T2-low Asthma Research Articles

Signature Proteins in Small Extracellular Vesicles of Granulocytes and CD4+ T-Cell Subpopulations Identified by Comparative Proteomic Analysis.

Several studies have described the proteomic profile of different immune cell types, but only a few have also analysed the content of their delivered small extracellular vesicles (sEVs). The aim of the present study was to compare the protein signature of sEVs delivered from granulocytes (i.e., neutrophils and eosinophils) and CD4+ T cells (i.e., TH1, TH2, and TH17) to identify potential biomarkers of the inflammatory profile in chronic inflammatory diseases. Qualitative (DDA) and quantitative (DIA-SWATH) analyses of in vitro-produced sEVs revealed proteome variations depending on the cell source. The main differences were found between granulocyte- and TH cell-derived sEVs, with a higher abundance of antimicrobial proteins (e.g., LCN2, LTF, MPO) in granulocyte-derived sEVs and an enrichment of ribosomal proteins (RPL and RPS proteins) in TH-derived sEVs. Additionally, we found differentially abundant proteins between neutrophil and eosinophil sEVs (e.g., ILF2, LTF, LCN2) and between sEVs from different TH subsets (e.g., ISG15, ITGA4, ITGB2, or NAMPT). A "proof-of-concept" assay was also performed, with TH2 biomarkers ITGA4 and ITGB2 displaying a differential abundance in sEVs from T2high and T2low asthma patients. Thus, our findings highlight the potential use of these sEVs as a source of biomarkers for diseases where the different immune cell subsets studied participate, particularly chronic inflammatory pathologies such as asthma or chronic obstructive pulmonary disease (COPD).

Antibiotic Therapy in Asthma as One of First Step Treatment, a Phase 3 Randomized Clinical Trial

Background: Focus of this study was on subjects suffering from new onset asthma, but actually, they may involve with an infection. Objectives: The target of this study was to determine the frequency of total control of asthma in new onset asthma. Methods: this is a phase 3 randomized clinical trial. The participants were 50 new onset asthma, who feel suffering from respiratory infection, however the physician diagnosis was asthma according to wheezy chest, spirometry and clear chest roentgenogram. Age less than 18 years and pregnant women were excluded. The subjects were randomly divided into two groups, doxycycline hyclate and the placebo arms. The drugs were repacked in similar in shape container. Primary endpoint was time to first recurrence. Secondary endpoints were frequency of total control of asthma, dyspnea, cough, asthma control test (ACT) score, FEV1, FEV1/FVC, eosinophil and neutrophil in blood and sputum. Results: The difference of clinical findings between two groups before the trial were not significant. Ten percent reported acute attack of asthma during last two months. Treatment with Doxycyline revealed significant improvement of clinical findings, asthma attack and ACT score after two months of treatment, however, complete resolution of clinical findings were significantly higher in Doxycyline group compare to placebo. Clinical findings and FEV1 percent predicted in Doxycyline group T2low asthma group showed significant improvement which were not depicted in T2high group. Eighteen months follow up of the subjects showed complete resolution of asthma symptoms in 12 (48%) on Doxycyline group, which was significantly higher than control group (5 (20%). Time to first exacerbation in doxycycline group was 13.6±5.64 months which was significantly longer than control group (7.49±6.95, P=0.002). Time to first exacerbation in CRP positive was significantly longer (13.64±5.35 months) than CRP negative subjects (9.67±7.76 months, P=0.02). Conclusion: Doxycycline is an effective antibiotic for preventing recurrence of asthma, in selected new subjects who suspicious for respiratory infection.

Anti-aminoacyl-tRNA synthetase-interacting multifunctional protein-1 antibody improves airway inflammation in mice with house dust mite induced asthma

BackgroundSeveral biologics have been developed and used to treat severe asthma. However, commercialized biologics have limitations in treating T2-low asthma because their main target is the T2 inflammation marker. Therefore, there is an unmet need for treating T2-low severe asthma. Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is an auxiliary protein in the mammalian multi-aminoacyl-tRNA synthetase complex. AIMP1 also acts as a cytokine and induces the secretion of proinflammatory cytokines. Since anti-AIMP1 has been shown to reduce interleukin (IL)-6, tumor necrosis factor-α, and IL-17A levels in a mouse model, it could be effective in the treatment of T2-low severe asthma. MethodsWild-type BALB/c mice were sensitized and challenged with intranasal inoculation of a crude HDM extract. Atliximab, a chimeric AIMP1 antibody, was administered once (20 μg, 40 μg, 100 μg) on Day 14. We evaluated airway hyperresponsiveness (AHR), performed cellular analyses of the bronchoalveolar lavage fluid (BALF), measured inflammatory cytokine levels, and examined peribronchial histological features. ResultsAtliximab reduced AIMP1 levels in asthmatic mice in a dose-dependent manner. AHR and Inflammatory cells such as neutrophils and eosinophils in the BALF decreased in asthmatic mice treated with atliximab. The levels of IL-6, IL-13, and transforming growth factor-β (TGF-β) in the lung tissue decreased in asthmatic mice treated with a high dose of atliximab (100 μg). Atliximab also reduced goblet cell hyperplasia and peribronchial fibrosis. ConclusionsAtliximab improved asthmatic airway inflammation including neutrophilic inflammation in HDM-induced asthma mice. These data suggest that anti-AIMP1 plays an important role in the treatment of severe T2-low asthma.

P1061 TEV-48574, an anti-TL1A antibody in development for use in IBD, is safe and well tolerated following 16 weeks of subcutaneous treatment in adults with severe uncontrolled T2-low/non T2 asthma

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). It is in clinical development as a potential treatment for ulcerative colitis (UC) and Crohn’s disease (CD). TL1A signalling is believed to amplify immune-mediated inflammation in asthma and inflammatory bowel disease (IBD); thus, targeting TL1A may mitigate over-activation of immune responses. A proof-of-concept phase 2A study evaluated safety, tolerability and efficacy of TEV-48574 as treatment for adults with severe uncontrolled asthma (Clinicaltrials.gov NCT04545385). Although the study terminated (after meeting pre-specified criteria for futility at a preplanned interim analysis) the drug demonstrated favourable safety, tolerability and immunogenicity data, supporting the potential use of anti-TL1A treatment in patients with UC and CD. Methods TEV-48574 was administered as a loading dose followed by 7 maintenance doses given subcutaneously (sc) every 2 weeks for 16 weeks in adult patients (n = 65) with severe T2-low asthma with no/low inflammation at baseline. The primary efficacy endpoint was reduction in patients who experience loss of asthma control (LoAC). Patients were monitored for LoAC at bi-weekly visits and daily by use of a handheld spirometer/e-diary. Safety was assessed throughout the study. Results Of 65 randomized patients, 64 received at least one dose of study drug and were included in the safety analysis (33 active drug; 31 placebo). There were no severe AEs, treatment related SAEs, deaths, or withdrawals due to adverse events, and no medical device-related issues. There were no clinically meaningful changes in lab parameters, vital signs or ECGs. Furthermore, there was no evidence of immune suppression, opportunistic infections, or malignancies. Mild treatment-related adverse reactions occurred in both treatment groups (erythema and pruritus in two placebo patients; erythema in one TEV-48574 treated patient). Mild injection site reactions occurred more frequently (not statistically different) in the TEV-48574 group. Treatment-emergent anti-drug antibodies were reported in patients taking TEV-48574 (3 patients; 9.09%), with no anaphylactic or severe systemic reactions. Conclusion Overall, TEV-48574 administered every 2 weeks over 16 weeks demonstrated a favourable safety and tolerability profile with no emerging safety signals or evidence of immunosuppression. This is consistent with TL1A being an amplifier of inflammation. Treatment with TEV-48574 may dampen excessive inflammation without inducing a state of immunodeficiency in patients with conditions such as UC or CD, supporting further development in these indications.

Healthcare Resource Utilisation of Severe Uncontrolled T2low and Non-T2low Asthma in Finland During 2018-2021.

Patients with asthma and low levels of type 2 inflammatory biomarkers (T2 low) have limited effective treatment options. Such biomarkers include eg blood eosinophils (b-eos) and fractional exhaled nitric oxide (FeNO). The healthcare resource utilisation (HCRU) of severe uncontrolled T2 low asthma remains unexplored. Thus, this study aimed to estimate the HCRU of T2 low and non-T2 low severe uncontrolled asthma patients using real-world data in Finland. Adult patients with an asthma diagnosis during baseline (2012-2017) at the pulmonary department of Turku University Hospital were included and followed during 2018-2021, or until death. Total HCRU costs and respiratory-related HCRU costs were evaluated. The main drivers for the HCRU and costs were assessed with gamma and negative binomial regression models. Of the severe uncontrolled asthma patients with T2 status available, 40% (N=66) were identified with T2 low and 60% (N=103) with non-T2 low asthma. The average cumulative cost per patient was similar in patients with T2 low compared with non-T2 low, with all-cause costs cumulating in four years of follow-up to 37,524€ (95% CI: 27,160, 47,888) in T2 low compared to 34,712€ (25,484, 43,940) in non-T2 low. The corresponding average cumulative respiratory-related costs were 5178€ (3150, 7205) in T2 low compared to 5209€ (4104, 6313) in non-T2 low. Regression modelling identified no differences between the T2-status groups when assessing all-cause healthcare costs per patient-year (PPY). On the other hand, the regression modelling predicted more inpatient days PPY for severe uncontrolled patients with T2 low status compared to the patients with non-T2 low status. Patients with uncontrolled severe T2 low asthma use equal healthcare resources as corresponding non-T2 low patients. This study brought new insights into the HCRU of severe uncontrolled asthma patients per T2 status, which has not previously been investigated.

T2-low asthma in school-aged children: unacknowledged and understudied

T2-low asthma in school-aged children: unacknowledged and understudied

Comprehensive Characterization of Difficult-to-Treat Asthma Reveals Near Absence of T2-Low Status.

Asthma is conventionally stratified as type 2 inflammation (T2)-high or T2-low disease. Identifying T2 status has therapeutic implications for patient management, but a real-world understanding of this T2 paradigm in difficult-to-treat and severe asthma remains limited. To identify the prevalence of T2-high status in difficult-to-treat asthma patients using a multicomponent definition and compare clinical and pathophysiologic characteristics between patients classified as T2-high and T2-low. We evaluated 388 biologic-naive patients from the Wessex Asthma Cohort of difficult asthma (WATCH) study in the United Kingdom. Type 2-high asthma was defined as 20 parts per billion or greater FeNO , 150 cells/μL or greater peripheral blood eosinophils, the need for maintenance oral corticosteroids, and/or clinically allergy-driven asthma. This multicomponent assessment identified T2-high asthma in 93% of patients (360 of 388). Body mass index, inhaled corticosteroid dose, asthma exacerbations, and common comorbidities did not differ by T2 status. Significantly worse airflow limitation was found in T2-high compared with T2-low patients (FEV1/FVC 65.9% vs 74.6%). Moreover, 75% of patients defined as having T2-low asthma had raised peripheral blood eosinophils within the preceding 10 years, which left only seven patients (1.8%) who had never had T2 signals. Incorporation of sputum eosinophilia 2% or greater into the multicomponent definition in a subset of 117 patients with induced sputum data similarly found that 96% (112 of 117) met criteria for T2-high asthma, 50% of whom (56 of 112) had sputum eosinophils 2% or greater. Almost all patients with difficult-to-treat asthma have T2-high disease; less than 2% of patients never display T2-defining criteria. This highlights a need to assess T2 status comprehensively in clinical practice before labeling a patient with difficult-to-treat asthma as T2-low.

Type 2 Low Biomarker Stability and Exacerbations in Severe Uncontrolled Asthma.

We investigated the stability of T2 low status, based on low levels of T2 biomarkers, and exacerbation rates in T2 low and non-T2 low asthma from clinical retrospective data of severe uncontrolled asthma patients. Knowledge of the T2 low biomarker profile is sparse and biomarker stability is uncharted. Secondary care patients with severe uncontrolled asthma and at least two blood eosinophil counts (BEC) and fractional exhaled nitric oxide (FeNO) measured for determination of type 2 inflammation status were evaluated from a follow-up period of 4 years. Patients were stratified into four groups: T2 low150 (n = 31; BEC < 150 cells/µL and FeNO < 25 ppb), non-T2 low150 (n = 138; BEC > 150 cells/µL and/or FeNO > 25 ppb), T2 low300 (n = 66; BEC < 300 cells/µL and FeNO < 25 ppb), and non-T2 low300 (n = 103; BEC > 300 cells/µL and/or FeNO > 25 ppb). Exacerbation rates requiring hospital care, stability of biomarker status, and cumulative OCS and ICS doses were assessed during follow-up. Among patients with severe uncontrolled asthma, 18% (n = 31) were identified as T2 low150, and 39% (n = 66) as T2 low300. In these groups, the low biomarker profile was stable in 55% (n = 11) and 72% (n = 33) of patients with follow-up measures. Exacerbation rates were different between the T2 low and non-T2 low groups: 19.7 [95% CI: 4.3-45.6] in T2 low150 vs. 8.4 [4.7-13.0] in non-T2 low150 per 100 patient-years. BEC and FeNO are useful biomarkers in identifying T2 low severe uncontrolled asthma, showing a stable follow-up biomarker profile in up to 72% of patients. Repeated monitoring of these biomarkers is essential in identifying and treating patients with T2 low asthma.

Comparison of the effects of itraconazole and prednisolone on fibroblast growth factor-2 gene expression and clinical manifestations in patients with persistent severe asthma.

Considering the possible role of fungal sensitization in the treatment of resistant asthma, which may lead to the remodeling of bronchial structure, we theorized that itraconazole could result in better control of asthma. In this regard, this study aimed to compare the effects of itraconazole and prednisolone (routinely prescribed) on clinical, structural, and biomarker findings of the remodeling of asthma. This double-blind controlled randomized clinical trial was performed on 70 adult patients suffering from severe persistent asthma. The intervention group received 200 mg of itraconazole per day, and the control group received 10 mg of prednisolone per day, for 32 weeks, in addition to the classic treatment of asthma. The subjects were randomly divided into two groups, and assigned by sealed envelope. Blinding was performed by repacking the drug in a similar container. Primary outcomes were asthma control test score, fibroblast growth factor 2, and wall area percentage on RB1 bronchus measured by computed tomography. The outcomes were compared in subjects classified as allergic, eosinophilic, T2 low asthma, and four types of inflammatory cell classification in sputum. Seventy subjects finished the 32-week trial (35 subjects in each group). Baseline data did not show significant differences between groups. A comparison of asthma variants showed significantly more severe cough and dyspnea in the allergic variant and higher spirometry results in T2-low asthma. Sputum cytology revealed a mixed pattern as the most frequent type (47%). After the trial, two groups improved in many parameters; however, FGF-2 improved more significantly by itraconazole (4.66±16.92 decreased to 1.14±2.98), and FEV1/FVC was significantly higher in the itraconazole group, compared to the control group. These results did not change in terms of asthma variants and sputum classification. Itraconazole was superior to prednisolone in the treatment of many clinical and spirometry aspects in severe persistent asthma.

Mitochondria dysfunction in airway epithelial cells is associated with type 2-low asthma.

Background: Type 2 (T2)-low asthma can be severe and corticosteroid-resistant. Airway epithelial cells play a pivotal role in the development of asthma, and mitochondria dysfunction is involved in the pathogenesis of asthma. However, the role of epithelial mitochondria dysfunction in T2-low asthma remains unknown. Methods: Differentially expressed genes (DEGs) were identified using gene expression omnibus (GEO) dataset GSE4302, which is originated from airway epithelial brushings from T2-high (n = 22) and T2-low asthma patients (n = 20). Gene set enrichment analysis (GSEA) was implemented to analyze the potential biological pathway involved between T2-low and T2-high asthma. T2-low asthma related genes were identified using weighted gene co-expression network analysis (WGCNA). The mitochondria-related genes (Mito-RGs) were referred to the Molecular Signatures Database (MSigDB). T2-low asthma related mitochondria (T2-low-Mito) DEGs were obtained by intersecting the DEGs, T2-low asthma related genes, and Mito-RGs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to further explore the potential function of the T2-low-Mito DEGs. In addition, the hub genes were further identified by protein-protein interaction (PPI), and the expressions of hub genes were verified in another GEO dataset GSE67472 and bronchial brushings from patients recruited at Tongji Hospital. Results: Six hundred and ninety-two DEGs, including 107 downregulated genes and 585 upregulated genes were identified in airway epithelial brushings from T2-high and T2-low asthma patients included in GSE4302 dataset. GSEA showed that mitochondrial ATP synthesis coupled electron transport is involved in T2-low asthma. Nine hundred and four T2-low asthma related genes were identified using WGCNA. Twenty-two T2-low-Mito DEGs were obtained by intersecting the DEGs, T2-low asthma and Mito-RGs. The GO enrichment analysis of the T2-low-Mito DEGs showed significant enrichment of mitochondrial respiratory chain complex assembly, and respiratory electron transport chain. PPI network was constructed using 22 T2-low-Mito DEGs, and five hub genes, ATP5G1, UQCR10, NDUFA3, TIMM10, and NDUFAB1, were identified. Moreover, the expression of these hub genes was validated in another GEO dataset, and our cohort of asthma patients. Conclusion: This study suggests that mitochondria dysfunction contributes to T2-low asthma.

T2-Low Asthma: A Discussed but Still Orphan Disease

Asthma affects 10% of the worldwide population; about 5% of cases are severe with the need for target therapies such as biologics. All the biologics approved for asthma hit the T2 pathway of inflammation. T2-high asthma is classified as allergic and non-allergic, whereas T2-low asthma can be further defined as paucigranulocytic asthma, Type 1 and Type-17 inflammation and the neutrophilic form that accounts for 20-30% of all patients with asthma. Neutrophilic asthma's prevalence is even higher in patients with severe or refractory asthma. We searched Medline and PubMed archives from the past ten years for articles with the subsequent titles: "neutrophilic asthma", "non-type 2 asthma" and "paucigranulocytic asthma". We identified 177 articles; 49 were considered relevant by the title and 33 by the reading of the abstract. Most of these articles are reviews (n = 19); only 6 are clinical trials. No study identified an effective treatment. We used the literature reported by these articles to search for further biologic treatments that target pathways different from T2. We identified 177 articles, 93 of which were considered relevant for the review and included in the present article. In conclusion, T2-low asthma remains poorly investigated in terms of biomarkers, especially as a therapeutic orphan disease.

Evaluating the effects of vitamin D Level on airway obstruction in two asthma endotypes in humans and in two mouse models with different intake of vitamin D during early-life.

Asthma is primarily divided into two categories: type 2 (T2-high) and non-type 2 (T2-low). A relationship between asthma severity and vitamin D deficiency has been identified, but its impact on each asthma endotype remains unknown. We clinically examined the influence of vitamin D on patients with T2-high (n = 60) or T2-low asthma (n = 36) compared with controls (n = 40). Serum 25(OH)D levels, inflammatory cytokines and spirometry were measured. Mouse models were then used to further analyze the effects of vitamin D on both asthmatic endotypes. BALB/c mice were fed with vitamin D-deficient (LVD), -sufficient (NVD), or -supplemented diets (HVD) throughout lactation and offspring followed the same diet after weaning. Offspring were sensitized/challenged with ovalbumin (OVA) to establish "T2-high" asthma or OVA combined with ozone exposure (OVA + ozone) to induce "T2-low" asthma. Spirometry and serum, bronchoalveolar lavage fluid (BALF), and lung tissues were analyzed. Serum 25(OH)D levels were decreased in asthmatic patients compared with controls. Patients with vitamin D deficiency (Lo) had varying degrees of elevation of the pro-inflammatory cytokines IL-5, IL-6, and IL-17A, decreased expression of the anti-inflammatory cytokine IL-10, and altered forced expiratory volume in the first second as a percentage of predicted value (FEV1%pred) in both asthmatic endotypes. Vitamin D status had a stronger correlation with FEV1%pred in T2-low asthma than T2-high asthma, and 25(OH)D level was only positively linked to maximal mid-expiratory flow as a percentage of predicted value (MMEF%pred) in the T2-low group. Inflammation, hyperresponsiveness, and airway resistance (RL) was increased in both asthma models compared with controls while vitamin D deficiency further increased airway inflammation and airway obstruction. These findings were particularly prominent in T2-low asthma. The potential function and mechanisms of vitamin D and both asthma endotypes should be studied individually, and further analysis of the potential signaling pathways involved with vitamin D on T2-low asthma is warranted.

Phenotype characterization and biomarker evaluation in moderate to severe type 2-high asthma.

There are two major pathological phenotypes of asthma, type 2 (T2)-high and T2-low asthma, which are important in determining treatment strategies. However, the characteristics and phenotypes of T2-high asthma have not yet been fully identified. This study aimed to identify the clinical characteristics and phenotypes of patients with T2-high asthma. This study used data from a nationwide asthma cohort study in Japan, NHOM Asthma Study. T2-high asthma was defined as a blood eosinophils count ≥ 300 /μL and/or fractional exhaled nitric oxide level ≥ 25 ppb, and the clinical characteristics and biomarkers were compared between T2-high and T2-low asthma. Furthermore, T2-high asthma was phenotyped via hierarchical cluster analysis using Ward's method. Patients with T2-high asthma were older, less likely to be female, had longer asthma duration, had lower pulmonary function, and had more comorbidities, including sinusitis and SAS. Patients with T2-high asthma showed higher serum thymus and activation-regulated chemokine and urinary leukotriene E4 levels and lower serum ST2 levels than those with T2-low asthma. There were four phenotypes among patients with T2-high asthma: Cluster 1 (youngest, early-onset, and atopic), Cluster 2 (long duration, eosinophilic, and low lung function), Cluster 3 (elderly, female-dominant, and late-onset), and Cluster 4 (elderly, late-onset, and asthma-COPD overlap-dominant). Patients with T2-high asthma have distinct characteristics and four distinct phenotypes, in which eosinophil-dominant Cluster 2 is the most severe phenotype. The present findings may be useful in precision medicine for asthma treatment in the future.

A Retrospective Claims Database Study to Clarify Disease Burden of Severe Asthma Patients with Type 2 High or Low Inflammation

The disease burden of severe asthma patients stratified by type 2 (T2) biomarkers is not well studied in large patient samples, especially for T2-low severe asthma patients. Using a Japanese medical record database, we investigated disease and economic burdens in T2-high and T2-low severe asthma patients. Data of severe asthma patients (receiving high-dose inhaled corticosteroids and additional asthma-related controller medications or oral corticosteroids [OCS] prescription [≥183 days] during the 1-year baseline period) were analyzed in the Real World Data database, comprising electronic medical records from Japanese medical institutions. Severe asthma patients were stratified into a T2-high population with higher eosinophils (≥150 cells/μL) and/or higher total immunoglobulin E (IgE, ≥75 IU/mL) or a T2-low population with lower eosinophils (<150 cells/μL) and lower total IgE (<75 IU/mL). The incidence of asthma exacerbation events and drug costs were analyzed for each population. Different T2 thresholds were explored, including eosinophil count 300 cells/μL and/or IgE 150 IU/mL. Of the 732 severe asthma patients, 599 (81.8%) patients had T2-high type, and 133 (18.2%) had T2-low type. Proportions of the T2-high patients (30.6%) with asthma exacerbations, defined as a composite outcome, including OCS burst, injectable steroid use, and hospitalization, were similar to those of T2-low type (34.6%). The annual drug cost was similar between T2-high (175,487 JPY) and T2-low (165,322 JPY) populations. In this large-scale study, both T2-high and T2-low severe asthma patients in Japan were shown to have a high disease burden and high economic burden, suggesting an unmet treatment need.

Sounding the alarmins-The role of alarmin cytokines in asthma.

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Monoclonal antibodies in the management of asthma: Dead ends, current status and future perspectives.

Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that target key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on anti-IgE, anti-IL-5 and other immunological pathways indicate these therapies to offer reduced exacerbation rates, improved lung function, greater asthma control and better quality of life. However, as several patients still do not achieve satisfactory clinical response with the antibodies available, many more biologics, aiming different immunological pathways, are under evaluation. This review summarizes recent data on existing and potential monoclonal antibodies in asthma. Recent advances have resulted in the registration of a new antibody targeting TSLP (tezepelumab), with others being under development. Some of the researched monoclonal antibodies (e.g. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secukinumab) have shown optimistic results in preliminary research; however, these have been discontinued in asthma clinical research. In addition, as available monoclonal antibody treatments have shown little benefit among patients with T2-low asthma, research continues in this area, with several antibodies in development. This article summarizes the available pre-clinical and clinical data on new and emerging drugs for treating severe asthma, discusses discontinued treatments and outlines future directions in this area.

EE41 Healthcare Resource Utilization of Severe, Uncontrolled T2LOW and Non-T2LOW Asthma in Finland During 2018-2021

Patients with asthma and low levels of type 2 inflammation biomarkers (T2low) have limited effective treatment options and healthcare resource utilization (HCRU) of severe, uncontrolled T2low asthma remains unexplored. We estimated HCRU of T2low and non-T2low patients using real world data.

Primary antibody deficiencies represent an underestimated comorbidity in asthma patients: efficacy of immunoglobulin replacement therapy in asthma control

Objective Primary antibody deficiencies (PAD) are an underestimated comorbidity in asthma and its treatment could improve disease control. Methods a retrospective cohort of asthmatics, affected by IgG subclass deficiency or unclassified antibody deficiency and treated with low-dose intravenous immunoglobulin replacement therapy (IRT) was recruited. Demographic and clinical data, chest CT scan, blood eosinophils, atopy, chronic oral corticosteroid (OCS) therapy were evaluated at baseline. Asthma exacerbations, lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI) and asthma-related hospitalizations were assessed after one and two years of IRT. Results 57 moderate-to-severe asthmatics were enrolled, mostly affected by T2 low asthma (39/57, 68.4%). After one year, IRT was effective in improving, irrespective of bronchiectasis, atopy, eosinophils and PAD type: 1) trough IgG (826.9 ± 221.3 vs 942.2 ± 195.1 mg/dl; p < 0.0001) and IgG subclasses (IgG1 355.4 ± 88.4 vs 466.7 ± 122.3, p < 0.0001; IgG2 300.1 ± 130.1 vs 347.6 ± 117.3, p < 0.0005) serum levels. 2) asthma exacerbations (6.4 ± 4.1 vs 2.4 ± 1.9, p < 0.0001), LRTI (4.3 ± 3.9 vs 1.3 ± 1.5, p < 0.0001) and hospitalization rate (0.26 ± 0.7 vs 0.05 ± 0.2, p < 0.01). These results persisted after 2 years of therapy. Estimated mean cumulative OCS exposure was reduced by 4500 mg over the 2-year period. Conclusions low-dose IRT is effective in improving asthma control and lessening OCS burden in asthmatics affected by PAD.

IL1RAP expression and the enrichment of IL-33 activation signatures in severe neutrophilic asthma.

Interleukin (IL)-33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes. To derive gene signatures from in vitro studies of IL-33-stimulated cells and use these to determine IL-33-associated enrichment patterns in asthma. Signatures downstream of IL-33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U-BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes. IL-33-activated gene signatures were cell-specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF-κB, IL-17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL-33-activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL-33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL-33 receptor, was up-regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co-receptor, was greatest in severe neutrophilic and mixed granulocytic asthma. IL-33-activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co-receptor expression. This suggests incorporating T2-low asthma in anti-IL-33 trials.

Severe non-atopic asthma: omalizumab can reduce severe asthma exacerbations

Introduction Humanized monoclonal anti-IgE antibody (omalizumab) has demonstrated efficacy in severe atopic asthma. However, few studies have assessed its efficacy in non-atopic and even less in T2-low severe asthma. The objective was to determinate the omalizumab response according to atopic status. Methods This retrospective, real-world study was performed in the Chest Diseases Department of Strasbourg University Hospital from January 1, 2006, to June 30, 2017. The response to omalizumab was assessed in 139 patients 4, 6, and 12 months after treatment and compared to data collected prior to omalizumab initiation. Results Forty-four patients (31.7%) had severe non-atopic asthma and 95 (68.3%) had a severe atopic asthma. In the non-atopic group, omalizumab significantly reduced the severe exacerbation rate by 44% (95% CI 18-64%, p < 0.05), 43% (CI 95% 20-60%, p < 0.05), and 54% (CI 95% 36-67%, p < 0.05), at 4, 6 and 12 months, respectively. A trend toward improvement in FEV1, asthma control and oral corticosteroid use was also observed. These results were not significantly different from those obtained in atopic asthmatics except a more effective oral corticosteroid sparing in atopic group (p < 0.05). Similar reduction of severe exacerbation rates were observed in T2-low asthma subgroup (non-atopic, non-eosinophilic). Conclusion Omalizumab was effective in severe asthma, regardless of atopic status.