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BACKGROUND: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete. OBJECTIVE: We sought to determine phenotypic factors associated with FEV1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort. METHODS: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV1 and prebronchodilator FEV1/forced vital capacity. RESULTS: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV1 include baseline Feno (B, -49 mL/log2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV1; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV1 at each successive year. CONCLUSIONS: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV1 over time. Boys with recurrent exacerbations are at high risk of lower FEV1 through childhood.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

BackgroundCurrently, there is limited knowledge regarding which imaging assessments of asthma are associated with accelerated longitudinal decline in lung function.ObjectivesWe aimed to assess whether quantitative computed tomography (qCT) metrics are associated with longitudinal decline in lung function and morbidity in asthma.MethodsWe analyzed 205 qCT scans of adult patients with asthma and calculated baseline markers of airway remodeling, lung density, and pointwise regional change in lung volume (Jacobian measures) for each participant. Using multivariable regression models, we then assessed the association of qCT measurements with the outcomes of future change in lung function, future exacerbation rate, and changes in validated measurements of morbidity.ResultsGreater baseline wall area percent (β = -0.15 [95% CI = -0.26 to -0.05]; P < .01), hyperinflation percent (β = -0.25 [95% CI = -0.41 to -0.09]; P < .01), and Jacobian gradient measurements (cranial-caudal β = 10.64 [95% CI = 3.79-17.49]; P < .01; posterior-anterior β = -9.14, [95% CI = -15.49 to -2.78]; P < .01) were associated with more severe future lung function decline. Additionally, greater wall area percent (rate ratio = 1.06 [95% CI = 1.01-1.10]; P = .02) and air trapping percent (rate ratio =1.01 [95% CI = 1.00-1.02]; P = .03), as well as lower decline in the Jacobian determinant mean (rate ratio = 0.58 [95% CI = 0.41-0.82]; P < .01) and Jacobian determinant standard deviation (rate ratio = 0.52 [95% CI = 0.32-0.85]; P = .01), were associated with a greater rate of future exacerbations. However, imaging metrics were not associated with clinically meaningful changes in scores on validated asthma morbidity questionnaires.ConclusionsBaseline qCT measures of more severe airway remodeling, more small airway disease and hyperinflation, and less pointwise regional change in lung volumes were associated with future lung function decline and asthma exacerbations.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

BackgroundTools for quantification of asthma severity are limited.ObjectiveWe sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations.MethodsBaseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics.ResultsASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall.ConclusionsThe ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

BackgroundAirway type 2 inflammation is usually corticosteroid sensitive, but the role of type 2 inflammation as a mechanism of asthma in patients receiving high-dose inhaled corticosteroids (ICSs) is uncertain.ObjectiveWe sought to determine whether airway type 2 inflammation persists in patients treated with ICSs and to evaluate the clinical features of patients with steroid-resistant airway type 2 inflammation.MethodsWe used quantitative PCR to generate a composite metric of type 2 cytokine gene expression (type 2 gene mean [T2GM]) in induced sputum cells from healthy control subjects, patients with severe asthma receiving ICSs (n = 174), and patients with nonsevere asthma receiving ICSs (n = 85). We explored relationships between asthma outcomes and T2GM values and the utility of noninvasive biomarkers of airway T2GM.ResultsSputum cell T2GM values in asthmatic patients were significantly increased and remained high after treatment with intramuscular triamcinolone. We used the median T2GM value as a cutoff to classify steroid-treated type 2-low and steroid-resistant type 2-high (srT2-high) subgroups. Compared with patients with steroid-treated type 2-low asthma, those with srT2-high asthma were older and had more severe asthma. Blood eosinophil cell counts predicted srT2-high asthma when body mass index was less than 40 kg/m2 but not when it was 40 kg/m2 or greater, whereas blood IgE levels strongly predicted srT2-high asthma when age was less than 34 years but not when it was 34 years or greater.ConclusionDespite ICS therapy, many asthmatic patients have persistent airway type 2 inflammation (srT2-high asthma), and these patients are older and have more severe disease. Body weight and age modify the performance of blood-based biomarkers of airway type 2 inflammation.

Background: Clinical trials and real-world experience have provided evidence for the clinical benefit of mepolizumab, an anti-IL-5 biologic, in severe asthma. However, limited data exists regarding the impact of mepolizumab on airway remodelling., Objective: We thus investigated the effect of mepolizumab on airway structural remodelling in patients treated for severe asthma in routine clinical care., Methods: MESILICO is a multicenter study involving 8 Pulmonology Departments in Greece. This study focused on patients who initiated mepolizumab for severe asthma with an eosinophilic phenotype and had late-onset disease with obstructive patterns (impaired reversibility). Forty-seven patients were recruited, of whom 41 were enrolled in the bronchoscopy sub-study. The findings were related to clinical outcome., Results: After 12 months, mepolizumab treatment was associated with significant improvements in lung function and ACT score, along with a significant decrease in severe exacerbation events (p<0.001). Thirty four of the 41 participants (83%) had paired biopsies for comparative analysis. There was a significant reduction from baseline in sub-basement membrane thickness, airway smooth muscle area, airway smooth muscle layer thickness and extent of epithelial damage, as well as a decrease in tissue eosinophil numbers (all p<0.001). The extent of ASMLT reduction positively correlated with the submucosal eosinophil reduction (r= 0.599, p<0.001)., Conclusion: This study identifies that 12 month of mepolizumab treatment in patients with late-onset severe asthma, who are also characterized by eosinophilic and impaired reversibility phenotypes, leads not only to clinical improvement but also reduces indices of airway tissue remodelling suggestive of a disease modifying effect., (Copyright © 2024. Published by Elsevier Inc.)

Background: Switching biologics is now common practice in severe eosinophilic asthma. After insufficient response to anti-IL-5 or 5 receptor (anti-IL-5/5R), the optimal switch between an anti-IL-4R mAb (interclass) or another anti-IL-5/5R drug (intraclass) remains unknown., Objective: We sought to compare the effectiveness of these 2 strategies in asthma control in patients with severe eosinophilic asthma and insufficient response to an anti-IL-5/5R mAb., Methods: We emulated a target randomized trial using observational data from the Recherche sur les AsthMes SEvèreS (RAMSES) cohort. Eligible patients were switched to an anti-IL-4R mAb or another anti-IL-5/5R drug after insufficient response to an anti-IL-5/5R mAb. The primary outcome was the change in Asthma Control Test score at 6 months., Results: Among the 2046 patients in the cohort, 151 were included in the study: 103 switched to an anti-IL-4R mAb and 48 to another anti-IL-5/5R. At 6 months, the difference in Asthma Control Test score improvement was not statistically significant (mean difference groups, 0.82 [-0.47 to 2.10], P = .213). The interclass group exhibited greater cumulative reduction in oral corticosteroid dose (P inter-intra , -1.05 g [-1.76 to -0.34], P = .041). The interclass group had a better effect, although not significantly, on reducing exacerbations (Δ inter-intra , -0.37 [-0.77 to 0.02], P = .124) and increasing lung function (FEV 1 ) (126.8 mL [-12.7 to 266.4], P = .124)., Conclusions: After anti-IL-5/5R mAb insufficient response, switching to dupilumab demonstrated similar improvement in Asthma Control Test scores compared with intraclass switching. However, it appeared more effective in reducing oral corticosteroid use. Larger studies are warranted to confirm these results., Competing Interests: Disclosure statement The RAMSES cohort is funded by the French Pneumology Society (SPLF, Société de Pneumologie de Langue Française), AstraZeneca, GlaxoSmithKline, Sanofi as well as Boston Scientific and Novartis. The funders were not involved in the study initiative, statistical analysis plan, interpretation of results, and decision to publish the current study. The Délégation à la Recherche Clinique et à l’Innovation de l'Assistance Publique-Hôpitaux de Paris is the sponsor of the RAMSES cohort. S.V. was awarded a research grant “Année Recherche” by the Regional Health Agency (Agence Régionale de Santé, Ile-de-France). Disclosure of potential conflict of interest: C. Taillé received fees from Sanofi, AstraZeneca, GlaxoSmithKline, and Novartis for advisory board education and has been an investigator for trials sponsored by Sanofi, AstraZeneca, GlaxoSmithKline, and Novartis, outside of this work. C. Chenivesse received grants from AstraZeneca, GlaxoSmithKline, Novartis, and Santelys, personal fees from ALK-Abelló, AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, and Sanofi-Regeneron, and congress support from AstraZeneca, Boehringer-Ingelheim, Chiesi, Novartis, and Sanofi-Regeneron. G. Devouassoux received grants for clinical research from GlaxoSmithKline and Sanofi, consulting fees from Sanofi, AstraZeneca, GlaxoSmithKline, Chiesi, Menarini, and ALK, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Sanofi, AstraZeneca, GlaxoSmithKline, Chiesi, Menarini, and ALK, and for expert testimony and attending meetings and/for travel from Sanofi, AstraZeneca, and GlaxoSmithKline. P. Bonniaud received research grants from AstraZeneca, payment or honoraria for symposium from Sanofi and AstraZeneca, support for attending medical and research meetings from AstraZeneca, Novartis, Sanofi, Boehringer, and Stallergene, and personal fees for advisory board from AstraZeneca, Novartis, Sanofi, GlaxoSmithKline, and Boehringer. A. Beurnier received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca and Sanofi. A. Bourdin received grants or contracts from AstraZeneca, Boeringher, and GlaxoSmithKline, consulting fees from AstraZeneca, Sanofi, GlaxoSmithKline, Chiesi, Celtrion, Boeringher, and Novartis, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca, Sanofi-Regeneron, GlaxoSmithKline, Boeringher, and Novartis, support for attending meetings and/or travel from AstraZeneca and Sanofi, and participation on a Data Safety Monitoring Board or Advisory Board from ABscience. A. Boudjemaa received consulting fees from AstraZeneca, payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca, Sanofi Genzyme, GlaxoSmithKline, support for attending meetings and/or travel from AstraZeneca, Sanofi Genzyme, and GlaxoSmithKline, and participation on a Data Safety Monitoring Board or Advisory Board from Astra Zeneca, Sanofi Genzyme, GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility., Objectives: We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti-type 2 (T2) asthma biomarker., Methods: Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation., Results: Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10 -3 ). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10 -3 ) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of T H 2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of T H 1 and inflammation genes (IL12A, MUC5B, and CC16) and T H 17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10 -6 )., Conclusions: Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma., Competing Interests: Disclosure statement Supported by National Institutes of Health grants HL142769 and AI149754. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1β overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1β production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients., Objective: We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway., Methods: We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed in vitro and in vivo., Results: When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1β production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1β release in NA., Conclusions: IL-1β overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Rhinovirus (RV) infections trigger wheeze episodes in children. Thus, understanding of the lung inflammatory response to RV in children with wheeze is important., Objectives: This study sought to examine the associations of RV on bronchoalveolar lavage (BAL) granulocyte patterns and biomarkers of inflammation with age in children with treatment-refractory, recurrent wheeze (n = 616)., Methods: Children underwent BAL to examine viral nucleic acid sequences, bacterial cultures, granulocyte counts, and phlebotomy for both general and type-2 inflammatory markers., Results: Despite the absence of cold symptoms, RV was the most common pathogen detected (30%), and when present, was accompanied by BAL granulocytosis in 75% of children. Compared to children with no BAL pathogens (n = 341), those with RV alone (n = 127) had greater (P < .05) isolated neutrophilia (43% vs 16%), mixed eosinophils and neutrophils (26% vs 11%), and less pauci-granulocytic (27% vs 61%) BAL. Children with RV alone furthermore had biomarkers of active infection with higher total blood neutrophils and serum C-reactive protein, but no differences in blood eosinophils or total IgE. With advancing age, the log odds of BAL RV alone were lower, 0.82 (5th-95th percentile CI: 0.76-0.88; P < .001), but higher, 1.58 (5th-95th percentile CI: 1.01-2.51; P = .04), with high-dose daily corticosteroid treatment., Conclusions: Children with severe recurrent wheeze often (22%) have a silent syndrome of lung RV infection with granulocytic bronchoalveolitis and elevated systemic markers of inflammation. The syndrome is less prevalent by school age and is not informed by markers of type-2 inflammation. The investigators speculate that dysregulated mucosal innate antiviral immunity is a responsible mechanism., Competing Interests: Disclosure Statement W.G. Teague has received funding from the UVA Ivy Foundation Distinguished Chair, National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants 1RO1AI 176171 and 5R21AI151496, NIH/National Heart, Lung, and Blood Institute grant 5UG1HL139126, NIH/integrated Translational Health Research Institute of Virginia Clinical and Translational Science Award UL1TR003015, and NIH/Small Business Innovation Research grant RFA-MD-22-004. L. Borish has received funding from the NIH/National Institute of Allergy and Infectious Diseases (grants UO1 AI123337 and R56 AI 158519). C.D. Griffiths has received funding from the Human Frontier Science Program Fellowship LT000469/2021-L. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Airway remodeling is a prominent feature of asthma, which involves increased airway smooth muscle mass and altered extracellular matrix composition. Bronchial thermoplasty (BT), a bronchoscopic treatment for severe asthma, targets airway remodeling., Objective: We sought to investigate the effect of BT on extracellular matrix composition and its association with clinical outcomes., Methods: This is a substudy of the TASMA trial. Thirty patients with severe asthma were BT-treated, of whom 13 patients were treated for 6 months with standard therapy (control group) before BT. Demographic data, clinical data including pulmonary function, and bronchial biopsies were collected. Biopsies at BT-treated and nontreated locations were analyzed by histological and immunohistochemical staining. Associations between histology and clinical outcomes were explored., Results: Six months after treatment, it was found that the reticular basement membrane thickness was reduced from 7.28 μm to 5.74 μm (21% relative reduction) and the percentage area of tissue positive for collagen increased from 26.3% to 29.8% (13% relative increase). Collagen structure analysis revealed a reduction in the curvature frequency of fibers. The percentage area positive for fibulin-1 and fibronectin increased by 2.5% and 5.9%, respectively (relative increase of 124% and 15%). No changes were found for elastin. The changes in collagen and fibulin-1 negatively associated with changes in FEV 1 reversibility., Conclusions: Besides reduction of airway smooth muscle mass, BT has an impact on reticular basement membrane thickness and the extracellular matrix arrangement characterized by an increase in tissue area occupied by collagen with a less dense fiber organization. Both collagen and fibulin-1 are negatively associated with the change in FEV 1 reversibility., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids., Objectives: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores., Methods: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated., Results: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level., Conclusions: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication., Objective: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs., Methods: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression., Results: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs., Conclusions: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Therapies directed against epithelial-derived cytokines, often referred to as alarmins, have been studied in large randomized trials, and reports suggest possible benefit for non-type 2 as well as type 2 severe asthma., Methods: We performed a systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process, and Web of Science databases from inception to March 2022. We performed a random-effects pairwise meta-analysis of randomized controlled trials addressing antialarmin therapy in severe asthma. Results use relative risk (RR) values and 95% confidence intervals (CIs). For continuous outcomes, we report mean difference (MD) values and 95% CIs. We define high eosinophils as ≥300 cells/μL and low eosinophils as <300 cells/μL. We used Cochrane-endorsed RoB 2.0 software to assess the risk of bias of trials, and we used the Grades of Recommendation Assessment, Development, and Evaluation (aka GRADE) framework to assess the certainty of the evidence., Results: We identified 12 randomized trials including 2391 patients. Antialarmins probably reduce annualized exacerbation rates in patients with high eosinophils (RR 0.33 [95% CI 0.28 to 0.38]; moderate certainty). Antialarmins may reduce this rate in patients with low eosinophils (RR 0.59 [95% CI 0.38 to 0.90]; low certainty). Antialarmins improve FEV 1 in patients with high eosinophils (MD 218.5 mL [95% CI 160.2 to 276.7]; high certainty). Antialarmin therapy probably does not improve FEV 1 in patients with low eosinophils (MD 68.8 mL [95% CI 22.4 to 115.2]; moderate certainty). Antialarmins reduce blood eosinophils, total IgE, and fractional excretion of nitric oxide across studied subjects., Conclusion: Antialarmins are effective at improving lung function and probably reduce exacerbations in patients with severe asthma and blood eosinophils ≥300 cells/μL. The effect on patients with lower eosinophils is less certain., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Severe asthma in childhood confers substantial patient- and society-level burdens. Although biologics have been available for the management in adults and adolescents for nearly 20 years, research on the efficacy and safety of biologics in children and adolescents has lagged. Fortunately, more recent research specifically in children has provided an evidence base for biologic use in this age group. Most children with severe asthma demonstrate a type 2 inflammatory phenotype, the primary target of currently approved biologics. Three biologics, omalizumab, mepolizumab, and duplilumab, are Food and Drug Administration-approved for children as young as 6 years, whereas benralizumab and tezepelumab are approved for adolescents older than 12 years. All these agents reduce the rates of severe asthma exacerbations, whereas their effects on pulmonary function vary across agents. Safety profiles are reassuring, although additional long-term safety data in children are still needed. The choice of a biologic agent follows a careful assessment of other factors that contribute to uncontrolled asthma and includes biomarkers of blood eosinophils, fractional exhaled nitric oxide, allergic sensitization, and IgE levels. This review focuses on the underlying pathophysiology of childhood asthma, an approach to phenotyping patients, and the efficacy, safety, and use of biologics in children and adolescents with severe asthma., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Airway hyperresponsiveness (AHR) and eosinophilia are hallmarks of persistent asthma., Objective: We investigated whether eosinophil depletion with benralizumab might attenuate indirect mannitol AHR in severe uncontrolled asthma using a pragmatic open-label design., Methods: After a 4-week run-in period with provision of usual inhaled corticosteroids and/or long-acting β-agonist (baseline), adults with mannitol-responsive uncontrolled severe eosinophilic asthma received 3 doses of open-label benralizumab 30 mg every 4 weeks, followed by 16 weeks' washout after the last dose. The primary outcome was doubling difference (DD) in provocative dose of mannitol required to decrease FEV 1 by 10% (PD 10 ) at the end point after 12 weeks, powered at 90% with 18 patients required to detect 1 DD. Secondary outcomes included measures assessed by the asthma control questionnaire and mini-asthma quality of life questionnaire., Results: Twenty-one patients completed 12 weeks' benralizumab therapy at the end point at week 12. Mean (SEM) age was 53 (4) years, and FEV 1 80.2% (4.1%) inhaled corticosteroid dose was 1895 (59) μg, with 12 receiving long-acting muscarinic antagonist and 13 leukotriene receptor antagonists. Improvement in AHR was significant by 8 weeks, with a mean 2.1 DD (95% confidence interval 1.0, 3.3; P < .01) change in PD 10 at week 12, while mean changes in asthma control questionnaire and mini-asthma quality of life questionnaire were significant by week 2 and sustained over 12 weeks, both exceeding the minimal important difference. Peripheral blood eosinophils were depleted by 2 weeks (439 to 6 cells/μL). No significant improvement occurred in lung function after 12 weeks. Domiciliary peak flow and symptoms also improved with benralizumab., Conclusion: Eosinophil depletion results in clinically meaningful attenuated AHR in severe uncontrolled asthma patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Unsupervised clustering of biomarkers derived from noninvasive samples such as nasal fluid is less evaluated as a tool for describing asthma endotypes., Objective: We sought to evaluate whether protein expression in nasal fluid would identify distinct clusters of patients with asthma with specific lower airway molecular phenotypes., Methods: Unsupervised clustering of 168 nasal inflammatory and immune proteins and Shapley values was used to stratify 43 patients with severe asthma (endotype of noneosinophilic asthma) using a 2 "modeling blocks" machine learning approach. This algorithm was also applied to nasal brushings transcriptomics from U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes). Feature reduction and functional gene analysis were used to compare proteomic and transcriptomic clusters. Gene set variation analysis provided enrichment scores of the endotype of noneosinophilic asthma protein signature within U-BIOPRED sputum and blood., Results: The nasal protein machine learning model identified 2 severe asthma endotypes, which were replicated in U-BIOPRED nasal transcriptomics. Cluster 1 patients had significant airway obstruction, small airways disease, air trapping, decreased diffusing capacity, and increased oxidative stress, although only 4 of 18 were current smokers. Shapley identified 20 cluster-defining proteins. Forty-one proteins were significantly higher in cluster 1. Pathways associated with proteomic and transcriptomic clusters were linked to T H 1, T H 2, neutrophil, Janus kinase-signal transducer and activator of transcription, TLR, and infection activation. Gene set variation analysis of the nasal protein and gene signatures were enriched in subjects with sputum neutrophilic/mixed granulocytic asthma and in subjects with a molecular phenotype found in sputum neutrophil-high subjects., Conclusions: Protein or gene analysis may indicate molecular phenotypes within the asthmatic lower airway and provide a simple, noninvasive test for non-type 2 immune response asthma that is currently unavailable., (Copyright © 2022. Published by Elsevier Inc.)

Biologics or molecularly targeted drugs are often highly effective for the treatment of allergic diseases and other immunologic disorders, and they are relatively safe for short-term use as compared with conventional approaches such as the systemic use of corticosteroids. A number of studies published in 2021 consistently demonstrated their effectiveness and also revealed unanticipated findings. Among them, clinical trials for asthma and chronic obstructive pulmonary disease using biologics targeting thymic stromal lymphopoietin, IL-33, and IL-33 receptor demonstrated that these type 2 alarmin cytokines are also involved in non-type 2, noneosinophilic inflammation. Randomized controlled trials reporting the efficacies of 2 small-molecule oral drugs targeting Janus kinase-1 had a substantial impact on the management of atopic dermatitis. These drugs demonstrated superiority over dupilumab, which has previously demonstrated efficacy and is in wide use in clinical practice. As a concern, biologics are generally costly, and it should be noted that racial/ethnic minority populations may be less likely to receive biologics in the real world. Here, we have reviewed recent clinical trials and related topics dealing with the effects of biologics on allergic and immunologic diseases; in addition, we discuss how our understanding of the pathophysiology of these disorders has progressed., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Airway inflammation in asthma involves complex, interactive, and redundant cascades mediated by an array of proinflammatory cytokines, including a type 2 (T2) pattern of injury. T2 inflammation is characterized by elevations in absolute peripheral or sputum eosinophil counts and levels of IgE (total and allergen-specific) and fractional exhaled nitric oxide, which serve as biomarkers for the presence of this type of inflammation. T2 inflammation is mediated by key "downstream" cytokines, particularly IL-4, IL-5, and IL-13, which act at the effector cell level, as well as upstream cytokines, or "alarmins," such as thymic stromal lymphopoietin, IL-25, and IL-33 generated by epithelial cells. The relevance of these pathways has led to the development of biologic therapies targeting these T2 cytokines, which have not only resulted in modifying these biomarker signatures for inflammation but have also reduced the disease burden associated with asthma exacerbations, systemic corticosteroid use, and lung function compromises. This review will summarize experiences with anticytokine biologics to highlight which specific asthma outcomes they affect and how these effects reflect inflammatory pathways modified by biologics and may relate to pathophysiologic features of asthma., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Severe asthma is a heterogeneous disease encompassing different phenotypes and endotypes. Although patients with severe asthma constitute a small proportion of the total population with asthma, they largely account for the morbidity and mortality associated with asthma, indicating a clear unmet need. Being distinct from mild and moderate disease, new insights into the immunopathogenesis of severe asthma are needed. The disease endotypes have provided better insights into the immunopathogenic mechanisms underlying severe asthma. Current stratified approach of treating severe asthma based on phenotypes is met with shortcomings, necessitating unbiased multidimensional endotyping to cope with disease complexity. Therefore, in this review, we explore the distinct endotypes and their mechanistic pathways that characterize the heterogeneity observed in severe asthma., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Asthma is classically described as having either a type 2 (T2) eosinophilic phenotype or a non-T2 neutrophilic phenotype. T2 asthma usually responds to classical bronchodilation therapy and corticosteroid treatment. Non-T2 neutrophilic asthma is often more severe. Patients with non-T2 asthma or late-onset T2 asthma show poor response to the currently available anti-inflammatory therapies. These therapeutic failures result in increased morbidity and cost associated with asthma and pose a major health care problem. Recent evidence suggests that some non-T2 asthma is associated with elevated T H 17 cell immune responses. T H 17 cells producing Il-17A and IL-17F are involved in the neutrophilic inflammation and airway remodeling processes in severe asthma and have been suggested to contribute to the development of subsets of corticosteroid-insensitive asthma. This review explores the pathologic role of T H 17 cells in corticosteroid insensitivity of severe asthma and potential targets to treat this endotype of asthma., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Among patients with asthma, reliance on the type/dose of prescribed medication and symptom control does not adequately capture those at risk of adverse outcomes, and we need biomarkers for risk and treatment stratification that are consistently accurate, readily quantifiable, and reproducible. Most patients with severe asthma, regardless of age, have predominant type-2 inflammation-mediated disease, making airway/blood eosinophils, fractional exhaled nitric oxide, periostin, and/or allergic sensitization potentially important biomarkers for severe disease. In both adult and pediatric asthma, there is scope to improve prediction of severe attacks by using a composite type-2 biomarker of blood eosinophils and fractional exhaled nitric oxide. Technological advances in component-resolved diagnostics microarray technologies coupled with the development of interpretation software offer a possibility to use component-resolved diagnostics as biomarkers of asthma severity among sensitized patients with asthma. Genetic predisposition and polygenic risk scores of relevant traits (eg, lung function, host immune responses, biomarkers of exposure from the indoor and outdoor environment, infection, and microbial dysbiosis) may also contribute to prediction algorithms. We challenge the idea that asthma can be accurately defined in an individual patient by a discrete and static "endotype" (eg, type-2-high asthma). As we traverse the new era of molecular endotyping in asthma, we need to understand how relevant mechanisms impact patient outcomes, and in parallel develop new tools and approaches to stratify therapies and define individual patient trajectories., (Copyright © 2021. Published by Elsevier Inc.)

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases., Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma., Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort., Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T H 2, and T H 17/T H 22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T H 22/IL-22 pathways., Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Many patients with severe asthma (SA) fail to respond to type 2 inflammation-targeted therapies. We previously identified a cohort of subjects with SA expressing type 1 inflammation manifesting with IFN-γ expression and variable type 2 responses., Objective: We investigated the role of the chemotactic receptors C-X-C chemokine receptor 3 (CXCR3) and C-C chemokine receptor 5 (CCR5) in establishing type 1 inflammation in SA., Methods: Bronchoalveolar lavage microarray data from the Severe Asthma Research Program I/II were analyzed for pathway expression and paired with clinical parameters. Wild-type, Cxcr3 -/- , and Ccr5 -/- mice were exposed to a type 1-high SA model with analysis of whole lung gene expression and histology. Wild-type and Cxcr3 -/- mice were treated with a US Food and Drug Administration-approved CCR5 inhibitor (maraviroc) with assessment of airway resistance, inflammatory cell recruitment by flow cytometry, whole lung gene expression, and histology., Results: A cohort of subjects with increased IFN-γ expression showed higher asthma severity. IFN-γ expression was correlated with CXCR3 and CCR5 expression, but in Cxcr3 -/- and Ccr5 -/- mice type 1 inflammation was preserved in a murine SA model, most likely owing to compensation by the other pathway. Incorporation of maraviroc into the experimental model blunted airway hyperreactivity despite only mild effects on lung inflammation., Conclusions: IFNG expression in asthmatic airways was strongly correlated with expression of both the chemokine receptors CXCR3 and CCR5. Although these pathways provide redundancy for establishing type 1 lung inflammation, inhibition of the CCL5/CCR5 pathway with maraviroc provided unique benefits in reducing airway hyperreactivity. Targeting this pathway may be a novel approach for improving lung function in individuals with type 1-high asthma., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)