Inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma.

BACKGROUND AND OBJECTIVE: Severe asthma is a heterogeneous disease with subtype classification according to dominant airway infiltrates, including eosinophilic (Type 2 high), or non-eosinophilic asthma. Non-eosinophilic asthma is further divided into paucigranulocytic or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in the airways. Severe non-eosinophilic asthma has few effective treatments and many patients do not qualify for biologic therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease and has proven a valuable therapeutic target. We hypothesized that the CFTR may also play a role in non-eosinophilic asthma. METHODS: Patient-derived human bronchial epithelial cells (hBECs) were isolated and differentiated at the air-liquid interface. Single cell RNA-sequencing (scRNAseq) was used to identify epithelial cell subtypes and transcriptional activity. Ion transport was investigated with Ussing chambers and immunofluorescent quantification of ionocyte abundance in human airway epithelial cells and murine models of asthma. RESULTS: We identified that hBECs from patients with non-eosinophilic asthma had reduced CFTR function, and did not differentiate into CFTR-expressing ionocytes compared to those from eosinophilic asthma or healthy donors. Similarly, ionocytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic asthma. Treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture led to a reduction in ionocytes. CONCLUSION: Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target.

[Efficacy of biologics for severe asthma on allergic comorbidities]. / Efficacité des biothérapies de l'asthme sévère sur les comorbidités allergiques.

Identification of therapeutic targets other than asthma can guide the choice of biologics in cases of severe asthma. Some of the allergic diseases (atopic dermatitis, food allergies, allergic rhinoconjunctivitis) that may be associated with asthma can be treated with biologics. In this review, we aim to assess the effectiveness of these biologic therapies on the allergic comorbidities of asthma. In the treatment of atopic dermatitis, only Dupilumab, an anti-IL4Rα, has proven its effectiveness and has received reimbursement authorization for this indication. In patients presenting with allergic rhinoconjunctivitis, Omalizumab has shown effectiveness, but has not been approved for this indication. Data from post-hoc analyses of studies on severe asthma likewise suggest the effectiveness of Dupilumab regarding allergic rhinitis. While these two biologic therapies have shown positive signals, inducing oral food tolerance, the relevant data are not robust. Biologic therapies targeting IL-5 or its receptor (Mepolizumab, Benralizumab) have seldom been evaluated in allergic comorbidities, excepting atopic dermatitis, for which their effectiveness has not been proven. Lastly, there are interesting data on the combination of biologic therapy and allergen immunotherapy in cases of allergic rhinitis and food allergies, but they need to be confirmed by randomized studies.

Improvement in health-related quality of life questionnaires with biologic treatment in severe asthma and comorbid chronic rhinosinusitis with or without nasal polyposis: a real-life experience.

BACKGROUND: Patients with severe asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, that can increase the symptom burden and complicate treatment. Real-life clinical data on the impact of biologic treatments on CRS-specific quality-of-life questionnaires are still lacking. MATERIALS AND METHODS: In this retrospective real-life study, we collected data from patients with severe asthma with comorbid CRS with/without nasal polyposis at baseline, and after 3, 6 and 12 months of treatment with omalizumab, mepolizumab, benralizumab or dupilumab. In particular, we evaluated improvements in HRQoL as measured by SinoNasal Outcome Test-22 (SNOT-22, 0 - 110), Visual Analog Scale symptom scores (VAS, 0-10), and Asthma Control Test (ACT, 5-25) and the proportion of patients meeting the minimal clinically important difference (MCID). RESULTS: Disease-specific HRQoL, as measured by SNOT 22 and VAS score improved in all patients at 3, 6, and 12 months of treatment compared with baseline (SNOT-22: 14, IQR: 0-52 vs 10, IQR:0-30 vs 0, IQR:0-15 vs 0, IQR:0-12, p < 0.001, VAS score: 1, IQR: 0-5 vs 0, IQR:0-3 vs 0, IQR:0-2 vs 0, IQR 0-1, p < 0.001). After 3 months of treatment >80% of patients reached the MCID for ACT, while only patients on dupilumab showed to reach a MCID in 100% of cases. The effect size depended upon the symptom burden at baseline. CONCLUSIONS: The study confirms the efficacy of omalizumab, mepolizumab, benralizumab, and dupilumab in a real-life setting, with a rapid improvement in CRS-specific HRQoL and general health status. These data highlight the importance of targeting type 2 inflammation in asthmatic patients with co-existing upper and lower airways disease.The Authors disclose that preliminary data and analysis of the present study have been presented in abstract form during the "X International Workshop on Lung Health - Respiratory Disease and Immune Response", held in Nice on 19-21 January 2023.

Real-World Studies of Biologics for the Treatment of Moderate-to-Severe Asthma.

Presently, there are 6 biologic agents available for treatment of asthma. Each of these agents has undergone robust clinical trials in their approval programs. Such studies rely upon very rigid entry criteria that may not translate to real-world efficacy. Thus, exploring the efficacy of these agents in a larger, more heterogeneous, population brings a sense of comfort regarding their efficacy in the real-world. This review explores the available literature regarding the use of biologics in the real world, with a focus on markers of likely response to therapy.

Assessing prospective molecular biomarkers and functional pathways in severe asthma based on a machine learning method and bioinformatics analyses.

BACKGROUND: Severe asthma, which differs significantly from typical asthma, involves specific molecular biomarkers that enhance our understanding and diagnostic capabilities. The objective of this study is to assess the biological processes underlying severe asthma and to detect key molecular biomarkers. METHODS: We used Weighted Gene Co-Expression Network Analysis (WGCNA) to detect hub genes in the GSE143303 dataset and indicated their functions and regulatory mechanisms using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) annotations. In the GSE147878 dataset, we used Gene Set Enrichment Analysis (GSEA) to determine the regulatory directions of gene sets. We detected differentially expressed genes in the GSE143303 and GSE64913 datasets, constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model, and validated the model using the GSE147878 dataset and real-time quantitative PCR (RT-qPCR) to confirm the molecular biomarkers. RESULTS: Using WGCNA, we discovered modules that were strongly correlated with clinical features, specifically the purple module (r = 0.53) and the midnight blue module (r = -0.65). The hub genes within these modules were enriched in pathways related to mitochondrial function and oxidative phosphorylation. GSEA in the GSE147878 dataset revealed significant enrichment of upregulated gene sets associated with oxidative phosphorylation and downregulated gene sets related to asthma. We discovered 12 commonly regulated genes in the GSE143303 and GSE64913 datasets and developed a LASSO regression model. The model corresponding to lambda.min selected nine genes, including TFCP2L1, KRT6A, FCER1A, and CCL5, which demonstrated predictive value. These genes were significantly upregulated or under expressed in severe asthma, as validated by RT-qPCR. CONCLUSION: Mitochondrial abnormalities affecting oxidative phosphorylation play a critical role in severe asthma. Key molecular biomarkers like TFCP2L1, KRT6A, FCER1A, and CCL5, are essential for detecting severe asthma. This research significantly enhances the understanding and diagnosis of severe asthma.

Characteristics of Severe Asthma Clinic Patients with Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis associated with varying clinical presentations and overlapping multiorgan involvement. Asthma is a predominant feature of EGPA, typically in its prodromal phase, often severe and precedes vasculitic complications. However, there is paucity of studies describing the prevalence and characteristics of EGPA in the asthma population. OBJECTIVE: We aim to describe the clinical and serological characteristics and longitudinal therapeutic outcomes of patients with EGPA in the severe asthma (SA) cohort. METHODS: Retrospective study of patients with EGPA attending the multidisciplinary SA clinic in a tertiary hospital from 2011 to 2023 was conducted. Baseline demographics, organ manifestations, biological markers, lung function and therapeutic outcomes were assessed. RESULTS: 23 out of 596 patients in the SA registry were identified to have EGPA. Median time interval between asthma and EGPA diagnosis was 10 years (range 2.5 to 32 years). Almost all patients (95.7%) had peak blood eosinophil count of >1.0 x 109/L (range 0.47 - 14.08 x 109/L). Upper airway involvement was the most detected manifestation in addition to asthma, followed by neuropathy and renal involvement. Patients who were treated with biologic therapy were significantly younger, had more upper airway, renal, pulmonary involvement and lower five factor score (FFS). CONCLUSION: The prevalence of EGPA in the SA population was 3.9% in our cohort. Its diagnosis requires high clinical suspicion in patients with SA and blood eosinophilia, prompting stringent evaluation for extrapulmonary manifestations and multidisciplinary involvement.

Sensitization to Staphylococcus Enterotoxin: Relationship with Aspects of Disease Severity.

Background/Objective: Sensitization to specific IgE Staphylococcus aureus enterotoxins (SEs) is associated with an increased risk for severe asthma development. Limited data exist regarding the association of seropositivity for specific IgE SEs and the different aspects of severe asthma. We aimed to determine whether the presence of SEs is associated with asthma-related parameters such as inflammatory cells in the airways, features of airway remodeling, and other variables relating to asthma assessment and severity. Methods: Fifty patients with severe asthma were recruited in the study. Demographics, comorbidities, asthma duration, and asthma medication were recorded by treating physicians. Specific IgE SE measurement, lung function, atopic status, asthma control test (ACT), sputum induction, bronchoscopy with BAL, and indices of airway remodeling were also assessed. Results: Twelve patients were positive to enterotoxin sensitization. Patients seropositive to specific IgE SEs significantly differed in regard to FEV1% pred and FEV1/FVC ratio compared to seronegative ones. Analyzing the inflammatory variables obtained from induced sputum, BAL, and endobronchial biopsies, the only significant difference was that of smooth muscle area (SMA), which was greater in specific IgE SE seropositive patients. The multivariate linear regression analysis showed two significant associations of specific IgE SE seropositivity. We found a negative with FEV1% pred with beta standardized coefficient 95%CI -0.054 (-0.083, -0.031), p < 0.001, and a positive with SMA with beta standardized coefficient 95%CI 0.054 (0.081, 0.037), p < 0.001. Conclusions: Seropositivity to specific IgE SEs in severe asthma is associated with more severe airflow limitation, obstruction, and upregulation in SMA, indicating a possible role in the remodeling process.

Real-World Efficacy of Biological Therapies in Severe Asthma: A Focus on Small Airways.

Background: Severe asthma is a challenging condition that often resists traditional treatments and requires high-dose inhaled corticosteroids and other controllers to manage uncontrolled symptoms. Recent advances include the use of biologic agents targeting specific inflammation pathways, which have improved symptom control and quality of life, although their effects on small airways remain less understood. Methods: This prospective observational study, conducted at Tor Vergata University Hospital in Rome from July 2021 to March 2024, aims to evaluate the efficacy of treatments in patients with uncontrolled severe asthma. It involves baseline assessments and follow-ups at 1 and 3 months post-biological therapy initiation, focusing on both spirometric and non-spirometric (oscillometry) measurements of the small airways to provide a comprehensive evaluation of respiratory function. Results: This study, conducted from July 2021 to March 2024, enrolled 40 patients with severe asthma, ultimately analyzing data from 31 participants who underwent biological therapy. The results showed significant improvements in asthma symptoms, the ACT scores increased significantly from visit 1 to visit 2 (p = 0.00008) and from visit 1 to visit 3 (p = 0.00047), and pulmonary function tests, with notable increases in FEV1 (from visit 1 (74.97 ± 23.43%) to visit 2 (82.96 ± 26.57%, p = 0.041) and to visit 3 (88.89 ± 31.41%, p = 0.003)) and quality of life scores, and substantial reductions in specific airway resistance and small airway dysfunction markers (the PEF, %pr post-BD showed significant improvement from visit 1 to visit 3 (p = 0.012)). However, oscillometric measurements showed no significant changes post-therapy. Conclusions: The study concluded that there was an improvement in the small airways measured by non-oscillometric values, without significant improvements in oscillometric parameters. Additionally, a significant improvement in symptoms was observed after the first month of therapy. There was also a significant increase in respiratory function after one to three months of therapy.

Fatigue in severe pediatric asthma patients: Results of the PANDA study.

BACKGROUND: Fatigue is a commonly reported clinical symptom, yet research on fatigue in children with severe asthma is missing. We aimed to explore the extent of fatigue in severe pediatric asthma and identify associated factors. METHOD: This study was conducted within the Pediatric Asthma Non-Invasive Diagnostic Approaches (PANDA), an observational cohort of 6- to 17-year-old Dutch children with severe asthma. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL™-MFS) was used to measure self-reported fatigue. Fatigue levels were compared with a general pediatric Dutch population using linear regression, and quantifying the prevalence of "fatigued" (-2 < Standard deviations [SD] ≤ -1) and "severely fatigued" (SD ≤ -2) children. Secondly, we performed linear regression analyses to explore whether fatigue levels were independently associated with asthma attacks, comorbidities, medication, pulmonary function, symptom control, and asthma-related quality of life (QoL). RESULTS: Severe pediatric asthma patients (n = 78, mean age 11.8 ± 3.1 years) reported significantly more fatigue than Dutch peers (n = 328, mean age 11.8 ± 3.2 years) mean difference in z-score: -0.68; 95%CI -0.96, -0.40. In the severe asthma group, 28.2% scored as "fatigued" and 15.4% as "severely fatigued," compared with 14.0% and 3.4% in the general population. In pediatric asthma patients, asthma-related QoL (ß = 0.77, p < .01, ΔR2 = .43), symptom control (ß = 0.56, p < .01, ΔR2 = .24) and a dysfunctional breathing pattern (ß = -0.36, p < .01, ΔR2 = .12) were most strongly associated with fatigue scores. CONCLUSION: Fatigue is a common symptom in children with severe asthma and is associated with multiple clinical factors and patient-reported outcomes. It should be considered as an important treatment target.

A one-year weight management programme for difficult-to-treat asthma with obesity: a randomised controlled study.

BACKGROUND: Obesity-associated asthma results in increased morbidity and mortality. We report one-year asthma outcomes with the Counterweight-Plus weight management programme (CWP) compared to usual care (UC) in a single-centre, randomised, controlled trial in patients with difficult-to-treat asthma and obesity. RESEARCH QUESTION: Can CWP use result in improved asthma control and quality of life compared to UC at one-year in patients with difficult-to-treat asthma and obesity? STUDY DESIGN AND METHODS: We randomised (1:1 CWP:UC) adults with difficult-to-treat asthma and body mass index ≥30kg/m2. CWP with dietitian support: 12-week total diet replacement phase (850kcal/day low-energy formula); food reintroduction and maintenance phases up to one-year. Outcomes include Asthma Control Questionnaire (ACQ-6), Asthma Quality of Life Questionnaire (AQLQ) and healthcare usage. Minimal clinically important difference (MCID) is 0.5 for ACQ-6 and AQLQ. RESULTS: Of 36 recruited, 29 attended at 52-weeks: 13 CWP, 16 UC. CWP resulted in greater weight change (median -14kg [IQR -15, -9]) compared to UC (2kg [-7, 8]; p=0.015) at 52-weeks. A greater proportion achieved MCID with CWP vs UC in AQLQ (71% vs 6% respectively; p<0.001). No between-group differences were observed in ACQ-6. Median exacerbation frequency reduced over 52-weeks with CWP from 4 (IQR 2, 5) to 0 (0, 2) (p<0.001), though no between-group difference was observed. 70% of the CWP group lost ≥10% body weight and had improvement in ACQ-6 (mean difference -1.1, 95%CI -1.9, -0.3; p=0.018) and AQLQ (1.2, 95%CI 0.4, 2.1; p=0.011) across 52-weeks. INTERPRETATION: Use of a dietitian-supported weight management programme results in sustained weight-loss and is a potential treatment for obesity in asthma. CWP resulted in a higher proportion achieving MCID improvement in AQLQ compared to UC. Within group differences in AQLQ and exacerbation frequency suggest potential with CWP. These encouraging signals justify a larger sample study to further assess asthma-related outcomes.

Tezepelumab for severe asthma: elevating current practice to recognize epithelial driven profiles.

BACKGROUND: An increasing amount of evidence supports the relevance of epithelium across the wide spectrum of asthma pathobiology. On a clinical ground tezepelumab, selectively binding TSLP, a major epithelial cytokine, has demonstrated to be effective in asthma patients regardless their specific phenotype. In order to avoid the risk of considering tezepelumab as a not-specific option, the present perspective aims to sketch the tezepelumab best eligible patient profile and to propose some hallmarks of epithelial-driven disease by reviewing the published evidence on the drug mechanism of action and efficacy data. MAIN BODY: Although it cannot rely on standardised or exclusive "markers", the relationship between environment and poor asthma control might suggest a major relevance of the epithelial barrier dysfunction. In that light, allergy and asthma exacerbations concomitant with specific exposures (pathogens, pollutants, chemicals), as well as increased susceptibility to infections can be considered as the hallmark of an impaired epithelial immune response. Tezepelumab is effective in allergic patients, being able to reduce asthma exacerbations precipitated by the exposure to seasonal or perennial aeroallergens, including fungi. In addition, tezepelumab reduced the incidence of co-occurring respiratory illness and asthma exacerbations. In terms of inflammation, epithelial immune response has been related to an impaired mucus hypersecretion and plugging. A placebo-controlled trial demonstrated a significant reduction of mucus plugging in treated patient. Airways hyperreactivity (AHR), airways obstruction and remodelling have been described as an expression of epithelial orchestrated immunological activation. Of note, a significantly higher incidence of mannitol negative test in patients treated with tezepelumab when compared to placebo group has been observed. In addition, A 130 mL improvement in pre-BD FEV1 has been described in patients assuming Tezepelumab. The above-mentioned data suggest that bronchial reversibility and AHR can be considered "functional biomarkers" supporting patients' phenotyping and the identification of tezepelumab best responders. CONCLUSION: Integrating "functional biomarkers" to the inflammatory ones and a better characterization of asthma exacerbations might pave the way to a different and more transversal phenotyping, which overcomes the "restrictive" labels including T2 high, allergic/atopic or T2 low asthma. Precisely defining the disease characteristics and potential targets for a better control even in tezepelumab eligible subjects is essential to avoid the block buster temptation and optimize the personalized medicine approach according to each patient's individuality.

Reduced Effectiveness of Anti-IgE Treatment Among Adults with Severe Asthma with Older Age of Asthma Onset: Results from the CHRONICLE Study.

Purpose: Younger age of asthma onset (AAO) has been associated with an allergic phenotype, whereas eosinophilic phenotypes have been associated with older AAO. In randomized trials, biologic efficacy among adults with severe asthma (SA) has varied by age at asthma onset. To determine whether these associations observed in trials apply to real-world outcomes, this study examined biologic effectiveness by AAO and biologic class in a large, real-world cohort. Patients and methods: CHRONICLE is an ongoing, real-world study of US adults with subspecialist-treated SA receiving biologics, maintenance corticosteroids, or who are uncontrolled on high-dosage inhaled corticosteroids with additional controllers. Patients enrolled between February 2018 and February 2022 who initiated a biologic for SA and had complete data for analysis were included. A locally estimated scatterplot smoothing (LOESS) analysis was used to plot the relationship between percentage exacerbation rate reduction and AAO by biologic class. Results: Of 578 patients with complete data, 198, 149, and 231 were diagnosed with asthma at age <18, 18-39, and ≥40 years, respectively. Across subgroups, patients were predominantly White (72-78%), female (67-73%), and commercially insured (54-71%). In the LOESS analysis, exacerbation rate reductions were similar for anti-IgE and anti-IL-5/5R and anti-IL-4R subgroups with younger AAO, but the exacerbation rate reduction diminished for patients with older AAO receiving anti-IgE therapy, particularly with asthma onset age ≥40 years. Conclusion: Clinicians should consider age of onset in biologic treatment decisions, given reduced effectiveness of omalizumab in patients with asthma onset at age ≥40 years. Clinicaltrialsgov Identifier: NCT03373045.

Psyllium husk (Metamucil®) induced perennial asthma: A case report.

Metamucil®, a soluble fiber supplement for constipation, triggered new onset asthma symptoms in a 44-year-old sensitised nurse after a single inhaled exposure. After the initial event, she had no further exposures. She continued to face challenges with exacerbations, poor asthma control, and chronic cough. Despite 30 years of clinic follow-up, her asthma remained difficult to manage, requiring chronic prednisone. While tapering off corticosteroids, she developed polymyalgia rheumatica. This case underscores that psyllium in Metamucil® can cause reactions ranging from mild to severe, even with a single inhaled exposure, emphasising the need for caution in those without a history of asthma.

E-Cigarette-Associated Acute Severe Asthma in a Smoking-Naïve Adolescent: A Case Report.

Electronic cigarettes (e-cigarettes) have become a prevalent phenomenon among adolescents and young adults, particularly as a perceived less harmful alternative to traditional tobacco cigarettes. A number of potential health risks associated with e-cigarettes have been identified, including links to cardiovascular diseases, asthma, and cancer. Given that adolescents have not yet completed their physical development, they are particularly susceptible to adverse health effects associated with e-cigarettes. This case report details the presentation of a healthy 16-year-old female patient who developed her first episode of acute severe asthma and a concomitant lower respiratory tract infection in a primary care practice setting. Prior to the onset of her symptoms, the smoking-naïve patient intermittently shared a nicotine-containing e-cigarette with a friend over a three-day period. Following outpatient treatment with inhaled corticosteroids, beta-2 agonists, and antibiotics, the asthma and lower respiratory tract infection were found to be reversible within the first week of treatment initiation. It is imperative that preventive measures at the political level be implemented to counteract the appeal and use of e-cigarettes among adolescents.

Effect of biologic therapies on quality of life in severe asthma: Findings from the PRISM study.

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

Real-world phenotyping and risk assessment of childhood asthma burden using national registries.

BACKGROUND: Phenotype classification contributes to risk assessment of asthma. Previous studies have applied this concept primarily to adult populations and in the setting of research protocol assessments which may not be applicable to clinical settings. OBJECTIVE: Exploring the value of routinely collected clinical data for phenotype classification and risk assessment of childhood asthma. METHODS: Using hospital and laboratory data, 29,851 children in a Danish nationwide database aged 2-17 years with ICS-treated asthma in 2015 followed for two years (730 days) were classified to have T2 (elevated blood eosinophils (>300 cells/µL) and/or elevated total- or specific-IgE), and/or non-T2 risk factors (in utero tobacco exposure and/or severe viral infections). Logistic regression was applied to quantify associations of risk factors with asthma severity, control, and exacerbation risk. RESULTS: In a complete case analysis, 85.8 % children had at least one T2 risk factor and 29.3 % had mixed T2/non-T2 risk factors. Elevated blood eosinophils and total/specific IgE were associated with exacerbations (ORs 1.55 (1.38-1.73) and 1.41 (1.20-1.66) and higher asthma severity (1.42 (1.24-1.63) and 1.31 (1.08-1.60)), respectively. Dose-dependency was observed between blood eosinophil counts, total IgE levels, and risk of adverse outcomes. Furthermore, accumulation of risk factors demonstrated an increasing risk, with children with all four risk factors having a high risk of any adverse asthma-related outcome (OR 3.13 (2.03-4.82) CONCLUSION: Asthma phenotypic markers defined in research protocols can be reliably applied in real-world settings by utilizing data collected during routine clinical care and enable better classification of risk of adverse asthma outcomes.

Choosing the Right Biologic for the Right Patient With Severe Asthma.

In this instalment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With 6 biologics now approved for use in this area comprising 4 different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data. We use 4 variations of a case of severe uncontrolled asthma to develop concepts and considerations introduced in the previous installment ("Workup of Severe Asthma") and discuss pregnancy-related, biomarker-related, comorbidity-related, and corticosteroid dependency-related considerations when choosing a biologic. The related questions of deciding when, why, and how to switch from one biologic to another also are discussed. Overall, we consider that the choice of biologics should be based on the available clinical trial data for the desired efficacy outcomes, the biomarker profile of the patient, safety profiles (eg, when pregnancy is considered), and opportunities to target 2 comorbidities with 1 biologic. Using systemic and airway biomarkers (blood eosinophils and exhaled nitric oxide) and other phenotypic characteristics, we suggest a framework to facilitate therapeutic decision-making. Post hoc studies and new comparative studies are needed urgently to test this framework and to determine whether it allows us to make other clinically useful predictions.

The consistently up-regulated expression of NLRP3 in severe asthma patients from mRNA microarray and ovalbumin-induced mouse model of asthma.

Background: Severe asthma (SA) is a chronic lung disease, resistant to current treatments, symbolized by repeated symptoms of reversible airflow obstruction, airway hyper-responsiveness, and inflammation. The aim of this study was to identify genes exhibiting differential expression in individuals without asthma and SA patients. We aimed to pinpoint hub differentially expressed genes (DEGs) by utilizing a mouse model of asthma sensitized to ovalbumin (OVA). Methods: Microarray data for SA were acquired from the Gene Expression Omnibus (GEO) databases. DEGs were identified, and functional enrichment analyses were carried out. STRING and Cytoscape were utilized to design a protein-protein interaction (PPI) network and conduct module analysis. An OVA-induced asthma mice model was established. Lung tissue from the mice was collected for quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry (IHC) to assess the expression of DEGs. Results: A total of 545 DEGs were identified, among which 172 genes were upregulated in SA patients compared to healthy controls. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) was significantly up-regulated in SA patients [adjusted P value (Padj) =0.001]. Analysis of lung tissue using qRT-PCR, western blot, and IHC revealed higher expression of NLRP3 in OVA-induced asthma mice compared to the control group. Enrichment analysis suggests the involvement of NLRP3 in pathways related to pyroptosis, c-type lectin receptor signaling, and NOD-like receptor signaling. Conclusions: Through bioinformatics analysis, we identified a multitude of DEGs that could potentially contribute significantly to the development of SA. Notably, our findings highlight NLRP3 as a potential pivotal player in asthma pathogenesis, underscoring its prospective utility as a biomarker for SA.