INTRODUCTION: In randomized controlled trials (RCTs), many patients receiving placebo show improvement in clinical outcomes including lung function. Regression to the mean and increased adherence to medication are potential explanatory mechanisms. Given that type-2 inflammation is a treatment-responsive characteristic, we hypothesized that baseline type-2 biomarker levels (blood eosinophil count (BEC) and exhaled nitric oxide (FeNO)) are associated with the magnitude of lung function improvement over time in the placebo groups in RCTs. METHODS: The OxfoRd Asthma attaCk risk scaLE (ORACLE2) patient-level meta-analysis dataset was used to identify prognostic variables associated to lung function changes. The dataset includes control arms of 22 RCTs assessing fixed treatment regimens on asthma exacerbation rates over at least 24 weeks. We excluded open-label RCTs, and we excluded trials missing Forced Expiratory Volume in 1 second (FEV1) at the 52-week follow-up. Multiple imputation by chained equations was used for others missing values in 10 iterations. Lung function change was defined as the change in FEV1 (mL) over one year. Adjusted regression coefficients (aRC)[95% confidence intervals (CI)] were computed using linear regression. Interactions terms between in FeNO and BEC was assessed in this model and restricted cubic spline curves were plotted to visualize the potential interaction. RESULTS: Patients with moderate-to-severe asthma (n=2,675), from 9 RCTs with a placebo arm were included. An improvement in lung function was observed in the placebo group across trials. Factors associated with lung function change (ΔFEV1 (mL)) included (aRC [95%CI]) (Figure A): FeNO (per 10-fold increase: 67 ml [28-107]), age (per 10-year increase: -42 ml [-53--31]), baseline FEV1 (per 10% decrease: 54 ml [44-64]), FEV1 reversibility (per 10% increase: 128 ml [114-142]), and presence of nasal polyposis (40 ml [0-80]). FeNO and BEC have a significant positive interaction (interaction term [95%CI]: 133[24-242]) (Figure B). CONCLUSION: Type 2 inflammatory biomarkers, particularly FeNO, emerged as a factor associated with lung function improvement on placebo in asthma trials. Low adherence in pre-trial among patients with high FeNO may partially explain the observed lung function improvements in this group within the placebo arm of RCTs. Further research is needed to understand the mechanisms underlying this observation and its impact on the outcomes of RCTs. REGISTRATION: PROSPERO-CRD42021245337 JSP&SML= co-primary authors

INTRODUCTION: Preventing attacks is a key goal in asthma management. The type-2 inflammatory biomarkers blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) are established and modifiable risk factors. Given the complexity and multifaceted nature of asthma, we hypothesized that their prognostic value might vary based on interactions with clinical risk factors. METHODS: We analyzed data from the OxfoRd Asthma attaCk risk scaLE (ORACLE2) patient-level meta-analysis, which includes placebo participants from 22 randomized controlled trials (RCTs) investigating the effects of fixed treatment regimens on severe asthma attack rates over a minimum of 24 weeks. Multiple imputation by chained equations was used for missing values in 10 iterations. Multivariable negative binomial models were fit to assess interactions between inflammatory biomarkers (FeNO and BEC) and other key risk factors, such as the Global Initiative for Asthma (GINA) treatment step, Asthma Control Questionnaire (ACQ)-5 score, attack history, and forced expiratory volume in 1 second (FEV1). A Benjamini-Hochberg procedure adjusted for multiplicity of testing (false discovery rate (FDR)<0.05 significant). Spline curves were plotted to visualize significant interactions. As an exploratory analysis, other potential interactions between asthma attacks risk factors and baseline characteristics were evaluated (FDR<0.05). RESULTS: The 6,513 analysed participants experienced 4615 attacks over 5482 person·years. BEC (per 10-fold increase) was found to interact with FEV1 (per 10% decrease) (interaction term: 1.11 [1.03; 1.21], p-value = 0.01). FeNO (per 10-fold increase) negatively interact with a low treatment step (GINA step 1-2 versus GINA step 3-5) (0.28 [0.11; 0.68], p-value = 0.005) and positively interact with a history of severe attacks in the last 12 months (2.42 [1.51; 3.87], p-value = 2×10⁻⁴). The spline curves illustrated the prognostic value of these inflammatory biomarkers according to subgroups based on the identified interactions (Figure A-C). In an exploratory analysis, a strong positive interaction between Immunoglobulin E (IgE) (per 10-fold increase) and a positive history of nasal polyposis was identified (1.58 [1.25; 1.98], p-value = 9×10⁻⁵). The spline curve illustrated the dichotomous prognostic value of IgE on asthma attack risk according to the presence (n=584) or absence (n=3522) of nasal polyposis (Figure D). CONCLUSIONS: This analysis underscores the complex interactions between inflammatory biomarkers and other asthma attack risk factors. The prognostic value of BEC is stronger in those with reduced lung function, while FeNO's prognostic value depends on recent attack history and treatment step. A potential prognostic interaction between IgE and nasal polyposis was also identified. Registration:PROSPERO-CRD42021245337

BACKGROUND:Targeted type 2 (T2) biologics have transformed asthma care, but the clinical response to biologic therapy varies between patients. OBJECTIVE:We sought to assess airways inflammation in T2-high asthmatic patients treated with anti-IL-5 biologics to investigate whether differential mechanism of airway inflammation explains varied response to biologics. METHODS:Proteomic analysis (Olink, 1463 protein panel) and high-sensitivity cytokine analysis (ELISAs) were performed on induced sputum from T2-high severe asthmatic patients in the UK multicenter Mepolizumab EXacerbation study. Samples included were pre-mepolizumab (n = 28), stable on mepolizumab (n = 43), and at first exacerbation (n = 26). RESULTS:Clustering of sputum proteins while stable on mepolizumab identified 2 clusters. Cluster 1 had increased differentially expressed sputum proteins pre-mepolizumab, stable on mepolizumab, and at exacerbation. Patients in cluster 1 were younger at diagnosis, had a longer duration of asthma, lower FEV1%, and higher 5-Question Asthma Control Questionnaire score on mepolizumab. Cluster 1 had increased expression of proinflammatory cytokines (IL-1β, IL-6, and soluble IL-6R), epithelial alarmins (thymic stromal lymphopoietin [TSLP] and IL-33), and neutrophil activation (myeloperoxidase [MPO], neutrophil elastase [NE], and neutrophil extracellular trap concentration [NET]). All patients were T2-high with no difference in fractional exhaled nitric oxide, eosinophil number, or activity (eosinophil-derived neurotoxin, EDN) across the 2 clusters. CONCLUSIONS:In a cohort of T2-high severe asthmatic patients, a subgroup of patients with long duration of disease had worse clinical parameters, increased sputum proteins with increased markers of neutrophil activity, proinflammatory cytokines, and epithelial alarmins even when stable on mepolizumab. This suggests the presence of biology not treated by targeted T2 biologics, which may contribute to poorer outcomes on biologics and could be a treatable airways trait in severe asthma.

Introduction: Patients with type 2 (T2) low airway disease such as asthma poorly respond to current inhaled corticosteroid therapy and biologics targeting T2 inflammation. In addition, T2 low airways are prone to be colonized by bacterial pathogens. Fractional exhaled nitric oxide (FeNO) is an established biomarker for T2 inflammation based on IL-4Rα-mediated upregulation of nitric oxide synthase (NOS2) and subsequent NO release by epithelial cells. Conversely, pharmacologic inhibition of IL-4Rɑ signaling in asthma reduces FeNO. We have identified a mutually exclusive relationship between elevated FeNO levels and high airway load of Haemophilus influenzae in asthmatic patients with frequent exacerbations. Given that nasal epithelial NO production mediates bacterial killing in co-culture experiments in vitro we hypothesized that bronchial epithelial NO has a direct antimicrobial function and underlies the microbial and FeNO relationship. We examined whether bacterial killing is enhanced by acute NOS2 induction mediated by IL-13 treatment of normal human bronchial epithelial cells (NHBECs). Methods: Primary NHBECs differentiated at air-liquid interface (ALI) culture were stimulated with IL-13 (20 ng/mL) for 24 h. A non-typeable strain of H. influenzae (NTHi) was co-cultured on the apical surface of terminally differentiated NHBECs for 4 h with or without an iNOS pharmacological inhibitor, L-NAME. Bactericidal activity of NHBECs was assessed by flow cytometry-based BacLight assay and was further validated by counting colony forming units (CFU) plated after co-culture. Expression of T2 signature genes in NHBECs was studied using qPCR. Results: Acute treatment of fully differentiated NHBECs with IL-13 induced a significant upregulation of NOS2, along with T2 gene signature genes, POSTN, SERPINB2, and CLCA1. This condition was associated with increased extracellular antibacterial potential of NHBECs as evident by 8-fold reduction in CFU count of NTHi and elevation of dead bacterial population in flow cytometry analysis. Mechanistically, IL-13-induced antibacterial activity of NHBECs was suppressed upon iNOS blockade, by L-NAME, suggestive of an NO-dependent antibacterial mechanism of action. IL-13 and L-NAME did not directly affect planktonic growth of NTHi in the absence of NHBECs suggestive of no direct bactericidal activity of IL-13 on this pathogen. Conclusions: Bronchial epithelial release of extracellular NO mediated by IL-4Rɑ signaling has antimicrobial function in vitro and may mechanistically underlie NTHi colonization in T2/FeNO low airway disease contexts. These data provide a potential mechanistic basis for bacterial colonization for intrinsic and pharmacologically induced T2/FeNO low contexts and support that the assessment of specific bacteria-host interactions could influence clinical decision-making in asthma.

In the context of climate change and increasing global populations, thunderstorm asthma may become a greater threat at both individual and population levels. The unpredictable nature of epidemic thunderstorm asthma events makes them challenging to study; however, they can have devastating consequences. Novel approaches are required to characterise the mechanisms driving these events to allow researchers and other stakeholders to understand who is at risk and when. This will support the development of interventions that protect patients and healthcare services. In this commentary, we provide an overview of thunderstorm asthma and briefly describe an epidemic affecting Leicester, UK in June 2023. Our analysis highlights Cladosporium spores as a key player in mediating UK thunderstorm asthma. Low levels of background treatment in adults and an increase in emergency assessments but not hospitalisations in children suggest that epidemics could be prevented by improving awareness and ensuring access to standard inhaled therapies. Finally, we consider future risk and suggest research priorities with an ultimate goal of minimising the adverse impact related to thunderstorm asthma going forward.

Rationale: Nasal polyposis is a comorbidity of asthma that is associated with type 2 inflammation. Non-invasive biomarkers of type 2 inflammation, particularly fractional exhaled nitric oxide (FeNO), have been proposed as potentially useful in predicting the presence of nasal polyposis. In this study, we evaluated the ability of inflammatory biomarkers to identify patients with a history of nasal polyposis among patients with asthma. Methods: We analyzed data from the OxfoRd Asthma attaCk risk scaLE (ORACLE2) patient-level meta-analysis (PROSPERO: CRD42021245337), which includes 6,513 participants from 22 Randomized Controlled Trials (RCTs) investigating the effects of fixed treatment regimens on severe asthma exacerbation rates over a minimum of 24 weeks. In a complete case analysis, we included patients with data on nasal polyposis history (any mention or timing of nasal polyposis or previous nasal polypectomy in comorbidity list) and inflammatory biomarkers (FeNO, blood eosinophil count (BEC), and serum immunoglobulin E (IgE)). We then evaluated the ability of each inflammatory biomarker to identify patients with a history of nasal polyposis by calculating the Area Under the Curve (AUC) using Receiver Operating Characteristic (ROC) analysis. RESULTS: We included 4,165 patients from 15 RCTs, with n=598 (14%) reporting nasal polyposis. The analysis population comprised moderate-to-severe asthma (n=1,265 severe). Data were available for FeNO (n=3,884), BEC (n=4,120), and IgE (n=4,110). The performance of FeNO and BEC in identifying a history of nasal polyposis was poor, with AUC values of 0.62 [0.59; 0.64] and 0.62 [0.59; 0.64], respectively. For FeNO ≥ 74 ppb, specificity attained 90% [95% CI 89-91] and for BEC ≥ 0.61x109/L, specificity attained 90% [95% CI 89-91]. For both these cut-offs, sensitivity was very low (< 22%) and the positive likelihood ratio (PLR) was insufficient to identify nasal polyposis (PLR <10: FeNO ≥ 73 ppb, PLR=1.7; BEC ≥ 0.61x109/L, PLR=2.2). Furthermore, IgE was not a discriminative biomarker for nasal polyposis (AUC: 0.50 [0.48; 0.52]) CONCLUSION: Biomarkers (FeNO, BEC, IgE) are not features accurately distinguishing patients with asthma reporting a history of nasal polyposis and those who do not. These results suggest that type-2 biomarkers are not substantially affected by the presence of nasal polyposis. REGISTRATION: PROSPERO-CRD42021245337

Background: Mepolizumab is an anti-IL-5 mAb treatment for severe eosinophilic asthma that reduces asthma exacerbations. Residual airway inflammation with mepolizumab therapy may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations. Objective: Our study aimed to explore the corticosteroid responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway. Methods: The MAPLE trial was a multicenter, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for severe eosinophilic asthma. We analyzed paired sputum (n = 16) and plasma (n = 25) samples from the MAPLE trial using high-throughput Olink proteomics. We analyzed additional sputum proteins using ELISA. Results: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type 2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type 2 proteins were also downregulated in plasma, combined with IL-12, IFN-g, and IP-10. IL-10 and amphiregulin were upregulated. Conclusions: At stable state, prednisolone has broad antiinflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations. (J Allergy Clin Immunol 2024;154:1146-58.)

Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids have broad anti-inflammatory effects and remain the main treatment for these residual exacerbations. Our study aimed to explore the nature and corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms. The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in patients treated with mepolizumab for SEA. We analysed sputum and plasma samples from the MAPLE trial using high-throughput Olink proteomics. We also analysed plasma microRNA, sputum proteins using ELISA, and nasal mucosal bulk RNA sequencing. In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Tissue repair and neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. In the nasal transcriptome, prednisolone suppressed genes involved in leucocyte chemotaxis, mast cell tryptase, 15-lipoxygenase and MMP12. By contrast, mepolizumab differentially regulated only Galectin-10 in plasma and no sputum proteins, and in nasal tissue affected genes related to cilia, keratinisation, extracellular matrix formation, and IL-4/13 signalling. At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab.### Competing Interest StatementIH has received a conference travel grant from GSK. FY and SED have received speaker fees from AstraZeneca. JC, VB, and EM report no declarations of interest. AA is currently an employee of AZ. PJM has received support to attend educational meetings from Chiesi. JB has received personal fees from NuvoAir, and a research grant to his Institute from AstraZeneca, outside the submitted work. CB has received speakers fees from AZ and GSK and has received advisory board fees from AZ. LH has received grants from GSK, Astra Zeneca, Roche/Genentech, has given lectures supported by Astra Zeneca, Sanofi, Circassia, GlaxoSmithKline, has received travel grants from AstraZeneca and GSK, and has honoraria for Advisory Board Meetings from Novartis, Roche/Genentech, GSK, Teva and Celltrion. IDP has received speakers honoraria for speaking at sponsored meetings from Astra Zeneca, Boehringer Inglehiem, Aerocrine, Almirall, Novartis, Teva, Chiesi, Sanofi/Regeneron, Menarini and GSK and payments for organising educational events from AZ, GSK, Sanofi/Regeneron and Teva. He has received honoraria for attending advisory panels with Genentech, Sanofi/Regeneron, Astra Zeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi and Knopp and payments to support FDA approval meetings from GSK. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim, GSK, Astra Zeneca, Teva and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. He is co-patent holder of the rights to the Leicester Cough Questionnaire and has received payments for its use in clinical trials from Merck, Bayer and Insmed. In 2014-5 and 2019-20 he was an expert witness for a patent dispute involving Astra Zeneca and Teva. CEB has received grants and consultancy fees from 4D Pharma, Areteia, AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, Mologic, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi. RC has received lecture fees from GSK, AZ, Teva, Chiesi, Sanofi and Novartis; honoraria for Advisory Board Meetings from GSK, AZ and Celltrion; sponsorship to attend international scientific meetings from Chiesi, Sanofi and GSK and a research grant to her Institute from AZ for a UK multi-centre study. TSCH has received grants from the Wellcome Trust, grants from The Guardians of the Beit Fellowship, and grants from the NIHR Oxford Biomedical Research Centre during the conduct of the study; and grants from Pfizer Inc., grants from University of Oxford, personal fees from Astra Zeneca, personal fees from TEVA, personal fees from Peer Voice outside the submitted work. ### Clinical TrialThis study is registered on Clinicaltrials.gov ([NCT03610685][1]).### Funding StatementThis study was funded jointly by the Medical Research Council (MRC) UK (MR/M016579/1) and industrial partners within the MRC Refractory Asthma Stratification Programme consortium and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Proteomics and transcriptomics analysis was funded by GSK (ID: 215294). TSCH is supported by a Wellcome Trust Fellowship (211050/Z/18/z). All authors had full access to the full data in the study and accept responsibility to submit for publication. ### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was approved by the Medical Ethics Committee (West of Scotland Research Ethics Service 3, Reference number 18/WS/0060). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAnonymised patient level data analysed and presented in this study are available from the corresponding author on reasonable request, providing the request meets local ethical and research governance criteria after publication. Data will be available immediately after publication for 10 years. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03610685&atom=%2Fmedrxiv%2Fearly%2F2024%2F02%2F15%2F2024.02.14.24302812.atom

BACKGROUND: Mucus plugs in asthmatic airways are associated with airway obstruction and the activity of inflammatory cytokines, specifically interleukin (IL)-5 and IL-13, and they may provide an opportunity for targeted therapy. This analysis of the CASCADE (Study to Evaluate Tezepelumab on Airway Inflammation in Adults With Uncontrolled Asthma) placebo-controlled trial used computed tomography (CT) imaging to assess mucus plugs in patients with moderate-to-severe, uncontrolled asthma who received tezepelumab or placebo. METHODS: CASCADE was an exploratory, double-blind, placebo-controlled trial examining the anti-inflammatory effect of tezepelumab. Patients (aged 18 to 75 years old) were randomly assigned 1:1 to 210 mg tezepelumab or placebo every 4 weeks subcutaneously for at least 28 weeks. An expert radiologist, blinded to treatment groups and time points, objectively scored 18 lung segments for the presence of mucus plugs in CT scans obtained before and after treatment; greater numbers of mucus plugs resulted in higher mucus plug scores. RESULTS: Absolute change from baseline (mean [±standard deviation]) in mucus plug score was −1.7±2.6 in patients receiving tezepelumab (n=37) and 0.0±1.4 in patients receiving placebo (n=45). At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers (blood eosinophils, eosinophil-derived neurotoxin, fractional exhaled nitric oxide, IL-5, and IL-13) and negatively with lung function measures (prebronchodilator forced expiratory volume in 1 second and forced mid-expiratory flow). In tezepelumab recipients, reductions in mucus plug scores were correlated with improvements in lung function and reductions in blood eosinophil count and levels of eosinophil-derived neurotoxin, a biomarker of eosinophilic degranulation. CONCLUSIONS: Tezepelumab was associated with a reduction in occlusive mucus plugs versus placebo in a randomized controlled trial in patients with moderate-to-severe, uncontrolled asthma. (Funded by AstraZeneca and Amgen Inc.; ClinicalTrials.gov number, NCT03688074.)

Background: Haemophilus has been identified as a key pathogen associated with adverse clinical outcomes in asthma. In vitro studies suggest bacteria-driven upregulation of MUC5AC as a potential mechanism (Wang, B et al. J Biol Chem. 2002 Jan 11;277(2):949-57) Objective: We analysed the airway microbiome in severe asthma subjects evaluated for evidence of airway remodelling. We hypothesised that relative abundance of Haemophilus in the airway microbiome would be associated with airway epithelial MUC5AC staining. Methods: We obtained protected bronchial brushings and biopsies from subjects with severe asthma participating in the RASP-UK bronchoscopy study (Khalfaoui et al. Allergy. 2022 Oct;77(10):2974-2986). 16S rRNA gene sequencing was performed on DNA extracted from brush samples. Biopsy samples were processed for immunohistochemistry (IHC) and stained for epithelial MUC5AC and other remodelling outcomes. Results: 37 subjects had paired microbiome and IHC data. Relative abundance of Haemophilus (%) was not significantly correlated with epithelial MUC5AC (% total epithelium stained positive), Spearman ρ -0.043. No other associations were observed between Haemophilus and epithelial neutrophils, nor other measures of airway remodelling. Conclusions: Airway mucus is not directly related to the proportion of Haemophilus in the airway microbiome suggesting a more complex relationship between mucus hypersecretion, airway microbial profile and airway inflammation.

FOR RELATED ARTICLE, SEE PAGE 1026Asthma and obesity, defined as a BMI ≥30 kg/m2, are both common conditions globally, and therefore overlap in a significant number of patients. However, it is increasingly recognized that, rather than simply coexisting within an individual, there is a complex interplay between the two conditions. FOR RELATED ARTICLE, SEE PAGE 1026 Comorbid obesity is linked particularly to poorly controlled asthma, associated with higher rates of exacerbation and hospital admission, longer hospital stays, and other characteristics that include medication resistance, many of which are features of more severe disease.1Peters U. Dixon A.E. Forno E. Obesity and asthma.J Allergy Clin Immunol. 2018; 141: 1169-1179Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar,2Sharma V. Cowan D.C. Obesity, inflammation, and severe asthma: an update.Curr Allergy Asthma Rep. 2021; 21: 46Crossref PubMed Scopus (7) Google Scholar Difficult-to-treat and severe asthma represent a minority of the total asthma population but account for a disproportionate burden on health care systems. Unbiased analyses of severe asthma cohorts based on clinical characteristics consistently have demonstrated an adult-onset obese phenotype that is associated with neutrophilic inflammation and female preponderance3Haldar P. Pavord I.D. Shaw D.E. et al.Cluster analysis and clinical asthma phenotypes.Am J Respir Crit Care Med. 2008; 178: 218-224Crossref PubMed Scopus (1555) Google Scholar; however, obesity has also been linked to early onset disease with elevated markers of T2 inflammation4Holguin F. Bleecker E.R. Busse W.W. et al.Obesity and asthma: an association modified by age of asthma onset.J Allergy Clin Immunol. 2011; 127: 1486-1493.e1482Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar and is known to impact on thoracic wall mechanics, which suggests that multiple disease mechanisms may be responsible for the observed negative impact on clinical outcomes. Irrespective of the underlying pathophysiologic mechanism, the bottom line is that weight management in obese difficult-to-treat or severe asthma represents a significant challenge for both patients and clinicians. Multicomponent interventions are recommended first line, including aspects of behavior modification, nutritional therapy, and increased physical activity, which lead on to pharmacotherapy and bariatric surgery in those who fail to achieve their targets despite adherence to initial interventions.5National Institute for Health and Care Excellence (NICE). Obesity: identification, assessment and managmement. 27 Nov 2014. Accessed March 3, 2023. https://www.nice.org.uk/guidance/cg189Google Scholar,6Cornier M.A. A review of current guidelines for the treatment of obesity.Am J Manag Care. 2022; 28: S288-S296PubMed Google Scholar For many of these patients, barriers to increasing exercise may include active asthma symptoms or the fear of precipitating symptoms and physical and/or psychologic comorbidities; repeated courses of high-dose oral corticosteroids may be required for episodes of acute deterioration, with corresponding effects on appetite and resultant weight gain difficult to overcome without support, especially in the context of unstable disease. For clinicians with finite time and resources, high-quality evidence to guide the logistical delivery of cost-effective weight management strategies is lacking, despite acknowledgment of the impact of obesity and related comorbidities, such as OSA, on disease control.7Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2022. Accessed March 3, 2023. https://ginasthma.org/wp-content/uploads/2022/07/GINA-Main-Report-2022-FINAL-22-07-01-WMS.pdfGoogle Scholar In this issue, Sharma et al8Sharma V Ricketts HC McCombie L et al.A total diet replacement weight management program for difficult-to-treat asthma associated with obesity: a randomized controlled feasibility trial.Chest. 2023; 163: 1026-1037Abstract Full Text Full Text PDF Scopus (1) Google Scholar report a randomized, controlled, proof-of-concept feasibility study, demonstrating that weight loss caused by the commercially available, dietician-supported weight management program, “Counterweight-Plus,” was associated with clinically significant improvements in asthma-specific outcomes related to disease control and quality of life over 16 weeks in patients who are obese with difficult-to-treat adult asthma who were recruited from hospital clinics. The intervention comprised three phases: (1) calorie-limited total diet replacement to 12 weeks, (2) food reintroduction, and weight loss maintenance from 19 to 52 weeks. Subjects in the intervention group safely achieved an impressive mean weight loss of 13.5kg or approximately 12% from baseline compared with a mean loss of 1.4 kg in those patients who received usual follow up alone, with trends towards greater benefit in those with weight loss of ≥15%. Improvements were not observed in other outcomes that related to exacerbation frequency and health care use; however, this likely relates to the relatively short study period reported. Further results from 1 and 2 years of follow up are awaited, with maintenance of weight loss as important, if not more so, than the promising results presented here. As mentioned earlier, severe and difficult-to-treat asthma represents an area of unmet clinical need. Although the cohort studied here had comparable baseline BMI to those included in previous trials of weight loss interventions,2Sharma V. Cowan D.C. Obesity, inflammation, and severe asthma: an update.Curr Allergy Asthma Rep. 2021; 21: 46Crossref PubMed Scopus (7) Google Scholar,8Sharma V Ricketts HC McCombie L et al.A total diet replacement weight management program for difficult-to-treat asthma associated with obesity: a randomized controlled feasibility trial.Chest. 2023; 163: 1026-1037Abstract Full Text Full Text PDF Scopus (1) Google Scholar the cohort demonstrated features of more severe and uncontrolled disease with a high burden of therapy that included maintenance and rescue corticosteroid use and high Asthma Control Questionnaire 6 score. Mental health issues have been associated extensively with obesity and are common in patients with severe asthma.9Chung K.F. Wenzel S.E. Brozek J.L. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir Jl. 2014; 43: 343-373Crossref PubMed Scopus (2537) Google Scholar It is unclear whether the high rates of psychologic comorbidity that were observed in this cohort relate to the presence of these conditions in concert; trials in larger numbers would be required to ascertain whether this feature specifically impacts on the response to this or other weight loss interventions. A larger trial could also inform whether there is a differential response to weight loss interventions in specific subgroups of difficult-to-treat or severe asthma, based on inflammatory or other characteristics, and could provide further insight into key pathophysiologic mechanisms. If this intervention is associated with positive outcomes over longer term follow up, health care services will need to consider delivery in the real-world setting. Weight management strategies such as this fit well into the “treatable traits” model of asthma care10McLoughlin R.F. McDonald V.M. The management of extrapulmonary comorbidities and treatable traits; obesity, physical inactivity, anxiety, and depression, in adults with asthma.Front Allergy. 2021; 2735030Crossref PubMed Google Scholar that has gained support within the pulmonology community in recent years, and the fact that this program is managed exclusively by experienced dieticians is attractive for both patients and asthma clinicians. However, the number of patients eligible for such an intervention is likely to far exceed the capacity for such regular reviews; therefore, further investigation may be required to understand whether this program can still achieve positive outcomes with less resource-intensive support or, alternatively, to define those subgroups most likely to respond. With rates of obesity rising dramatically, particularly in children and adolescents and in low- and middle-income countries, recent estimates suggest the condition will affect more than 50% of the global population by 2035 and cost the global economy nearly 3% of current global gross domestic product.11World Obesity Federation. World Obesity Atlas 2023. March 2023. Accessed March 3, 2023. https://s3-eu-west-1.amazonaws.com/wof-files/World_Obesity_Atlas_2023_Report.pdfGoogle Scholar Consequently, obesity-related poor disease control will undoubtedly become a growing challenge for asthma services, with an increasing urgency to identify and deliver effective treatment strategies, including those able to engage the most vulnerable patient groups.12Dixon A.E. Blake K.V. DiMango E.A. et al.The challenge of addressing obesity in people with poorly controlled asthma.Obes Sci Pract. 2021; 7: 682-689Crossref PubMed Scopus (4) Google Scholar Learning lessons from other major public health issues that have impacted directly on respiratory services, such as tobacco addiction, and establishing accessible dedicated weight management services coordinated by specialist advisors, as exemplified by the Counterweight-Plus program, could change the perception of the problem from “me” to “we”11World Obesity Federation. World Obesity Atlas 2023. March 2023. Accessed March 3, 2023. https://s3-eu-west-1.amazonaws.com/wof-files/World_Obesity_Atlas_2023_Report.pdfGoogle Scholar and may provide a potential framework to navigate this impending crisis. None declared. A Total Diet Replacement Weight Management Program for Difficult-to-Treat Asthma Associated With Obesity: A Randomized Controlled Feasibility TrialCHESTVol. 163Issue 5PreviewUsing a structured weight management program results in clinically important improvements in asthma control and quality of life over 16 weeks compared with UC in adults with difficult-to-treat asthma and obesity. This generalizable program is easy to deliver for this challenging phenotype. Longer-term outcomes continue to be studied. Full-Text PDF Open Access