Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils.

Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation.

Asthma innovations from the second International Collaborative Asthma Network (ICAN) forum.

Asthma continues to cause morbidity and mortality despite advances in treatment that include biologics targeting Type 2 inflammation. The International Collaborative Asthma Network (ICAN) forum was developed with the primary goal of promoting innovative, collaborative research that focuses on mechanisms and treatment for asthma that does not respond or that responds poorly to currently available treatments. The mission of ICAN is innovation, collaboration, translation, and increasing high quality research. At the second ICAN meeting, presenters covered a broad scope and depth of asthma-related topics in the categories of complex data, novel therapeutics and diagnostics, breath analysis and microbiome, disease mechanisms, systemic effects, and circadian rhythm. Key actionable needs and research topics were identified during the group discussions. The presentations and discussions that occurred at the second ICAN had an immediate impact on asthma research in the form of new collaborations and implementation of new research ideas and techniques. The forum also served to connect early-stage investigators with investigators who are well established, thereby fostering innovation, translation, and collaboration well into the future. A third ICAN meeting is planned for 2025 to further the innovations and collaborations that will translate into novel therapies and diagnostics to improve the lives of patients with asthma.

Multivariate time series approaches to extract predictive asthma biomarkers from prospectively patient-collected diary data: a systematic review.

OBJECTIVES: Longitudinal data are common in asthma studies, to assess asthma progression in patients and identify predictors of future outcomes, including asthma exacerbations and asthma control. Different methods can quantify temporal behaviour in prospective patient-collected diary variables to obtain predictive biomarkers of asthma outcomes. The aims of this systematic review were to evaluate methods for extracting biomarkers from longitudinally collected diary data in asthma and investigate associations between them and patient-reported outcomes (PROs) of patients with asthma. DESIGN: Systematic review and narrative synthesis. DATA SOURCES: MEDLINE, EMBASE, CINAHL and the Cochrane Library were searched for studies published between January 2000 and July 2023. ELIGIBILITY CRITERIA: Included studies generated biomarkers from prospective patient-collected peak expiratory flow, symptom scores, reliever use and nocturnal awakenings, and evaluated their associations with asthma PROs, namely asthma exacerbations, asthma control, asthma-related quality of life and asthma severity. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers used standardised methods to screen and extract data from included studies. Study quality and risk of bias were assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) and the Prediction model Risk Of Bias ASessment Tool (PROBAST), respectively. RESULTS: 24 full-text articles met the inclusion criteria and were included in the review. Generally, higher levels of variability in the diary variables were associated with poorer outcomes, especially increased asthma exacerbation risk, and poor asthma control. There was increasing interest in non-parametric methods to quantify complex behaviour of diary variables (6/24). TRIPOD and PROBAST highlighted a lack of consistent reporting of model performance measures and potential for model bias. CONCLUSION: Prospectively patient-collected diary variables aid in generating asthma assessment tools, including surrogate endpoints, for clinical trials and predictive biomarkers of adverse outcomes, warranting remote monitoring. Studies consistently lacked robust reporting of model performance. Future research should use diary variable-derived biomarkers.

Correction: Enantioselective total synthesis of atisane diterpenoids: (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one.

Correction for 'Enantioselective total synthesis of atisane diterpenoids: (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one' by Dattatraya H. Dethe et al., Chem. Commun., 2024, 60, 7866-7869, https://doi.org/10.1039/D4CC01982B.

Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study - PHOSP-COVID.

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group. Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge.

Impact of comorbidities on EQ-5D quality-of-life index in severe asthma.

Background: Severe asthma pathology encompasses a wide range of pulmonary and extrapulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health-related quality-of-life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. Objective: We sought to examine the impact of pulmonary and extrapulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centers. Methods: Patients' characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. Results: Patients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extrapulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms, and requirement for maintenance oral corticosteroids were observed. Conclusions: Both pulmonary and extrapulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasizing the importance of early identification and management of severe asthma before comorbidities develop.

Nasal epithelial gene expression identifies relevant asthma endotypes in the ATLANTIS study.

INTRODUCTION: Asthma is an inflammatory airways disease encompassing multiple phenotypes and endotypes. Several studies suggested gene expression in nasal epithelium to serve as a proxy for bronchial epithelium, being a non-invasive approach to investigate lung diseases. We hypothesised that molecular differences in upper airway epithelium reflect asthma-associated differences in the lower airways and are associated with clinical expression of asthma. METHODS: We analysed nasal epithelial gene expression data from 369 patients with asthma and 58 non-asthmatic controls from the Assessment of Small Airways Involvement in Asthma study. Unsupervised hierarchical clustering was performed on asthma-associated genes. Asthma-associated gene signatures were replicated in independent cohorts with nasal and bronchial brushes data by comparing Gene Set Variation Analysis scores between asthma patients and non-asthmatic controls. RESULTS: We identified 67 higher expressed and 59 lower expressed genes in nasal epithelium from asthma patients compared with controls (false discovery rate<0.05), including CLCA1, CST1 and POSTN, genes well known to reflect asthma in bronchial airway epithelium. Hierarchical clustering revealed several molecular asthma endotypes with distinct clinical characteristics, including an endotype with higher blood and sputum eosinophils, high fractional exhaled nitric oxide, and more severe small airway dysfunction, as reflected by lower forced expiratory flow at 50%. In an independent cohort, we demonstrated that genes higher expressed in the nasal epithelium reflect asthma-associated changes in the lower airways. CONCLUSION: Our results show that the nasal epithelial gene expression profile reflects asthma-related processes in the lower airways. We suggest that nasal epithelium may be a useful non-invasive tool to identify asthma endotypes and may advance personalised management of the disease.

Enantioselective total synthesis of atisane diterpenoids: (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one.

Enantioselective total synthesis of (+)-sapinsigin H, (+)-agallochaol C, and (+)-16α, 17-dihydroxy-atisan-3-one has been accomplished starting from enantiopure Wieland-Miescher ketone. Key features of the syntheses include a benzannulation step to construct the tricyclic core, an oxidative dearomatization step to generate the diene, and a Diels-Alder reaction with ethylene gas to establish the bicyclo[2.2.2]octane framework. Efficient late-stage functionalisation of the A-ring by aerobic oxidation and Baeyer-Villiger oxidation completed the atisane target molecules.

Sex differences in asthma control, lung function and exacerbations: the ATLANTIS study.

BACKGROUND: Asthma is a heterogeneous disease with a prevalence and severity that differs between male and female patients. QUESTION: What are differences between male and female patients with asthma with regard to asthma control, lung function, inflammation and exacerbations? METHODS: We performed a post hoc analysis in the ATLANTIS (Assessment of Small Airways Involvement in Asthma) study, an observational cohort study including patients with asthma from nine countries with a follow-up of 1 year during which patients were characterised with measures of large and small airway function, questionnaires, inflammation and imaging. We compared differences in baseline characteristics and longitudinal outcomes between male and female patients with asthma. RESULTS: 773 patients were enrolled; 450 (58%) of these were female. At baseline, female patients with asthma were in higher Global Initiative for Asthma (GINA) steps (p=0.042), had higher Asthma Control Questionnaire 6 (F: 0.83; M: 0.66, p<0.001) and higher airway resistance as reflected by uncorrected impulse oscillometry outcomes (ie, R5-R20: F: 0.06; M: 0.04 kPa/L/s, p=0.002). Male patients with asthma had more severe airway obstruction (forced expiratory volume in 1 s/forced vital capacity % predicted: F: 91.95; M: 88.33%, p<0.01) and more frequently had persistent airflow limitation (F: 27%; M: 39%, p<0.001). Blood neutrophils were significantly higher in female patients (p=0.014). With Cox regression analysis, female sex was an independent predictor for exacerbations. INTERPRETATION: We demonstrate that female patients are in higher GINA steps, exhibit worse disease control, experience more exacerbations and demonstrate higher airway resistance compared with male patients. The higher exacerbation risk was independent of GINA step and blood eosinophil level. Male patients, in turn, have a higher prevalence of persistent airflow limitation and more severe airflow obstruction. These findings show sex can affect clinical phenotyping and outcomes in asthma. TRIAL REGISTRATION NUMBER: NCT02123667.

Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

The exhaled breath represents an ideal matrix for non-invasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review we will specifically address volatile organic compounds in the breath, with a view towards fulfilling the promise of these as actionable biomarkers, in particular for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward, if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

Discovery and Validation of a Volatile Signature of Eosinophilic Airway Inflammation in Asthma.

RATIONALE: Volatile organic compounds (VOCs) in asthmatic breath may be associated with sputum eosinophilia. We developed a volatile biomarker-signature to predict sputum eosinophilia in asthma. METHODS: VOCs emitted into the space above sputum samples (headspace) from severe asthmatics (n=36) were collected onto sorbent tubes and analysed using thermal desorption gas chromatography-mass spectrometry (TD-GC-MS). Elastic net regression identified stable VOCs associated with sputum eosinophilia ≥3% and generated a volatile biomarker signature. This VOC signature was validated in breath samples from: (I) acute asthmatics according to blood eosinophilia ≥0.3x109cells/L or sputum eosinophilia of ≥ 3% in the UK EMBER consortium (n=65) and U-BIOPRED-IMI consortium (n=42). Breath samples were collected onto sorbent tubes (EMBER) or Tedlar bags (U-BIOPRED) and analysed by gas-chromatography-mass spectrometry (GC×GC-MS -EMBER or GC-MS -U-BIOPRED). MAIN RESULTS: The in vitro headspace identified 19 VOCs associated with sputum eosinophilia and the derived VOC signature yielded good diagnostic accuracy for sputum eosinophilia ≥ 3% in headspace (AUROC (95% CI) 0.90(0.80-0.99), p<0.0001), correlated inversely with sputum eosinophil % (rs= -0.71, p<0.0001) and outperformed FeNO (AUROC (95% CI) 0.61(0.35-0.86). Analysis of exhaled breath in replication cohorts yielded a VOC signature AUROC (95% CI) for acute asthma exacerbations of 0.89(0.76-1.0) (EMBER cohort) with sputum eosinophilia and 0.90(0.75-1.0) in U-BIOPRED - again outperforming FeNO in U-BIOPRED 0.62 (0.33-0.90). CONCLUSIONS: We have discovered and provided early-stage clinical validation of a volatile biomarker signature associated with eosinophilic airway inflammation. Further work is needed to translate our discovery using point of care clinical sensors.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic Omalizumab in Severe Asthma in Adults: Results of the SoMOSA Study.

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting ß-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-ß-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

The effects of inhaled corticosteroids on healthy airways.

BACKGROUND: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. OBJECTIVES: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. METHODS: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. RESULTS: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. CONCLUSIONS: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.

Biochemical and In Silico Studies on Triazole Derivatives as Tyrosinase Inhibitors: Potential Treatment of Hyperpigmentation Related Skin Disorders.

INTRODUCTION: Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting in hyperpigmentary skin disorders, such as dark spots, melasma, freckles, etc. Therefore, inhibition of tyrosinase is a therapeutic approach for the treatment of hyperpigmentation. METHODS: The current study focused on evaluating tyrosinase inhibitory activities of triazole derivatives 1-20, bearing different substituents on the phenyl ring. 17 derivatives have shown a potent tyrosinase inhibition with IC50 values between 1.6 to 13 µM, as compared to the standard drug, i.e., kojic acid (IC50 = 24.1 ± 0.5 µM). Particularly, compounds 11 and 15 displayed 12 times more potent inhibitory effects than the kojic acid. RESULTS: The structure-activity relationship revealed that substituting halogens at the C-4 position of the benzene ring renders remarkable anti-tyrosinase activities. Compounds 1-3 and 8 showed a competitive type of inhibition, while compounds 5, 11, and 15 showed a non-competitive mode of inhibition. Next, we performed molecular docking analyses to study the binding modes and interactions between the ligands (inhibitors) and the active site of the tyrosinase enzyme (receptor). Besides this, we have assessed the toxicity profile of inhibitors on the BJ human fibroblast cell line. CONCLUSION: The majority of the newly identified tyrosinase inhibitors were found to be noncytotoxic. The results presented herein form the basis of further studies on triazole derivatives as potential drug leads against tyrosinase-related diseases.

Impact of sex on severe asthma: a cross-sectional retrospective analysis of UK primary and specialist care.

INTRODUCTION: After puberty, females are more likely to develop asthma and in a more severe form than males. The associations between asthma and sex are complex with multiple intrinsic and external factors. AIM: To evaluate the sex differences in the characteristics and treatment of patients with severe asthma (SA) in a real-world setting. METHODS: Demographic, clinical and treatment characteristics for patients with SA in the UK Severe Asthma Registry (UKSAR) and Optimum Patient Care Research Database (OPCRD) were retrospectively analysed by sex using univariable and multivariable logistic regression analyses adjusted for year, age and hospital/practice. RESULTS: 3679 (60.9% female) patients from UKSAR and 18 369 patients (67.9% female) from OPCRD with SA were included. Females were more likely to be symptomatic with increased Asthma Control Questionnaire-6 (UKSAR adjusted OR (aOR) 1.14, 95% CI 1.09 to 1.18) and Royal College of Physicians-3 Question scores (OPCRD aOR 1.29, 95% CI 1.13 to 1.47). However, they had a higher forced expiratory volume in 1 second per cent (FEV1%) predicted (UKSAR 68.7% vs 64.8%, p<0.001) with no significant difference in peak expiratory flow. Type 2 biomarkers IgE (UKSAR 129 IU/mL vs 208 IU/mL, p<0.001) and FeNO (UKSAR 36ppb vs 46ppb, p<0.001) were lower in females with no significant difference in blood eosinophils or biological therapy. Females were less likely to be on maintenance oral corticosteroids (UKSAR aOR 0.86, 95% CI 0.75 to 0.99) but more likely to be obese (UKSAR aOR 1.67, 95% CI 145 to 1.93; OPCRD SA aOR 1.46, 95% CI 1.34 to 1.58). CONCLUSIONS: Females had increased symptoms and were more likely to be obese despite higher FEV1% predicted and lower type 2 biomarkers with consistent and clinically important differences across both datasets.

An examination of factorial invariance of the Asthma Control Questionnaire among adults with severe asthma.

BACKGROUND: The Asthma Control Questionnaire (ACQ) is used to assess asthma symptom control. The relationship between the questionnaire items and symptom control has not been fully studied in severe asthmatic patients, and its validity for making comparisons between subgroups of patients is unknown. METHODS: Data was obtained from patients in the United Kingdom Severe Asthma Registry whose symptom control was assessed using the five-item ACQ (ACQ5) (n = 2,951). Confirmatory factor analysis determined whether a latent factor for asthma symptom control, as measured by the ACQ5, was consistent with the data. Measurement invariance was examined in relation to ethnicity, sex and age; this included testing for approximate measurement invariance using Bayesian Structural Equation Modelling (BSEM). The fitted models were used to estimate the internal consistency reliability of the ACQ5. Invariance of factor means across subgroups was assessed. RESULTS: A one-factor construct with residual correlations for the ACQ5 was an excellent fit to the data in all subgroups (Root Mean Square Error Approximation 0.03 [90%CI 0.02,0.05], p-close fit 0.93, Comparative Fit Index 1.00, Tucker Lewis Index 1.00}. Expected item responses were consistent for Caucasian and non-Caucasian patients with the same absolute level of symptom control. There was some evidence that females and younger adults reported wakening more frequently during the night than males and older adults respectively with the same absolute level of symptom control (p<0.001). However approximate measurement invariance was tenable and any failure to observe strong measurement invariance had minimal impact when comparing mean levels of asthma symptom control between patients of different sexes or ages. Average levels of asthma symptom control were lower for non-Caucasians (p = 0.001), females (p<0.01)and increased with age (p<0.01). Reliability of the instrument was high (over 88%) in all subgroups studied. CONCLUSION: The ACQ5 is informative in comparing levels of symptom control between severe asthmatic patients of different ethnicities, sexes and ages. It is important that analyses are replicated in other severe asthma registries to determine whether measurement invariance is observed.

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma.

BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium. OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy. METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes. RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma. CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95). Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay. Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels. Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.

Clinical Trial Design Innovations for Precision Medicine in Asthma.

Severe asthma is a spectrum disorder with numerous subsets, many of which are defined by clinical history and a general predisposition for T2 inflammation. Most of the approved therapies for severe asthma have required clinical trial designs with population enrichment for exacerbation frequency and/or elevation of blood eosinophils. Moving beyond this framework will require trial designs that increase efficiency for studying nondominant subsets and continue to improve upon biomarker signatures. In addition to reviewing the current literature on biomarker-informed trials for severe asthma, this chapter will also review the advantages of master protocols and adaptive design methods for establishing the efficacy of new interventions in prospectively defined subsets of patients. The incorporation of methods that allow for data collection outside of traditional study visits at academic centers, called remote decentralized trial design, is a growing trend that may increase diversity in study participation and allow for enhanced resiliency during the COVID-19 pandemic. Finally, reaching the goals of precision medicine in asthma will require increased emphasis on effectiveness studies. Recent advances in real-world data utilization from electronic health records are also discussed with a view toward pragmatic trial designs that could also incorporate the evaluation of biomarker signatures.

Eosinophils and tissue remodeling: Relevance to airway disease.

The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways.