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Background: Although asthma does not appear to be a risk factor for severe coronavirus disease 2019 (COVID-19), outcomes could vary for patients with different asthma subtypes. The objective of this analysis was to compare COVID-19 outcomes in real-world cohorts in the United States among patients with asthma, with or without evidence of allergy., Methods: In a retrospective analysis of the COVID-19 Optum electronic health record dataset (February 20, 2020-January 28, 2021), patients diagnosed with COVID-19 with a history of moderate-to-severe asthma were divided into 2 cohorts: those with evidence of allergic asthma and those without (nonallergic asthma). After 1:1 propensity score matching, in which covariates were balanced and potential bias was removed, COVID-19 outcomes were compared between cohorts., Results: From a COVID-19 population of 591,198 patients, 1595 patients with allergic asthma and 8204 patients with nonallergic asthma were identified. After propensity score matching (n = 1578 per cohort), risk of death from any cause after COVID-19 diagnosis was significantly lower for patients with allergic vs nonallergic asthma (hazard ratio, 0.48; 95% CI 0.28-0.83; P = 0.0087), and a smaller proportion of patients with allergic vs nonallergic asthma was hospitalized within - 7 to + 30 days of COVID-19 diagnosis (13.8% [n = 217] vs 18.3% [n = 289]; P = 0.0005). Among hospitalized patients, there were no significant differences between patients with allergic or nonallergic asthma in need for intensive care unit admission, respiratory support, or COVID-19 treatment., Conclusions: Asthma subtype may influence outcomes after COVID-19; patients with allergic asthma are at lower risk for hospitalization/death than those with nonallergic asthma., (© 2022. The Author(s).)

Background: Lebrikizumab is a monoclonal antibody that modulates activity of interleukin-13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard-of-care treatment., Methods: Adolescents (aged 12-17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%-90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks., Results: Between August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg ( n  = 116) reduced the exacerbation rate at 52 weeks versus placebo ( n  = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28-0.83]; 51% rate reduction). Lebrikizumab 37.5 mg ( n  = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35-1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21-0.89]; 37.5 mg: 0.42 [95% CI 0.19-0.93]). Treatment-emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred., Conclusion: Lebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results., Clinical Trial Registration: NCT01875003 (www.ClinicalTrials.gov)., Competing Interests: Stanley J. Szefler reports consultancy during the time of this report and currently for Aerocrine, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Genentech, Inc., Merck, Novartis, Propeller Health, Regeneron, Roche, Sanofi and Teva and research support from the US National Institutes of Health; US National Heart, Lung, and Blood Institute; US National Institute of Allergy and Infectious Diseases; US National Institute of Environmental Health Sciences; US Environmental Protection Agency; Cancer, Cardiovascular and Pulmonary Disease Program; and GlaxoSmithKline. Graham Roberts was the lead investigator in the United Kingdom for this study. Adalberto S. Rubin reports fees from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Roche, Bristol, and Sanofi. Stefan Zielen reports grants and personal fees from bene‐Arzneimittel GmbH, grants from ALK Arzneimittel, personal fees from Novartis GmbH, Boehringer Ingelheim, Lofarma GmbH, IMS HEALTH GmbH and Co. OHG, GSK, Stallergen, Procter and Gamble, Allergopharma GmbH, AstraZeneca, Sanofi/Pasteur, and Aimmune outside the submitted work. Piotr Kuna reports personal fees from Astra, Boehringer Ingelheim, Berlin Chemie Menarini, GSK, Lekam, Novartis, Polpharma, Mylan, Orion, Teva, Adamed. Oral Alpan reports no disclosures that pertain to this submission. Cécile T J Holweg, and Wendy S. Putnam are former employees of Genentech, Inc. (a member of the Roche Group). Qiang Chen is an employee of Roche (China) Holding Ltd. Janusz Kaminski is a former employee of Roche Products Ltd. John G. Matthews is a former employee of Genentech, Inc. Judith Anzures‐Cabrera and Nikhil Kamath are employees of Roche Products Ltd., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Genome-wide association studies (GWAS) have identified many common variant loci associated with asthma susceptibility, but few studies investigate the genetics underlying moderate-to-severe asthma risk. Here, we present a whole-genome sequencing study comparing 3181 moderate-to-severe asthma patients to 3590 non-asthma controls. We demonstrate that asthma risk is genetically correlated with lung function measures and that this component of asthma risk is orthogonal to the eosinophil genetics that also contribute to disease susceptibility. We find that polygenic scores for reduced lung function are associated with younger asthma age of onset. Genome-wide, seven previously reported common asthma variant loci and one previously reported lung function locus, near THSD4, reach significance. We replicate association of the lung function locus in a recently published GWAS of moderate-to-severe asthma patients. We additionally replicate the association of a previously reported rare (minor allele frequency < 1%) coding variant in IL33 and show significant enrichment of rare variant burden in genes from common variant allergic disease loci. Our findings highlight the contribution of lung function genetics to moderate-to-severe asthma risk, and provide initial rare variant support for associations with moderate-to-severe asthma risk at several candidate genes from common variant loci., (© 2022. The Author(s).)

Introduction: Asthma exacerbations spike in the spring and autumn months, yet the seasonal variation of asthma symptoms and lung function is poorly studied., Methods: Seasonal variation of lung function, rescue medication use and patient-reported symptoms was evaluated by post hoc analyses of the Phase III lebrikizumab (anti-IL-13) LAVOLTA I and II studies in 2148 subjects with uncontrolled asthma. Lung function measurements (prebronchodilator FEV 1 , forced vital capacity (FVC) and peak expiratory flow (PEF)), rescue medication use and Standardised Asthma Quality of Life Questionnaire (AQLQ(S)) were measured every 4 weeks over 52 weeks. By-month estimates normalised by hemispheric season were based on mixed-effect models with repeated measures (MMRM), adjusted by study stratification factors as covariates when appropriate. The dependency of clinical outcomes with seasonal variability was assessed by employing linear contrasts comparing hemisphere normalised December versus July group means from an MMRM regression and presented as the difference in means (adjusted 95% CI)., Results: FEV 1 , FVC and PEF, rescue medication use and AQLQ(S) progressively worsened towards winter, unlike spring and autumn surges in asthma exacerbations. The December versus July mean differences were: (1) PEF=-6.5 (-8.7 to -4.2) L/min, 2) prebronchodilator FEV 1 =-42 (-57 to -27) mL, (3) FVC=-41 (-59 to -23) mL and (4) AQLQ(S)=-0.15 (-0.19 to -0.1) units. Among AQLQ questions, discomfort or distress related to cough was most variable with respect to season (-0.33 (-0.42 to -0.24) units)., Discussion: Interpretation of interventional studies biased by seasonal exposures may be confounded by seasonal variability., Trials Registration Numbers: NCT01867125 and NCT01868061., Competing Interests: Competing interests: RB, XY, TS, JO, CTJH, JA and DFC are employees of Genentech, Inc and hold Roche stocks and/or options. JGM was previously an employee of Genentech at the time of this study., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Identification of a biomarker for disease activity in eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) remains an unmet need. This study examined the value of serum periostin, a marker of type 2 inflammation, as a measure of disease activity in patients with EGPA., Methods: Participants enrolled in a multicenter, prospective cohort of patients with EGPA were included in this study if they had disease activity (defined as Birmingham Vasculitis Activity Score [BVAS] > 0) during follow-up. Serum levels of periostin were measured at flare visit as well as two pre- and two post-flare visits, if available. The outcome of disease activity was assessed either with BVAS or Physician Global Assessment (PGA). Mixed-effect models were used to examine the association between periostin levels and disease activity. Comparisons were made with a historical cohort of healthy individuals and patients with asthma., Results: In the 49 patients included in the study, the median periostin level was 60 ng/ml (IQR 50 to 73) in all visits and did not significantly change across visits. Multivariate analyses found no association between periostin level and presence or absence of flare according to the BVAS (adjusted OR 1.00 [95% CI 0.98 to 1.02], p = 0.98) but an increase in periostin level was significantly associated with greater disease severity during a flare according to the PGA (adjusted beta-coefficient 0.02 [95% CI 0.004 to 0.03], p = 0.01). Periostin levels in EGPA were significantly higher than previously studied healthy controls and patients with asthma., Conclusion: In EGPA serum periostin level is modestly associated with greater disease severity during a flare but does not discriminate active from inactive disease. Periostin levels in EGPA are higher than in other previously studied cohorts, including healthy populations and patients with asthma, and are relatively stable over time., Competing Interests: CTJH and KW are full-time employees of Genentech Inc. We confirm that CTJH and KW’s employment at Genentech, Inc does not alter our adherence to the journal’s policies on data sharing.

Background: Asthma is a heterogeneous and complex disease in both its clinical course and response to treatment. IL-13 is central to Type 2 inflammation and contributes to many features of asthma. In a previous Phase 2 study, lebrikizumab, an anti-IL-13 monoclonal antibody, did not significantly improve FEV 1 in mild-to-moderate asthma patients not receiving ICS therapy. This Phase 3 study was designed to further assess the efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma treated with daily short-acting β 2 -agonist therapy alone., Methods: Adult patients with mild-to-moderate asthma were randomised to receive lebrikizumab 125 mg subcutaneously (SC), placebo SC, or montelukast 10 mg orally for 12 weeks, with an 8-week follow-up period. The primary efficacy endpoint was absolute change in pre-bronchodilator FEV 1 from baseline at Week 12., Findings: A total of 310 patients were randomised and dosed in the study. The mean absolute change in FEV 1 from baseline at Week 12 was higher in the lebrikizumab-treated arm compared with placebo (150 mL versus 67 mL); however, this improvement did not achieve statistical significance (overall adjusted difference of 83 mL [95% CI: -3, 170]; p = .06). Montelukast did not improve FEV 1 as compared with placebo. Lebrikizumab was generally safe and well tolerated during the study., Interpretation: Lebrikizumab did not significantly improve FEV 1 in mild-to-moderate asthma patients at a dose expected to inhibit the IL-13 pathway. Inhibiting IL-13 in this patient population was not sufficient to improve lung function. These data support the findings of a previous trial of lebrikizumab in patients not receiving ICS., Clinical Trials Registry Number: This trial was registered under NCT02104674 at http://www.clinicaltrials.gov., (Copyright © 2017. Published by Elsevier Ltd.)

Asthma is characterized by episodic, reversible airflow obstruction associated with variable levels of inflammation. Over the past several decades, there has been an increasing appreciation that the clinical presentation of asthma comprises a diverse set of underlying pathologies. Rather than being viewed as a single disease entity, asthma is now thought of as a clinical syndrome with the involvement of multiple pathological mechanisms. While it is appreciated that eosinophilia is present in only a subset of patients, it remains a key feature of asthma and other eosinophilic disorders such as atopic dermatitis, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. Eosinophils are bone marrow-derived leukocytes present in low numbers in health; however, during disease the type 2 cytokines [interleukins (IL)-4, -5, and -13] can induce rapid eosinophilopoiesis, prolonged eosinophil survival, and trafficking to the site of injury. In diseases such as allergic asthma there is an aberrant inflammatory response leading to eosinophilia, tissue damage, and airway pathology. IL-13 is a pleiotropic type 2 cytokine that has been shown to be integral in the pathogenesis of asthma and other eosinophilic disorders. IL-13 levels are elevated in animal models of eosinophilic inflammation and in the blood and tissue of patients diagnosed with eosinophilic disorders. IL-13 signaling elicits many pathogenic mechanisms including the promotion of eosinophil survival, activation, and trafficking. Data from preclinical models and clinical trials of IL-13 inhibitors in patients have revealed mechanistic insights into the role of this cytokine in driving eosinophilia. Promising results from clinical trials further support a key mechanistic role of IL-13 in asthma and other eosinophilic disorders. Here, we provide a perspective on the role of IL-13 in asthma and other eosinophilic disorders and describe ongoing clinical trials targeting this pathway in patients with significant unmet medical needs.

Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDL NMR ). Serum periostin levels negatively correlated with total HDL NMR In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)