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Journal articleNorth CM, Konstantinidis I, Attia EF, et al., 2026, , Ann Am Thorac Soc
People with HIV (PWH) are at increased risk of a broad range of infectious and non-infectious pulmonary diseases. Since the last ATS Workshop on HIV-associated pulmonary disease, large national and international cohorts have demonstrated ongoing gaps in our understanding of lung disease in this vulnerable population that range from underappreciation of disease incidence and prevalence to lack of targeted treatments. Translational work on the underlying mechanisms of disease has demonstrated novel, HIV-specific mechanisms that may lend themselves to tailored therapies. Twenty-four experts in HIV-associated lung disease from across the translational spectrum were invited to participate in this ATS-sponsored Workshop utilizing a modified Delphi method that included a series of pre- and post-workshop electronic surveys and a two-day virtual workshop. Lung disease among PWH is driven by complex and interrelated mechanisms including persistent immune dysregulation, oxidative stress, accelerated aging, and microbiome alterations. Despite these advances in our understanding, important gaps persist between mechanistic insights and clinical care that include limited HIV-specific trials, underrepresentation of PWH in studies of lung disease, and the absence of tailored care strategies. These gaps are further accentuated by substantial variation in the availability of data from the most affected populations, particularly in sub-Saharan Africa and among children and adolescents. Overcoming these challenges will require coordinated, globally representative research efforts that leverage large cohorts, integrate multi-omics and longitudinal phenotyping, use mechanistic insights to inform clinical trials, and consider implementation science approaches with the ultimate goal of developing tailored prevention and treatment strategies for HIV-associated pulmonary diseases.
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Journal articleFinney LJ, Lodge KM, 2026, , European Respiratory Journal, Vol: 68, Pages: 2601496-2601496, ISSN: 0903-1936
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Journal articleAlferes de Lima Headley D, Richardson H, Hennayake C, et al., 2026, , Eur Respir J
BACKGROUND: Acute COVID-19 alters the airway microbiota. Whether these changes persist post-COVID-19 and contribute to long COVID is unknown. We aimed to describe the microbiota by long COVID severity and subtype, and identify links with inflammation. METHODS: Adults were prospectively recruited to the longitudinal UK Post-hospitalisation COVID-19 study (PHOSP-COVID). Patients were grouped by previously described "severity clusters" (of ongoing health impairments) and symptom subgroups. Oral and sputum microbiota (at 6鈥卪onths post-discharge) were characterised through 16S ribosomal RNA gene amplicon sequencing, and microbiota diversity was assessed. Co-occurrence network analysis identified keystone taxa. Associations between keystone taxa and plasma inflammatory proteins were assessed through Spearman's rank correlations. RESULTS: 771 participants had their microbiota assessed. Of participants with oral rinses and "severity cluster" assignment (mean age 57.5鈥厃ears), 278 out of 722 (38.5%) were women. The "very severe" cluster, in which disease was predominantly pulmonary in nature, was associated with a distinct microbiota profile post-COVID-19. Reduced lung function was associated with a distinct oral microbiota profile. Persistent neurocognitive symptoms were associated with a distinct oral microbiota profile, while gastrointestinal symptoms were associated with a distinct sputum microbiota profile. Microbiota keystone taxa shifted to a higher prevalence of lactic acid bacteria associated with worse health outcomes. Lactic acid bacteria abundance was associated with elevated blood inflammatory proteins. CONCLUSION: Distinct oral and sputum microbiota profiles were associated with pulmonary function and with neurocognitive and gastrointestinal symptoms in long COVID. Shifts in keystone microbiota taxa linked with inflammation, based on worse health outcomes, suggest a potential role change for lactic acid bacteria, which may be a
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Journal articleDiaz-Nicieza C, Sahyoun L, Michalaki C, et al., 2026, , Immun Ageing, Vol: 23, ISSN: 1742-4933
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Journal articleCawthorne W, Zhang Y, Val N, et al., 2026, , Biochemical Society Transactions, Vol: 54, Pages: 1359-1373, ISSN: 0300-5127
Rhinovirus (RV) infection is responsible for the majority of cases of viral exacerbations of asthma. Understanding the cellular and molecular mechanisms that cause asthma exacerbations is an absolute requirement for the development of effective treatments. Emerging literature suggests that cell death may have an important role in RV-induced exacerbations. Several types of programmed cell death (PCD) have been implicated in asthma, including apoptosis, necroptosis, pyroptosis, and ferroptosis. Increased presence of apoptotic airway epithelial cells in the sputum of adult and paediatric asthma patients is suggestive of defects in apoptosis. Elevated levels of phosphorylated mixed lineage kinase domain-like protein and receptor-interacting serine/threonine-protein kinase 3, markers of active necroptosis, have been found in the serum of asthmatic patients. Gasdermin B, a member of the gasdermin family of pyroptosis executioner proteins, has a strong genetic linkage to severe asthma. Expression level of GSDMB correlated with asthma exacerbations and antiviral pathways. Lipid peroxidation and increased airway iron levels, both suggestive of ferroptosis, have been observed in asthma patients. RV infection of epithelial cells triggers an inflammatory response, which can provide the necessary pro-inflammatory chemokines and cytokines to initiate PCD, such as tumour necrosis factor-α. RV exploits PCD such as apoptosis, necroptosis, pyroptosis, and ferroptosis to aid its replication and release, while modulating them probably to limit immune response. In the present review, we investigate the concept that pro-inflammatory PCD pathways modulated by RV infection in the context of asthma lead to prolonged inflammatory and immune responses that are key to asthma exacerbations.
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Journal articleGuo H, Li J, Lei M, et al., 2026,
The circadian rhythm gene BHLHE40 regulates inflammation in asthma patients and promotes ferroptosis through PTGS2 and SERPINB2 in lung fibroblast cells
, BMC Pulmonary Medicine, ISSN: 1471-2466BackgroundCircadian rhythm transcription factor basic helix-loop-helix family member e40 (BHLHE40) is a core regulator in the transcriptional response in immunoglobulin class switching to IgE. We describe here the results of our systematic investigations of BHLHE40 in inflammatory responses in lung epithelial cells and fibroblast cells, and particularly for its role in ferroptosis.MethodsBHLHE40 levels in serum and transcript levels in human peripheral blood mononuclear cells (PBMC) from asthma patients and healthy controls were quantified. BHLHE40 was silenced by siRNAs in human airway epithelial A549 cells and human lung fibroblast MRC5 cells. RNA sequencing was performed with BHLHE40-silenced MRC5 cells. Gene silencing or overexpression models for BHLHE40, PTGS2 and SERPINB2 were established with MRC5 cells. MRC5 cells were co-stimulated by lipopolysaccharide (LPS) and IL-13. Apoptosis, reactive oxygen species (ROS), Fe2+, lipid peroxide (LPO), malondialdehyde (MDA) and glutathione (GSH) levels were quantified. Levels of HMGB-1, IL-4, IL-6 and TNF-α in supernatants were measured by ELISAs. Expression levels of BHLHE40, GPX4, SLC7A11, PTGS2, and SERPINB2 were determined by qPCRs and Western blotting. RNA immunoprecipitation and dual-luciferase reporter assays were applied to detect gene interactions.ResultsBHLHE40 protein levels in serum and BHLHE40 transcript levels in PBMC were higher in asthma patients compared to the control group (P<0.001 and P<0.0001, respectively). BHLHE40 transcript levels were correlated with neutrophil counts in blood, FEV1%pred, PEF and FeNO levels in asthma patients. Silencing BHLHE40 in A549 and MRC5 cells resulted in a decrease of IL-6 and IL-8 levels after stimulation of IL-1β. Transcriptomic analysis for BHLHE40-silenced MRC5 cells showed 506 up-regulating genes and 512 down-regulated genes, which contained PTGS2 and SERPINB2. PTGS2 and SERPINB2 were highly expressed in asthma samples and positively correlated
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Journal articleFore F, Bagley DC, Martinez-Nunez RT, et al., 2026, , Sci Adv, Vol: 12
Epithelial barriers represent the first line of defense against pathogens, yet their role in innate immunity is typically relegated to pathogen detection and immune cell recruitment. This perspective ignores a fundamental biological principle: Epithelia defended against pathogens long before complex immune systems evolved. Here, we demonstrate that human bronchial epithelium retains this ancestral capacity, autonomously clearing rhinovirus (RV) within 24 hours by selectively extruding infected cells, a process that we term virus-induced cell extrusion (VICE). VICE occurs in two waves: a rapid response occurring independently of complete virus entry, followed by a replication-dependent wave. Barrier-defective epithelia that cannot extrude do not eliminate RV. While VICE maintains barrier integrity and reduces local infection, it also expels virus-laden cells, which can infect fresh epithelia. Thus, VICE enables leukocyte-independent epithelial defense while inadvertently promoting viral spread, redefining epithelia as central to viral pathogenesis and host protection.
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Journal articleConway F, Finney L, 2026, , Thorax
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Journal articleMa J, Burney P, Mannino D, et al., 2026, , Thorax, ISSN: 0040-6376
This study estimated birth cohort effects on lung function using BOLD data from 28,569 adults born between 1902 and 1976 across 41 sites in 34 countries. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the FEV1/FVC increased across successive birth cohorts in both high-income countries (HICs) and low- and middle-income countries (LMICs), with mean values rising steadily with later birth year. In fully adjusted models, FVC increased by 21.4 mL, FEV1 by 24.6 mL, and FEV1/FVC by 0.25% per birth year. These positive associations were consistent across sex, smoking status, and country-income subgroups (HICs and LMICs).
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Journal articleOzoh O, Owusu SK, Nantanda R, et al., 2026,
Prevalence of asthma among African children and adolescents: findings from the chronic respiratory disease observatory for Africa (CHEST-Africa)
, Thorax, ISSN: 0040-6376 -
Journal articleThorarinsdottir E, Benediktsd贸ttir B, Aspelund T, et al., 2026, , BMJ Open, Vol: 16, ISSN: 2044-6055
Objectives To estimate uptake of obstructive sleep apnoea (OSA) screening and initiation and long-term use of positive airway pressure (PAP) treatment in a middle-aged and older general population cohort.Design Prospective population-based cohort study.Setting Icelandic arm of the multinational Burden of Obstructive Lung Disease follow-up study II (2019–2021)Participants 378 non-institutionalised adults aged 54–91 years were invited from a general population cohort. 26 with prior OSA diagnosis were excluded. Of the remaining participants, 334 (88.4%) completed a technically adequate home sleep apnoea test.Interventions Those with an apnoea–hypopnoea index (AHI)≥15 events/hour were invited for clinical evaluation and when appropriate, referred for PAP treatment. Adherence was assessed 2 years after PAP initiation.Main outcome measures Primary outcomes were screening uptake and PAP initiation. Secondary outcomes included long-term PAP use and objective adherence 2 years after referral.Results AHI≥15 was identified in 132/334 participants (39.5%). Of these, 123 (93.2%) attended clinical evaluation and 99 (75.0%) were referred for PAP treatment. Of those not referred, six declined PAP and the remainder were advised alternative management or reassessment. At 2-year follow-up, 53/99 (53.5%) were long-term PAP users, 43/99 (43.4%) had discontinued and 3/99 (3.0%) never initiated PAP. Objective adherence data were available for 47/53 long-term users; 21/47 (44.7%) met adherence criteria (≥4 hours/night on ≥70% of nights in the preceding 30 days).Conclusions Most adults accepted OSA screening when offered. Among those with moderate-to-severe OSA identified through population screening, most accepted evaluation and PAP treatment, with approximately half becoming long-term users. These findings suggest that population-based detection of OSA followed by routine clinical management is feasible. Future studies should identify subgroups most li
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Journal articleMoffatt MF, Nishimura T, Cox MJ, et al., 2026, , American Journal of Respiratory and Critical Care Medicine, Vol: 212, Pages: 1962-1974, ISSN: 1073-449X
RationaleAsthma is characterized by disruption of the thoracic airway mucosae and loss of microbial diversity. Spatial profiling of the mucosal transcriptome may systematically discover mechanisms for microbial influences on immunity.ObjectivesWe investigated relationships between clinical measures, microbial communities, and the host mucosal transcriptome within different strata of bronchial biopsies in subjects with and without asthma.MethodsWe bronchoscoped 65 adult asthmatics and 44 healthy controls, quantifying bacterial operational taxonomic units (OTUs) in bronchial brushings by 16S rRNA gene amplicon sequences. Biopsy histologic features were scored blind to diagnosis. Following 16S rRNA in situ hybridization of 44 biopsies, bacterial foci were scored in epithelium, basement membrane and stroma. Global human gene expression was quantified in epithelial and stromal compartments using Digital Spatial Profiling.Measurements and main resultsClinical asthma was independently predicted by basement membrane abnormalities (BaseMA), endobronchial bacterial diversity and circulating eosinophil counts, but not by specific OTU abundances. 16S rRNA staining revealed bacteria within epithelium and mucosa of all biopsies. Intra-mucosal bacteria (IMCBs) counts correlated negatively with spatially organized co-expression networks encoding antigen-specific immunity, neutrophil functions, and matrix activation, whereas BaseMA correlated positively with the adaptive immunity module. Eosinophil counts correlated with epithelial bacterial counts and senescence pathways. Clinical asthma was accompanied by upregulation of a Treg cell network.ConclusionsAsthma and its related phenotypes are accompanied by complex mucosal events that extend beyond eosinophilic pathways. Components of diverse airway microbiota may modify immunity by beneficial interactions within the mucosa.
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Journal articleBaraldi F, Mah JSY, Almuhanna A, et al., 2026, , Am J Respir Crit Care Med, Vol: 212, Pages: 2071-2074
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Journal articleMa J, Quintero Santofimio V, Potts J, et al., 2026, , Chest, Vol: 170, Pages: 752-754, ISSN: 0012-3692
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Journal articleBell RV, Faulkner NB, Sinadinos A, et al., 2026, , Gene Ther, Vol: 33, Pages: 586-595
In pursuit of a gene transfer agent with efficient pulmonary transduction, the UK Respiratory Gene Therapy Consortium has developed a lentiviral vector pseudotyped with the envelope proteins, F and HN from Sendai virus (rSIV.F/HN). In contrast to other viral vectors, pulmonary rSIV.F/HN delivery achieves sustained gene expression ( ~ 2 years in mice) in the lungs and systemic circulation following a single dose. Here, we investigate the application of the rSIV.F/HN vector-platform for wider indications, including systemic disorders that require serum expression of therapeutic proteins. To assess the potential for rSIV.F/HN to produce systemic proteins, intravenous vector delivery was characterised and compared against intrapulmonary administration, achieved via 'nasal sniffing'. Both delivery routes achieved sustained (at least 1 year) systemic expression of the secreted reporter protein Gaussia luciferase. Systemic rSIV.F/HN delivery resulted in widespread protein expression across multiple organs, accompanied by the generation of significant anti-vector neutralising antibodies limiting vector readministration. Conversely, localised airway transduction was observed following pulmonary administration, which we have previously shown is not an impediment to efficient vector readministration. These data support intrapulmonary rSIV.F/HN delivery for systemic protein production, with sustained high-level transgene expression and feasible readministration.
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Journal articleJohannson KA, Barnes H, Peters CE, et al., 2026, , CHEST Pulm, Vol: 4
BACKGROUND: Many interstitial lung diseases (ILDs) are associated directly or indirectly with inhaled environmental and/or occupational exposures; exposure identification is critical for diagnosis and clinical management. However, there are currently few evidence-informed exposure questionnaires for ILD, and none are in widespread systematic use. This study sought to develop an evidence-informed ILD exposure questionnaire, leveraging international expert-based consensus on exposures that present relevant risk for ILD development. RESEARCH QUESTION: What environmental and occupational exposures are risk factors for the development of ILD and should be included on ILD-specific exposure questionnaires? STUDY DESIGN AND METHODS: Participants with expertise in ILD, occupational respiratory medicine, or exposure assessment were invited to complete 2 rounds of a modified Delphi survey to identify relevant exposures associated with the risk of developing ILD. Items in the first Delphi round were informed by prior data, including a systematic review/meta-analysis and scoping review of questionnaires. Items not meeting consensus in the first round were carried over to the second round, with additional items added or modified as suggested by participants. Well-established causal exposures were not included. A priori definitions of consensus were applied, indicating response distribution. RESULTS: A total of 38 of 43 experts (88%) participated in the Delphi survey, with 37 of 38 (97%) completing both rounds. A total of 11 exposures met consensus for agreement as relevant risk factors for ILD, whereas 9 met consensus for disagreement as being irrelevant to ILD risk. Six exposures did not achieve consensus. Incorporating these findings with prior evidence syntheses, we developed 2 exposure questionnaires (EXPO-ILD-Short and EXPO-ILD-Long) for ILD for application in both clinical and research settings. INTERPRETATION: This international modified Delphi identified clinically releva
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Journal articleJackson R, Bentley S, Davies JC, et al., 2026, , Paediatr Respir Rev, Vol: 59, Pages: 12-19
The availability of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators has transformed outcomes for people with cystic fibrosis (pwCF). Eligibility, conferred initially by clinical trial data, has evolved through advances in in vitro 'theratyping' and use of real鈥憌orld evidence. Since ivacaftor's approval for a single gating variant in 2012, eligibility has broadened to over 180 variants with the highly effective therapies elexacaftor/tezacaftor/ivacaftor and recently launched vanzacaftor/tezacaftor/deutivacaftor. Regulatory authorities have increasingly accepted non鈥憈raditional evidence, notably the FDA's 2017 ivacaftor extension based on cell鈥慴ased assays and, in 2025, the EMA's decision to extend elexacaftor/tezacaftor/ivacaftor to people ≥2 years with at least one non class I variant. However, clinical response remains variable, influenced in part by baseline characteristics, pharmacokinetics, pharmacogenetics, and environmental exposures. We outline evolving approaches to determining eligibility and strategies to improve methods to predict, verify, and monitor clinical response in an era of personalised medicine.
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Journal articleLawton A, Hughes D, 2026, , Paediatr Respir Rev, Vol: 59, Pages: 44-49
Proponents of artificial intelligence (AI) believe that it will revolutionise the modern world, affecting how healthcare is delivered and improve both the clinical care we provide and the ease with which we perform our work. In this paper we explain what is meant by 'artificial intelligence' and explore how this technology has been implemented, or might be implemented, with respect to paediatric respiratory medicine. We review the current literature on how AI has been used to improve diagnostics - including examples in radiology, primary ciliary dyskinesia (PCD) diagnostics, sleep medicine, and pulmonary function tests. We also review how AI has been applied to therapeutics and drug discovery, how it will impact evidence-based medicine and literature review, and how clinician support tools will assist us in our work.
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Journal articleAndersson LI, Kupczyk M, Dahl茅n B, et al., 2026, , Allergy, Vol: 81, Pages: 3206-3220
BACKGROUND: Obesity-related asthma (OBA) is a distinct asthma phenotype, with increased severity. Adipokine release from excessive adipose tissue is suggested to be a key feature of OBA pathophysiology. However, it is unclear how the clinical characteristics of severe asthma associate with adipokine mediators. We examined systemic adipokine levels and evaluated relationships with disease severity, weight, sex, and steroid treatment in asthma. METHODS: A multiplex immunoassay for nine adipokines with proposed involvement in obesity-related inflammation (adiponectin, adipsin, BAFF, chemerin, FGF-21, leptin, lipocalin-2/NGAL, osteonectin and resistin) was designed. Plasma adipokines were measured in 127 patients with mild-to-moderate asthma (MMA) or severe asthma (SA) from the European BIOAIR cohort at baseline and after a controlled 2-week oral corticosteroid (OCS) intervention. RESULTS: Leptin and chemerin were significantly increased in patients with SA vs. MMA. Leptin, adiponectin, adipsin, and NGAL were affected by sex, whereas leptin and adipsin were strongly affected by weight. OCS increased leptin and adiponectin, decreased adipsin and BAFF, and did not affect osteonectin, resistin, or chemerin. No adipokines showed positive associations with exhaled NO, blood or sputum eosinophils, although certain correlations with serum CRP, blood, and sputum neutrophils were observed. CONCLUSIONS: Overall, we observe variable relationships between the nine adipokines, obesity and asthma severity. There were no relationships between adipokine levels and type-2 airway inflammation, yet associations with systemic neutrophilic inflammation were seen. Although one adipokine, chemerin, was independently associated with asthma severity, deciphering the role of adipokines in OBA is complex due to the influence of sex, BMI, and OCS.
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Journal articleFinney LJ, Conway FM, Sethi DK, 2026, , Pulm Ther, Vol: 12, Pages: 763-783
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is entering a new era in precision medicine. Advances in disease endotyping have challenged the traditional view of COPD as a uniformly neutrophilic disorder and revealed biologically distinct subgroups in whom targeted immunomodulation may be effective. Reproducible signatures of type 2 (T2) inflammation and epithelial-derived alarmin activation have emerged as actionable pathways, reshaping therapeutic development in COPD. This narrative review synthesises mechanistic insights and clinical trial evidence for biologic therapies targeting key T2 cytokines such as interleukin-5 (IL-5) IL-4/IL-13 and upstream epithelial alarmins, including interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). We examine why earlier approaches targeting neutrophilic inflammation failed, and how biomarker-driven trial design has enabled success in selected populations. Across these programmes, therapeutic efficacy has depended not only on the pathway targeted but also on patient selection, disease stage and timing of intervention. We propose that the future of biologics in COPD lies in integrating biomarkers, treatable traits and longitudinal phenotyping to align the right patient with the right pathway at the right time, closing persistent treatment gaps in this common, overlooked and burdensome disease.
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