups: older CC group (n=46), older non-CC group (n=20), younger CC group (n=112) and younger non-CC group (n=132). Compared with the younger non-CC group, the older CC group had worse asthma control and quality of life and increased airflow obstruction. The older CC group showed an increase in moderate-to-severe exacerbations during the 12-month follow-up. There was a significant interaction effect of CC and ageing on the increased moderate-to-severe exacerbations (adjusted risk ratio 2.36, 95% CI 1.47-3.30)., Conclusion: Older asthma patients with CC have worse clinical outcomes, including worse asthma control and quality of life, increased airway obstruction and more frequent moderate-to-severe exacerbations, which can be partly explained by the interaction between CC and ageing., Competing Interests: Conflict of interest: W-J. Song is Deputy Chief Editor of this journal. The other authors declare that they have no relevant conflicts of interest., (Copyright ©The authors 2023.)

Background: Mitochondrial dysfunction and lung cellular senescence are significant features involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) stands as the primary contributing factor to COPD. This study examined mitochondrial dynamics, mitophagy and lung cellular senescence in COPD patients and investigated the effects of modulation of mitochondrial fusion [mitofusin2 (MFN2) and Optic atrophy 1 (OPA1)] on CS extract (CSE)-induced lung cellular senescence., Methods: Senescence-associated secretory phenotype (SASP) component mRNAs (IL-1β, IL-6, CXCL1 and CXCL8), mitochondrial morphology, mitophagy and mitochondria-related proteins (including phosphorylated-DRP1(p-DRP1), DRP1, MFF, MNF2, OPA1, PINK1, PARK2, SQSTM1/p62 and LC3b) and senescence-related proteins (including P16, H2A.X and Klotho) were measured in lung tissues or primary alveolar type II (ATII) cells of non-smokers, smokers and COPD patients. Alveolar epithelial (A549) cells were exposed to CSE with either pharmacologic inducer (leflunomide and BGP15) or genetic induction of MFN2 and OPA1 respectively., Results: There were increases in mitochondrial number, and decreases in mitochondrial size and activity in lung tissues from COPD patients. SASP-related mRNAs, DRP1 phosphorylation, DRP1, MFF, PARK2, SQSTM1/p62, LC3B II/LC3B I, P16 and H2A.X protein levels were increased, while MFN2, OPA1, PINK1 and Klotho protein levels were decreased in lung tissues from COPD patients. Some similar results were identified in primary ATII cells of COPD patients. CSE induced increases in oxidative stress, SASP-related mRNAs, mitochondrial damage and dysfunction, mitophagy and cellular senescence in A549 cells, which were ameliorated by both pharmacological inducers and genetic overexpression of MFN2 and OPA1., Conclusions: Impaired mitochondrial fusion, enhanced mitophagy and lung cellular senescence are observed in the lung of COPD patients. Up-regulation of MFN2 and OPA1 attenuates oxidative stress, mitophagy and lung cellular senescence, offering potential innovative therapeutic targets for COPD therapy., (© 2023. The Author(s).)

Background: Despite the increasing use of biologics in severe asthma, there is limited research on their use in asthma-chronic obstructive pulmonary disease overlap (ACO). We compared real-world treatment responses to biologics in ACO and asthma., Methods: We conducted a multicenter, retrospective, cohort study using data from the Precision Medicine Intervention in Severe Asthma (PRISM). ACO was defined as post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7 and a smoking history of >10 pack-years. Physicians selected biologics (omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab) based on each United States Food & Drug Administration (FDA) approval criteria., Results: After six-month treatment with biologics, both patients with ACO (N = 13) and asthma (N = 81) showed positive responses in FEV1 (10.69 ± 17.17 vs. 11.25 ± 12.87 %, P = 0.652), Asthma Control Test score (3.33 ± 5.47 vs. 5.39 ± 5.42, P = 0.290), oral corticosteroid use (-117.50 ± 94.38 vs. -115.06 ± 456.85 mg, P = 0.688), fractional exhaled nitric oxide levels (-18.62 ± 24.68 vs. -14.66 ± 45.35 ppb, P = 0.415), sputum eosinophils (-3.40 ± 10.60 vs. -14.48 ± 24.01 %, P = 0.065), blood eosinophils (-36.47 ± 517.02 vs. -363.22 ± 1294.59, P = 0.013), and exacerbation frequency (-3.07 ± 4.42 vs. -3.19 ± 5.11, P = 0.943). The odds ratio for exacerbation and time-to-first exacerbation showed no significant difference after full adjustments, and subgroup analysis according to biologic type was also showed similar results., Conclusions: Biologics treatment response patterns in patients with ACO and asthma were comparable, suggesting that biologics should be actively considered for ACO patients as well., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Author(s).)

Background: Delay in type II alveolar epithelial cell (AECII) regeneration has been linked to higher mortality in patients with acute respiratory distress syndrome (ARDS). However, the interaction between Doublecortin-like kinase 1 (DCLK1) and the Hippo signaling pathway in ARDS-associated AECII differentiation remains unclear. Therefore, the objective of this study was to understand the role of the DCLK1/Hippo pathway in mediating AECII differentiation in ARDS., Materials and Methods: AECII MLE-12 cells were exposed to 0, 0.1, or 1 μg/mL of lipopolysaccharide (LPS) for 6 and 12 h. In the mouse model, C57BL/6JNarl mice were intratracheally (i.t.) injected with 0 (control) or 5 mg/kg LPS and were euthanized for lung collection on days 3 and 7., Results: We found that LPS induced AECII markers of differentiation by reducing surfactant protein C (SPC) and p53 while increasing T1α (podoplanin) and E-cadherin at 12 h. Concurrently, nuclear YAP dynamic regulation and increased TAZ levels were observed in LPS-exposed AECII within 12 h. Inhibition of YAP consistently decreased cell levels of SPC, claudin 4 (CLDN-4), galectin 3 (LGALS-3), and p53 while increasing transepithelial electrical resistance (TEER) at 6 h. Furthermore, DCLK1 expression was reduced in isolated human AECII of ARDS, consistent with the results in LPS-exposed AECII at 6 h and mouse SPC-positive (SPC + ) cells after 3-day LPS exposure. We observed that downregulated DCLK1 increased p-YAP/YAP, while DCLK1 overexpression slightly reduced p-YAP/YAP, indicating an association between DCLK1 and Hippo-YAP pathway., Conclusions: We conclude that DCLK1-mediated Hippo signaling components of YAP/TAZ regulated markers of AECII-to-AECI differentiation in an LPS-induced ARDS model., (© 2023. The Author(s).)

Background: Current guidelines on the management of chronic cough do not provide recommendations for the operation of specialist cough clinics. The objective of the present study was to develop expert consensus on goals and standard procedures for specialist cough clinics., Methods: We undertook a modified Delphi process, whereby initial statements proposed by experts were categorised and presented back to panellists over two ranking rounds using an 11-point Likert scale to identify consensus., Results: An international panel of 57 experts from 19 countries participated, with consensus reached on 15 out of 16 statements, covering the aims, roles and standard procedures of specialist cough clinics. Panellists agreed that specialist cough clinics offer optimal care for patients with chronic cough. They also agreed that history taking should enquire as to cough triggers, cough severity rating scales should be routinely used, and a minimum of chest radiography, spirometry and measurements of type 2 inflammatory markers should be undertaken in newly referred patients. The importance of specialist cough clinics in promoting clinical research and cough specialty training was acknowledged. Variability in healthcare resources and clinical needs between geographical regions was noted., Conclusions: The Delphi exercise provides a platform and guidance for both established cough clinics and those in planning stages., Competing Interests: Conflict of interest: W-J. Song declares grants from Merck Sharp & Dohme Corp. and AstraZeneca, consulting fees from Merck, Bellus, AstraZeneca, Shionogi and GSK, and lecture fees from Merck, AstraZeneca, GSK, Sanofi and Novartis, outside the submitted work; and is Deputy Chief Editor of this journal. K.F. Chung has received honoraria for participating on advisory board meetings of GSK, AstraZeneca, Novartis, Merck, Nocion, Shionogi and Reckitt Benckiser, and on the scientific advisory board of the Clean Breathing Institute supported by GSK Health Care Consumer Products; he has also been remunerated for speaking engagements by AstraZeneca, Novartis and Merck. M. Dąbrowska reports fees from MSD for consultations on chronic cough and fees from Chiesi Poland for lectures on chronic cough. P. Dicpinigaitis reports consultant fees from Algernon, Boehringer Ingelheim, Bellus, Chiesi, Merck and Trevi, outside the submitted work. P.G. Gibson reports grant funding to his institution from GSK, MRFF and NHMRC; and funding to present educational lectures from AstraZeneca, GSK and Novartis, outside the submitted work. C.D. Ribas has acted as consultant for GSK, AstraZeneca and Sanofi; and has received funding for travel or speaker fees from ALK, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis, Stallergenes and Pfizer. J.H. Hull has received advisory fees from MSD Pharmaceuticals and is a medical advisor to Bellus Health; he is an Associate Editor of this journal. P. Kardos received personal consultation fees from Bayer, Klosterfrau, Merck Sharp & Dohme and Shionogi; honoraria for presentations from Bionorica, Engelhard, Klosterfrau, Merck Sharp & Dohme and Schwabe; and clinical trial participation fees from Bellus and Merck Sharp & Dohme. F. Lavorini received grants for research from Chiesi Farmaceutici, GSK and MSD Italy; and honoraria for talks or participation in advisory boards from AstraZeneca, Chiesi Farmaceutici, GSK, Menarini International, MSD Italy, HIKMA, Cipla and Trudell International. A.H. Morice has received consulting fees from Bayer, Bellus, Merck, NeRRi and Shionogi; lecture fees from Boehringer Ingelheim, Merck and Chiesi; and grant support from Bayer, Bellus, Merck, Nocion, Philips, NeRRi and Shionogi, outside the submitted work; and is an Associate Editor of this journal. A. Niimi reports grants from KYORIN Pharmaceutical Co., Ltd; payment or honoraria for speaker's fees from AstraZeneca K.K., KYORIN Pharmaceutical Co. Ltd, GSK K.K., Sanofi K.K. and Novartis Pharma K.K.; and participation on a data safety monitoring or advisory board of KYORIN Pharmaceutical Co., Ltd and MSD K.K. S.M. Parker reports advisory fees from Merck and Trevi. I. Satia reports grants and personal fees from Merck Canada, Bellus Health and GSK; clinical trial participation from Bayer; and personal fees from Respiplus, Genentech and AstraZeneca, outside the submitted work; and is an Associate Editor of this journal. The other authors declare that they have no competing interests., (Copyright ©The authors 2023.)