Immunoproteasome Inhibits Airway Type 2 Inflammation in Part through the Degradation of IL4-Ralpha 

Presented by: N. Schaunaman

Allergic asthma is a chronic disease induced by inhalation of environmental allergens which trigger an excessive immune response resulting in high levels of inflammatory cytokines like IL-4, IL-13, and IL-5, eosinophilic infiltration, etc. Antigen-specific T helper (Th) 2 cells are central mediators of this allergic reaction. Studies have shown the importance of the immunoproteasome in the activation and differentiation of T cells, cytokine secretion, and development of autoimmune disorders, making it an interesting therapeutic target for T helper cell-mediated diseases. Immunoproteasome inhibition in macrophages was associated with lower levels of IL-4Ralpha, a receptor shared by IL-13 and IL-4, and is effective in many inflammatory settings but its effect on allergic airway inflammation is unknown.

Objective: This study aims to determine if immunoproteasome can inhibit type 2 inflammation and airway hyperresponsiveness through IL4Ra regulation, to ascertain the therapeutic potential of immunoproteasome inhibition on Th2 cells in allergic asthma.

Method: Tracheobronchial epithelial cells were transduced with IL-4Ra CRISPR Cas-9 sgRNA and scrambled control (SC) sgRNA to produce IL-4Ra knockout cells. These cells were subsequently pre-treated with ONX-0914, an inhibitor of immunoproteasome subunit LMP7, for 2 hours, and then activated with 10ng/ml of IL-13. After 72 hours of stimulation, cells and supernatant were collected. To investigate the cleavage of IL-4Ra, lysates from airway epithelial cells of five healthy subjects were incubated with 5nM and 20nM concentrations of the whole immunoproteasome. IL-4Ra western blot analysis was performed. Precision cut lung slices (PCLS) obtained from six healthy donor lungs were subjected to pre-treatment with ONX-094 and subsequent stimulation with IL-13 at a concentration of 25ng/ml. Airway hyperresponsiveness (AHR) was measured 72 hours post-stimulation by administering escalating doses of methacholine, with airway imaging conducted every 30 seconds following each dose.

Result: 

• Cells lacking IL-4Ra exhibited a notable decrease in IL-4Ra protein levels compared to those with scrambled control. Treatment of scrambled control cells with ONX-0914 resulted in elevated IL-4Ra protein expression, both in the presence and absence of IL-13 stimulation.
• In scrambled control cells treated with both ONX-0914 and IL-13, there was an augmentation in Eotaxin-3 levels, an eosinophilic chemokine induced by IL-13, compared to cells treated with IL-13 alone. However, IL-4Ra knockout cells demonstrated significantly lower levels of Eotaxin-3 across all conditions compared to SC cells
• Immunoproteasome significantly reduced IL-4Ra protein levels in comparison to control lysates. The immunoproteasome inhibitor ONX-0914 increases airway contraction with and without IL-13 treatment in human PCLS.

Conclusion: Inhibiting the immunoproteasome leads to heightened IL-4Ra expression and release of Eotaxin-3, suggesting its pivotal role in dampening type-2 inflammation. The research underscores how immunoproteasome activity curtails allergic asthma exacerbation by degrading IL-4Ra. Consequently, boosting immunoproteasome expression or efficacy emerges as a promising avenue for mitigating allergic inflammation in asthma, presenting a novel therapeutic frontier in the field.

 

eNOSE - Derived Response Clusters in Severe Asthmatics Treated With Anti-IL5/5R Biologics

Presented by: P. Dixey

Electronic noses (eNOSE) serve as a non-invasive point-of-care instrument capable of phenotyping chronic respiratory diseases. In the U-BIOPRED study, eNOSE technology facilitated the supervised categorization of asthma into atopic and non-atopic types. However, eNOSE technology has not yet been applied to analyze the breath prints of severe asthmatics over time following anti-IL5/5Rα therapy to identify and characterize positive treatment responses.

Method (PRISM study): This observational study spanned 12 months and included four visits. During each visit, eNOSE measurements were taken alongside paired clinical-physiological and biomarker data. Breathprints from 38 severe asthmatics were collected at baseline (Visit 1), at 1 month (Visit 2), and at 6 months (Visit 3) using SpiroNose, a cloud-based eNOSE device, as part of the PRISM study. The 38 participants received treatment with either benralizumab or mepolizumab. Unsupervised clustering was performed using the Gaussian mixture model method, while consensus clustering with ‘NbClust’ was employed to determine the optimal number of clusters at each visit. The clinical-physiological data of cluster members were then compared using comparative statistics.

Result:

• At the baseline visit, before initiating biologic therapy, two distinct clusters were identified, differentiated primarily by serum IgE levels. These differences were independent of oral steroid use, and no other clinical, physiological, or questionnaire parameters distinguished the two groups.
• One month after therapy (Visit 2), four clusters were identified. Subjects in clusters 3 and 4 demonstrated significantly better scores in the AQLQ and the CQA, with a trend towards improved ACQ6 scores and FEV1% predicted values.
• By the six-month mark, members of clusters 3 and 4 showed significant improvements in response markers compared to clusters 1 and 2. The improvements were notable in ACQ6 scores (0.84 vs. 1.98, p = 0.013), AQLQ scores (5.99 vs. 4.57, p = 0.022), CQA scores (1.33 vs. 2.20, p = 0.007), SNOT-22 scores (1.12 vs. 2.21, p = 0.009), and FEV1% predicted values (82% vs. 63%, p = 0.039).
• In the GETE, 90% of subjects in clusters 3 and 4 reported complete control or marked improvement of their asthma, with 40% indicating complete control and 50% noting marked improvement.
• Comparatively, in clusters 1 and 2, 66% of patients felt their asthma was well managed by the treatment, with 22% reporting complete control and 44% indicating marked improvement.

Mild moderate asthma (MMA) vs Anti-IL5/IL5Rα treated severe asthma longitudinal comparison- Over the course of 12 months of treatment, the four sensors for severe asthma became comparable to those for MMA, indicating that the volatome of severe asthma following anti-IL5/IL5Rα therapy resembles that of MMA.

Conclusion: 

• eNOSE breath profile clusters phenotype severe asthma based upon TH2 markers and BMI
• eNOSE breath profile clusters of severe asthma, 1 month after treatment with anti-IL5/IL5Rα biologics, predict 12 month responder status.
• The volatome of severe asthma treated with anti-IL5/IL5Rα biologics becomes comparable with MMA after 12 months of treatment.

 

High Airway TSLP Levels in Asthma Associate With More Severe Disease and Multiple Biomarkers of Type 2 Inflammation

Presented by: K. Khanna

Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived cytokine that is produced in response to proinflammatory stimuli, leading to inflammation driven by type 2 helper T cells. It is well established that this alarmin regulates type 2 immune responses in asthma and may have roles in non-type 2 responses as well. TEZEPELUMAB, a monoclonal antibody that blocks TSLP and improves asthma control. However, little information is available about the levels of TSLP protein in the airway in asthma and how these levels relate to type 2 and type 1 inflammation.

Objective: The study aims to assess the role of TSLP in asthma, and its association with type 2 and type 1 inflammation.

Method: Using a V-Plex immunoassay from Meso Scale Discovery, by the ACRO Biosystems Group, TSLP protein concentrations were analyzed in stored sputum samples obtained from 414 participants enrolled in the Severe Asthma Research Program (SARP)-3, alongside samples from 105 healthy controls. The TSLP levels in healthy individuals served as a reference range for normal TSLP levels in sputum and facilitated the classification of asthma patients into TSLP-high and -low subsets. Subsequently, the clinical profiles of TSLP-high patients were delineated, along with the identification of inflammatory biomarkers associated with this TSLP-high status.

Result: 

• Sputum TSLP levels were high in asthma patients with 34.1% of the asthma patients being TSLP-high.
• TSLP high asthma is associated with low lung function and high type 2 inflammation, as evidenced by higher levels of nitric oxide in exhaled breath, and higher numbers of eosinophils in blood and sputum.
• Blood and sputum neutrophils were not different between TSLP-low and TSLP-high asthma, stating that TSLP-high asthma does not associate with non-type 2 inflammation.
• Expression of type 2 network genes in sputum cells in TSLP-high asthma was higher than in TSLP-low asthma. Although the expression of type 1 network genes in sputum cells in TSLP-high asthma was also higher than in TSLP-low asthma, this increase was not as strong when patients who were high for type 2 network genes were excluded from the analysis.

Conclusion: The study confirms a notable elevation in airway TSLP protein levels among individuals with asthma. Within the SARP-3 cohort, TSLP-high asthma, characterized by elevated TSLP protein levels in sputum, is prevalent in 34% of participants. Moreover, individuals classified as TSLP-high exhibit more severe asthma symptoms, with airway TSLP levels strongly related to markers of type 2 inflammation, and not non-type 2 inflammation.  

Single-cell RNA Sequencing Analysis of Blood and Nasal Brushing From Asthma Patients Receiving a Single Dose of SAR443765, A Novel, Bispecific Anti-TSLP/Anti-IL-13 NANOBODY Molecule Reveals Significant Impact on Multiple Pathological Immune Cell Populations and Downregulation of CCL26 Expression in Epithelial Cell Subpopulations

Presented by: Manisha Brahmachary

• Sanofi’s Lunsekimig (SAR443765), the first multi-targeting NANOBODY molecule for asthma, blocks both TSLP and IL-13. This multi-targeted approach demonstrated greater potency than mono-targeting TSLP or IL-13 in preclinical models. In a Phase Ib study (NCT05366764) with patients having FeNO-high, mild-to-moderate asthma, Lunsekimig significantly reduced Fraction exhaled nitric oxide (FeNO) and improved lung function.
• Thirty-six patients with mild-to-moderate asthma and FeNO ≥25 ppb received a subcutaneous 400 mg dose of SAR443765 or a placebo on Day 1. Nasal brushings and peripheral blood cells were collected for scRNAseq analysis at pre-dose and on Day 29 (Lunsekimig n=10, placebo n=5). Cell type annotation for immune, epithelial, and other non-immune cell populations was conducted using in-house methods. Analyses included comparisons of cell type proportions, differential gene expression, and correlation of cell proportions with FeNO changes.
• Result: Lunsekimig significantly reduced the proportion of non-classical monocytes in nasal brushings and CD8 T-effector memory and NK cells in blood. It down-regulated CCL26 expression in nasal epithelial cell subpopulations and hemoglobin-beta in blood CD8 T-effector memory cells. A significant positive correlation was observed between the reduction in NK cell proportion and the decrease in FeNO following Lunsekimig treatment in blood.
• Conclusion: The scRNAseq analysis indicates that a single dose of Lunsekimig specifically affects nasal brushing and blood classical/non-classical monocyte populations. It also downregulates CCL26 expression in nasal epithelial cells, suggesting a reduction in inflammatory cell chemotaxis in the lungs.

 

Upper Airway Expression of 3 Epithelial and Immune Cell Genes Predict Responsiveness to Mepolizumab Therapy in Children

Presented by: M. C. Altman

Method: The MUPPITS-2 (Mechanisms Underlying Asthma Exacerbations Prevented and Persistent with Immune-based Therapy: A Systems Approach Phase 2) study (n=290) evaluated the efficacy of mepolizumab in urban children with exacerbation-prone asthma and blood eosinophil counts ≥150/μL. Participants received guidelines-based asthma care and were randomized (1:1) to receive either a placebo or mepolizumab for 52 weeks. Nasal lavage samples collected at randomization underwent RNA sequencing, which was analyzed at the modular and gene levels to assess baseline airway inflammation patterns (n=249) and predict treatment responsiveness. LASSO feature selection with 10-fold cross-validation, iterated 5 times, and followed by model-based recursive partitioning (MOB) was used to identify a concise nasal gene signature to predict response to mepolizumab versus placebo in cohort subgroups.

Result: 

• The primary outcome showed that the annualized rate of asthma exacerbations treated with systemic corticosteroids was 0.96 (95% CI, 0.78-1.17) for the mepolizumab group and 1.30 (95% CI, 1.08-1.57) for the placebo group (Rate Ratio 0.73; 95% CI, 0.56-0.96; p = 0.027).
• LASSO feature selection identified 20 genes predictive of exacerbation rates from nasal lavage RNA sequencing of 249 participants. MOB analysis further pinpointed three genes—SWAP70 (eosinophil-associated), TCIRG1 (neutrophil-associated), and ACER2 (epithelium-associated)—that significantly influenced the response to mepolizumab.
• A subgroup of 30 individuals with the highest SWAP70 expression showed the best response to mepolizumab (Rate Ratio 0.18; 95% CI, 0.08-0.41; p < 0.0001). Conversely, 33 individuals with high ACER2, low SWAP70, and low TCIRG1 expression exhibited a negative response, with increased exacerbations (Rate Ratio 1.88; 95% CI, 1.05-1.88; p = 0.035).
• Participants with high TCIRG1 and low SWAP70 expression had low exacerbation rates and a modest to no response to mepolizumab. Airway gene expression patterns were more accurate in predicting mepolizumab response than demographic variables, pulmonary functions, or blood cell counts, which did not significantly predict treatment outcomes.

Conclusion: These results demonstrate that mepolizumab significantly reduces asthma exacerbations, with specific nasal gene expression profiles (SWAP70, TCIRG1, ACER2) predicting treatment response. Airway gene patterns are more accurate predictors of mepolizumab efficacy than demographic, pulmonary, or blood cell metrics, highlighting the potential for personalized asthma therapy.

 

Efficacy and Safety of Dupilumab in Patients with Moderate-to-Severe COPD and Type 2 Inflammation: Phase 3 NOTUS Trial

Presented by: S.P. Bhatt

Objective: Phase III NOTUS (NCT04456673) aimed to confirm the efficacy and safety of dupilumab in patients with COPD and type 2 inflammation. A randomized, double-blind, placebo-controlled, parallel-group, multicenter, Phase III study to evaluate the efficacy and safety of dupilumab administered every 2 weeks in patients with moderate or severe COPD with type 2 inflammation.

Methods:

• In the Phase III, randomized, double-blind, placebo-controlled NOTUS study, patients were randomized to add-on dupilumab 300 mg or placebo every 2 weeks for 52 weeks.
• Key inclusion criteria: moderate-to-severe COPD with type 2 inflammation (screening blood eosinophils ≥300 cells/µL), age 40–85 years, current/former smoker (≥10 pack-years), on triple therapy (ICS, LABA, and LAMA) or dual therapy (LABA/LAMA) if ICS were contraindicated, post-bronchodilator ppFEV1 >30% to ≤70%, post-bronchodilator FEV1/FVC ratio <0.7, ≥2 moderate or ≥1 severe exacerbations in the previous year, and patient-reported history of chronic bronchitis/cough (emphysema was not an exclusion).
• Key exclusion criteria: current/history of asthma or other significant pulmonary disease.
• As per the pre-specified statistical analysis plan, the primary analysis was performed following a positive interim analysis, and included all available data for the 935 randomized participants, 721 of whom had the opportunity to reach Week 52.
• Secondary endpoints included change from baseline in pre-bronchodilator FEV1 and SGRQ total score.

Result: 

• In NOTUS study with 935 participants, 470 were randomized to receive dupilumab, while 465 received a placebo. Dupilumab reduced the annualized rate of moderate-to-severe exacerbations by 34% compared to placebo (relative risk [95% CI] 0.664 [0.535-0.823], p = 0.0002).
• By week 12, dupilumab significantly increased pre-BD FEV1, with a least squares mean difference of 82 mL (p < 0.0001) compared to placebo. This improvement was sustained at Week 52, with a least squares mean difference of 62 mL (p = 0.0182).
• Dupilumab also improved the SGRQ score at Week 52, showing a least squares mean difference of −3.37 (nominal p = 0.0068) compared to placebo. Safety findings were consistent with the BOREAS study, and treatment-emergent adverse events were similar between the dupilumab and placebo groups.

Conclusion: Dupilumab decreased the annualized rate of moderate-to-severe exacerbations by 34% compared to placebo. Additionally, dupilumab enhanced lung function and improved patient-reported quality of life in individuals with COPD and type 2 inflammation.

Effect of Dupilumab on Airway Oscillometry, Ventilation/Perfusion, and Mucus Plugging in Moderate-to-Severe Asthma: The VESTIGE Trial

Presented by: G. R. Washko

Asthma is characterized by type 2 inflammation, small airway dysfunction, mucus plugging, and airway remodeling, wherein airway modeling is poorly responsive to current therapies, contributing to airflow obstruction. Mucus plugs in patients with asthma are also associated with type 2 inflammation and play a role in airflow obstruction, leading to persistent symptoms. DUPIXENT (dupilumab) is a fully human monoclonal antibody that inhibits the signaling of the IL-4 and IL-13 pathways, key and central drivers of type 2 inflammation. 

Objective: VESTIGE (NCT04400318) is a phase IV randomized, double-blind, placebo-controlled study that aims to evaluate the effect of dupilumab on airway inflammation through assessments of lung function, mucus plugging, and other lung imaging parameters, through different techniques, including imaging and oscillometry, in patients with uncontrolled moderate-to-severe asthma.

Method: The study enrolled 109 adult patients aged 21 to 70 years with uncontrolled moderate-to-severe asthma and raised type 2 biomarkers (blood eosinophils ≥300 cells/µL and FeNO ≥25 ppb). During the 24-week treatment period, patients were randomized 2:1 to receive 300 mg of Dupixent (n=72) or matched placebo (n=37) every two weeks.

Result: 

• Substantial improvements in the ventilation/perfusion ratio at total lung capacity in upper/lower lungs were achieved with dupilumab at week 4, and these improvements became significant by week 24. Even air trapping in the lungs was reduced from baseline to week 24 with dupilumab. 
• Dupilumab also led to significant improvements in SAD, as measured by peripheral airway resistance and compliance, and to significant improvements in mucus plug score.
• Notably, the mean differences in peripheral resistance and compliance exceeded their respective biological values of 0.04 kPa/L/s and 0.39 kPa/L, indicating clinical relevance. Airway resistance and reactance area decreased from baseline to Week 24 with dupilumab.
• In addition, the mean improvement in small airway dysfunction as measured by FEF 25-75% also exceeded the biological value of 0.21 L/s. Safety was similar to the known dupilumab profile.

Conclusion: Dupilumab treatment led to meaningful improvements in measures of small airway dysfunction, resulting in improved ventilation and lung function in patients with moderate-to-severe type-2–high inflammatory asthma. It produced clinically relevant improvements in peripheral lung resistance and compliance, forced mid-expiratory flow, along with ameliorated ventilation/perfusion, and mucus plugging, indicating improvements in the ability to breathe more normally. 

 

An Update From The Precision Interventions For Severe And/Or Exacerbation-Prone Asthma (PreCISE) NETWORK

Presented by: Elliot Israel

Precision medicine tailors treatments to specific patient subgroups with shared characteristics, such as particular genetic variations or elevated blood eosinophil levels. Sponsored by the U.S. National Heart, Lung, and Blood Institute (NHLBI), the PrecISE clinical study investigates multiple treatments for severe asthma. It had an enrollment target of 800 adults and teenagers (aged 12 years and older) whose severe asthma remains poorly controlled despite high-dose inhaled corticosteroids, including those experiencing frequent asthma attacks. PrecISE administers various treatments to participants based on their asthma subtype and aims to elucidate effective treatment strategies for different forms of severe asthma through the application of precision medicine. 

Objective: The PrecISE trial is currently enrolling nationwide, using an innovative adaptive platform design to test five novel interventions in severe asthma, and this session aims to describe the demographics and clinical baseline characteristics of the study cohort and provide an update on the study progress.

Result: 

• The study is a biomarker-stratified multi-period platform trial, where after initial screening, there is biased randomization of subjects to targeted interventions based on the biomarker profile.
• After biomarker refinement, around 150 subjects in the target group are used for efficacy analysis.
• Due to COVID, there were analytic adaptations like sample size reduction to 395, performing nested subgroup analysis instead of biomarker refinement, etc. to accommodate delayed enrollment and reduced sample size.
• The trial has an eight-week initial screening Phase, followed by a double-blind placebo-controlled cross-over Phase and multiperiod cross-over Phase. In the study, every patient gets an active drug, and futility analysis removes the drugs without any early signal of an effect. Nearly 24% of the cohort was on biologic at study entry, and this continued during the trial.
• T2 biomarker levels were low in most participants, compared to elevated sputum neutrophils.
• The study completed enrollment in March 2024, with completion by December 2024, and data readout in spring 2024. 

Conclusion: PrecISE holds the potential to pioneer predictive biomarkers and corresponding treatments, ushering in a new era beyond the existing T2 paradigm. By meticulously characterizing patients with severe or exacerbation-prone asthma, the PrecISE Network endeavors to fast-track the adoption of precision-based therapies. This initiative aims not only to enhance patient outcomes but also to reshape the landscape of asthma management, potentially altering the trajectory of the disease itself.

 

Asthma Drivers of Disease: the effects of IL-5 on eosinophils and other cell types that contribute to airway remodeling and disease progression

Presented by: Chupp, Geoffrey

Key points of the presentation:

• Jane, a 48-year-old woman without allergies, has a history of asthma since the age of 35 years, along with chronic rhinosinusitis with nasal polyps. She undergoes polypectomy twice and experiences frequent asthma exacerbations, requiring oral corticosteroids and daily SABA inhaler use. Her treatment regimen includes ICS/LABA, LAMA inhaler, ICS nasal irrigation, and LTRA. Physical examination reveals bilateral nasal polyps, with wheezing on pulmonary exam.
• Asthma exhibits significant clinical and biological diversity, urging advancements in understanding and managing its varied presentations. Phenotypic categorizations, including childhood and adult onset, allergic, non-allergic, and other subtypes such as AERD or obesity-related asthma, inform the identification of distinct molecular mechanisms. Precision medicine aims to personalize diagnosis and treatment by targeting individual endotypes.
• IL-5 plays a crucial role in eosinophil development, maturation, and activation during inflammation. It stimulates eosinophil maturation in the bone marrow and promotes their survival by inhibiting apoptosis. Once activated, eosinophils migrate to inflamed tissues, where they contribute to pathologic effects, indicating inflammation when blood eosinophil count is elevated. 
• IL-5 plays a significant role in epithelial barrier dysfunction and fibrosis. Its receptor, IL-5Rα, is active on bronchial epithelial cells and fibroblasts. IL-5 contributes to cell damage through eosinophil granule protein release. It downregulates genes associated with innate immunity and tight junctions, potentially compromising epithelial response and barrier function, while also promoting lung fibroblast proliferation and activation.
• IL-5Rα expression and activity on human bronchial epithelial cells were confirmed through in vitro studies using rh-IL-5. This activation led to the downregulation of genes associated with tight junctions and innate immunity, potentially compromising epithelial barrier function and immune response. 
• In asthmatic bronchial epithelial cells, there's a notable reduction in immunoexpression of Caveolin and E-cadherin compared to non-asthmatic cells. This decrease may affect the integrity of tight junctions crucial for normal epithelial function. The findings suggest potential implications for asthma pathology regarding airway epithelial barrier function.
• IL-5Rα expression is heightened on lung fibroblasts in asthma patients compared to healthy individuals, suggesting increased responsiveness to IL-5. Stimulation with IL-5 enhances fibroblast proliferation and activation, evidenced by elevated ERK and AKT phosphorylation levels. This indicates a potential role for IL-5 in airway fibrosis and remodeling in asthma pathology.
• Primary human airway fibroblasts from asthma patients, exhibit significantly elevated expression of IL-5Rα compared to those from healthy individuals, suggesting a potential role for IL-5 in fibroblast activation in asthma pathology.
• In asthma, human fibroblasts exhibit heightened response to IL-5 stimulation, showing increased proliferation and activation as indicated by elevated ERK and AKT phosphorylation levels compared to normal fibroblasts.

 

Conclusion:

1. IL-5 exhibits diverse effects beyond eosinophilic inflammation, including:

1. Impacts on epithelial barrier dysfunction, fibrosis, and mucus plug formation, and airway remodeling.

2. Involvement in immune responses extending beyond eosinophils.

2. Endotyping and phenotyping facilitate precision medicine, allowing personalized diagnosis and treatment approaches for enhanced patient outcomes.

3. A deeper comprehension of asthma's molecular mechanisms enables the development of more precise treatment strategies, aiming for ambitious patient outcomes.

 

COPD and Asthma with Type 2 Inflammation Distinct Diseases with a Shared Cause

Presented by: Steve White

Objective: Sanofi and Regeneron presented data to demonstrate that COPD and Asthma with Type 2 inflammation are distinct diseases but with a shared cause. It presented an in-depth understanding of Type 2 inflammation and its role in COPD and asthma, about how Type 2 inflammation can contribute to hallmark symptoms of these lower airway diseases and influence patient outcomes.

Background: Asthma and COPD are complex, multifactorial airway diseases associated with significant morbidity and mortality. Despite their distinct clinical phenotypic features, there is considerable overlap of symptoms and pathogenesis, and both can be characterized by a cycle of type 2 inflammation, tissue remodeling, and symptoms driven by type 2 cytokines.

Localized inflammation due to external triggers in COPD and asthma like tobacco, smoke, air pollution, allergens, etc. leads to systemic inflammation, causing IgE production, elevated blood eosinophils, and fractional exhaled NO. Systemic inflammation further perpetuates localized inflammation leading to symptoms causing airway hyperresponsiveness, tissue remodeling, etc. 

COPD

COPD a systemic inflammation, is related to airway remodeling, while tissue remodeling is associated with exacerbation.

Type 2 inflammation contributes to a variety of diseases, affecting the upper airways, the lower airways, the GI tract, and the skin. The type 2 cytokines IL-4, IL-13, and IL-5, have distinct yet overlapping roles, like IL-5 is responsible for eosinophil differentiation in bone marrow. Tissue remodeling and immune cell infiltration are features of localized type 2 inflammation. 

COPD exacerbation and lung function decline contribute to a downward spiral, as severe exacerbation increases the risk of exacerbation and death. The study stated that the presence of mucus plugs was associated with an increased risk of death.

Blood eosinophils are a biomarker for Type-2 inflammation, and are associated with an increased risk of exacerbation. COPD with type-2 inflammation is also associated with higher hospital readmission. 

Initial treatment is based on symptoms, exacerbations, and evidence of type 2 inflammation, and despite maximal inhaled therapy, many still experience exacerbation.

Asthma

In asthma, type-2 inflammation contributes to a self-perpetuating cycle of impaired lung function and severe exacerbation. It drives diseases in over 84% of patients with asthma.

Elevated mucus blockages frequently correlate with heightened expression of type 2 cytokines, leading to diminished lung function. Moreover, type 2 inflammation plays a role in asthma that remains uncontrolled, primarily due to airflow obstruction stemming from heightened mucus production. 

Conclusion: Recognizing type 2 inflammation in COPD through elevated blood eosinophil levels holds significant predictive and prognostic value for patients. Likewise, pinpointing essential clinical markers suggestive of type 2 inflammation in asthma is pivotal for enhancing asthma management and control.

 

Type 2 Inflammation in the Pathophysiology of Asthma and COPD: What Is It and How Does It Impact Patients?

Presented by: Castro Mario, Christenson Stephanie, Hanania Nicola

Key points of the presentation:

1. Patient burden and airway remodeling in asthma.

• The Global Initiative for Asthma (GINA) defines uncontrolled asthma by criteria including frequent oral corticosteroid use, severe exacerbations, poor symptom control, and limited activity. Lung function should be assessed at treatment start, 3–6 months post-initiation, and periodically thereafter. Severe asthma is identified by high-dose ICS-LABA treatment or persistence despite this therapy.
• Uncontrolled persistent asthma imposes a significant burden on patients, with low FEV1 being a strong predictor of exacerbations regardless of symptoms. This condition leads to frequent exacerbations, medication adverse effects, reduced lung function, decreased quality of life, and increased mortality risk. Recent exacerbations significantly heighten the likelihood of future exacerbations and hospitalizations.
• FeNO is a versatile biomarker for adult asthma, reliably diagnosing asthma with levels >25 ppb and detecting type 2 airway inflammation with levels >20 ppb. This non-invasive, cost-effective test is more accurate than standard methods, aiding in diagnosis, prognosis, and personalized management, especially when used with blood eosinophils.
• High baseline FeNO levels can identify patients at risk for severe asthma exacerbations and rapid lung function decline. A study found that elevated FeNO levels significantly increased severe exacerbation rates and the risk of rapid FEV1 decline (OR, 2.73; 95% CI: 1.44-5.15; p < 0.01) over three years.

 

2. COPD with Type 2 Inflammation: Patient burden and fixed airway obstruction

• COPD is a heterogeneous disease with evolving phenotypes. Traditional descriptors like "pink puffer" (emphysema) and "blue bloater" (chronic bronchitis) are outdated and limited to severe cases. The GOLD report identifies current phenotypes as emphysema-predominant, bronchitis-predominant, and frequent exacerbator/rapid decliner, offering more precise clinical utility.
• Emerging COPD endotypes include neutrophilic inflammation and type 2 inflammation (e.g., EOS >300 cells/μL), reflecting a broader understanding beyond traditional chronic bronchitis and emphysema classifications.
• The GOLD 2024 guidelines classify and treat COPD based on symptoms and exacerbation history, using the ABE tool for initial assessment. This includes spirometry for airflow limitation, FEV1 grading, and exacerbation history. Current treatments focus on clinical presentation, with classifications from GOLD 1 (mild) to GOLD 4 (very severe).
• COPD exacerbations significantly increase the risk of cardiovascular events (CVD) and mortality. The risk of CVD peaks within 30 days post-exacerbation (HR: 3.8), while mortality risk escalates with the frequency of moderate exacerbations, particularly in those with severe exacerbations. These findings emphasize the critical impact of exacerbations on COPD prognosis.

 

3. Type 2 inflammation in the lower airway

• Type 2 immunity, characterized by specific cytokines and immune cells, is elevated in asthma and many COPD patients. Dysregulation of this immune response is implicated in various diseases. It plays roles in allergic conditions, chronic respiratory diseases, and other inflammatory disorders, emphasizing its significance in disease pathogenesis.
• According to GINA and GOLD definitions, asthma and COPD share commonalities. Asthma is characterized by variable symptoms and expiratory airflow limitation, while COPD involves chronic respiratory symptoms and persistent airflow obstruction. Both conditions exhibit heterogeneity and chronic inflammation, emphasizing similarities in their clinical presentations and underlying pathophysiology.
• Asthma and COPD may share a common type 2 inflammatory pathway, leading to disease-specific clinical manifestations. While asthma primarily involves airway hyperresponsiveness and inflammation, COPD is characterized by persistent symptoms, progressive lung function decline, exacerbations, and airway remodeling, emphasizing differences in their clinical outcomes and pathophysiology.
• Epithelial barrier dysfunction is a commonality in type 2 inflammatory airway diseases like asthma and COPD. Factors such as tobacco smoke, respiratory viruses, and allergens lead to damage in tight junctions, disrupting the airway epithelium. Increased barrier dysfunction is mediated by cytokines like IL-4 and IL-13.
• Persistent microbial colonization can exacerbate epithelial damage in COPD. Initiating factors like tobacco smoke and other harmful particles impair innate lung defenses, leading to microbial colonization. This results in airway epithelial injury, inflammatory responses, and acute exacerbations, contributing to the progression of COPD.
• Asthma and COPD with type 2 inflammation exhibit both shared and distinct mechanisms of airway remodeling. Both conditions involve increased inflammation and airway smooth muscle thickness. However, COPD additionally features thicker reticular basement membranes, fibrosis, alveolar disruption, goblet cell hyperplasia, mucus production, and barrier disruption compared to severe asthma.
• Variable inflammation distribution in asthma and COPD promotes airway constriction through several mechanisms. In asthma, submucosal inflammation and adventitial thickening amplify airway smooth muscle shortening and reduce airway-parenchyma interdependence. In COPD, alveolar attachment disruption and submucosal thickening increase airway narrowing and the risk of closure, especially with mucus during exacerbations.
• Severe asthma exacerbations are associated with potentially irreversible airflow limitation, as demonstrated in a study tracking patients with well-controlled asthma over three years. Those experiencing one or more exacerbations showed significant declines in lung function, indicating potential long-term adverse effects on airway structure and function.
• COPD exacerbations lead to progressive and irreversible lung damage, as evidenced by declines in lung function post-exacerbation. Frequent exacerbators experience faster FEV1 decline compared to infrequent ones. Low FEV1 is a risk factor for exacerbations and hospitalizations. Chronic bronchitis, high symptom burden, and lower FEV1 increase the risk of future exacerbations.
• Asthma and COPD share goblet cell hyperplasia, mucus overproduction, chronic inflammation, airflow limitation, and structural airway changes. Unique to asthma are smooth muscle hypercontractility and airway remodeling, while COPD features increased lymphoid follicles, fibrosis, airway hyperresponsiveness, exacerbations, and progressive lung function decline, often associated with type 2 inflammation.

Conclusion: The presentations underscored the shared and distinct features of asthma and COPD, particularly regarding type 2 inflammation and its impact on airway remodeling. Both conditions exhibit significant burdens on patients, with exacerbations contributing to irreversible lung damage. Understanding these nuances is crucial for accurate diagnosis, personalized management, and improved outcomes for individuals affected by these chronic respiratory diseases.