Titration of anti-IL-5 biologics in severe asthma: an open-label randomised controlled trial (the OPTIMAL study).

BACKGROUND: Anti-interleukin (IL)-5 biologics effectively reduce exacerbations and the need for maintenance oral corticosteroids (mOCS) in severe eosinophilic asthma. However, it is unknown how long anti-IL-5 treatment should be continued. Data from clinical trials indicate a gradual but variable loss of control after treatment cessation. In this pilot study of titration, we evaluated a dose-titration algorithm in patients who had achieved clinical control on an anti-IL-5 biologic. METHODS: In this open-label randomised controlled trial conducted over 52 weeks, patients with clinical control (no exacerbations or mOCS) on anti-IL-5 treatment were randomised to continue with unchanged intervals or have dosing intervals adjusted according to a titration algorithm that gradually extended dosing intervals and reduced them again at signs of loss of disease control. The OPTIMAL algorithm was designed to down-titrate dosing until signs of loss of control, to enable assessment of the longest dosing interval possible. RESULTS: Among 73 patients enrolled, 37 patients were randomised to the OPTIMAL titration arm; 78% of patients tolerated down-titration of treatment. Compared to the control arm, the OPTIMAL arm tended to have more exacerbations during the study (32% versus 17%; p=0.13). There were no severe adverse events related to titration, and lung function and symptoms scores remained stable and comparable in both study arms throughout. CONCLUSION: This study serves as a proof of concept for titration of anti-IL-5 biologics in patients with severe asthma with clinical control on treatment, and the OPTIMAL algorithm provides a potential framework for individualising dosing intervals in the future.

Tobacco Exposure and Efficacy of Biologic Therapy in Patients With Severe Asthma: A Nationwide Study From the Danish Severe Asthma Register.

BACKGROUND: Randomized trials of biologics in severe, uncontrolled asthma have excluded patients with a cumulative tobacco exposure of more than 10 pack-years. Therefore, our knowledge of the impact of smoking exposure on the clinical effects of biologics in severe asthma remains incomplete. However, because many patients with asthma are current or former smokers, investigating the potential impacts of tobacco exposure on the effects of biologic treatment is clinically important. OBJECTIVE: To investigate the impact of smoking history and tobacco exposure on the effectiveness of biologic therapy in real-life patients with severe asthma. METHODS: We used data from a complete nationwide cohort of patients with severe asthma who were receiving biologics, the Danish Severe Asthma Register. We divided patients according to smoking history and cumulative tobacco exposure and analyzed data at baseline and after 12 months of biologic treatment. RESULTS: A total of 724 bio-naive patients were identified in the Danish Severe Asthma Register, 398 of whom had never been smokers (55%), 316 were previous smokers (44%), and 10 were current smokers (1%). Within the group of current and former smokers, 37% had 1 to 9 pack-years of tobacco exposure, 26% had 10 to 19 pack-years, and 37% had 20 or more pack-years of tobacco exposure. Patients with tobacco exposure had similar reductions in the number of exacerbations, reductions in maintenance oral corticosteroid use, and improvements in asthma symptoms compared with patients with 0 pack-years. CONCLUSION: Former smoking history and lifetime tobacco exposure do not have an impact on the efficacy of biologics in patients with severe asthma.

Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.

BACKGROUND: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. OBJECTIVE: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. METHODS: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). RESULTS: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. CONCLUSION: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. CLINICAL TRIAL REGISTRATION: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).

Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies.

BACKGROUND: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal. RESEARCH QUESTION: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? STUDY DESIGN AND METHODS: The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined "clinical response" to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and a six-question Asthma Control Questionnaire score ≤ 1.5 following 12 months of treatment. RESULTS: Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy. INTERPRETATION: Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy.

Airway hyperresponsiveness correlates with airway TSLP in asthma independent of eosinophilic inflammation.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is released from the airway epithelium in response to various environmental triggers, inducing a type-2 inflammatory response, and is associated with airway inflammation, airway hyperresponsiveness (AHR), and exacerbations. TSLP may also induce AHR via a direct effect on airway smooth muscle and mast cells, independently of type-2 inflammation, although association between airway TSLP and AHR across asthma phenotypes has been described sparsely. OBJECTIVES: This study sought to investigate the association between AHR and levels of TSLP in serum, sputum, and bronchoalveolar lavage in patients with asthma with and without type-2 inflammation. METHODS: A novel ultrasensitive assay was used to measure levels of TSLP in patients with asthma (serum, n = 182; sputum, n = 81; bronchoalveolar lavage, n = 85) and healthy controls (serum, n = 47). The distribution and association among airway and systemic TSLP, measures of AHR, type-2 inflammation, and severity of disease were assessed. RESULTS: TSLP in sputum was associated with AHR independently of levels of eosinophils and fractional exhaled nitric oxide (ρ = 0.49, P = .005). Serum TSLP was higher in both eosinophil-high and eosinophil-low asthma compared to healthy controls: geometric mean: 1600 fg/mL (95% CI: 1468-1744 fg/mL) and 1294 fg/mL (95% CI: 1167-1435 fg/mL) versus 846 fg/mL (95% CI: 661-1082 fg/mL), but did not correlate with the level of AHR. Increasing age, male sex, and eosinophils in blood were associated with higher levels of TSLP in serum, whereas lung function, inhaled corticosteroid dose, and symptom score were not. CONCLUSIONS: The association between TSLP in sputum and AHR to mannitol irrespective of markers of type-2 inflammation further supports a role of TSLP in AHR that is partially independent of eosinophilic inflammation.

Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Bronchiectasis in severe asthma is associated with eosinophilic airway inflammation and activation.

Background: Bronchiectasis is a common comorbidity in severe asthma; causative pathogenic mechanisms are not fully understood but may differ from other causes of bronchiectasis. The role of eosinophilic airway inflammation, a classic feature of asthma predominantly driven by IL-5 and IL-13, in bronchiectasis is unclear, but association with disruption of the airway epithelium through eosinophil degranulation and increased mucus production is plausible. Objective: We sought to describe the prevalence of bronchiectasis in an unselected population of patients with severe asthma, and the association with the airway eosinophilic inflammation and activation. Methods: All patients with severe asthma according to European Respiratory Society/American Thoracic Society criteria (high-dose inhaled corticosteroids/oral corticosteroids), attending 4 respiratory clinics over a 1-year period, were included. All patients underwent high-resolution computed tomography and induced sputum was collected and analyzed for a cell differential count, free eosinophilic granules, and airway messenger RNA expression of T2 inflammatory pathways. Results: Bronchiectasis was present in 31% (34 of 108) of patients with severe asthma, and half (52%) of these patients had airway eosinophilia whereas only 16% of patients without bronchiectasis had airway eosinophilia. Patients with bronchiectasis had a significantly higher sputum eosinophil count (5.3 vs 0.8; P = .001) as well as more extensive eosinophil degranulation, compared with those without bronchiectasis (13% vs 2%; P = .05), suggesting a higher degree of eosinophil activation. Pairwise analyses identified significantly higher messenger RNA expression of Charcot-Leyden crystal galectin in patients with bronchiectasis (P = .02). Conclusions: Bronchiectasis in severe asthma was associated with eosinophilic airway inflammation and eosinophilic degranulation as well as messenger RNA expression of Charcot-Leyden crystal galectin.

Severe asthma trajectories in adults: findings from the NORDSTAR cohort.

BACKGROUND: There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma. METHODS: We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018. RESULTS: Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma. CONCLUSIONS: Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma.

Impact of Initiating Biologics in Patients With Severe Asthma on Long-Term Oral Corticosteroids or Frequent Rescue Steroids (GLITTER): Data From the International Severe Asthma Registry.

BACKGROUND: Effectiveness of biologics has neither been established in patients with high oral corticosteroid exposure (HOCS) nor been compared with effectiveness of continuing with HOCS alone. OBJECTIVE: To examine the effectiveness of initiating biologics in a large, real-world cohort of adult patients with severe asthma and HOCS. METHODS: This was a propensity score-matched, prospective cohort study using data from the International Severe Asthma Registry. Between January 2015 and February 2021, patients with severe asthma and HOCS (long-term OCSs for ≥1 year or ≥4 courses of rescue OCSs within a 12-month period) were identified. Biologic initiators were identified and, using propensity scores, matched 1:1 with noninitiators. The impact of biologic initiation on asthma outcomes was assessed using generalized linear models. RESULTS: We identified 996 matched pairs of patients. Both groups improved over the 12-month follow-up period, but improvement was greater for biologic initiators. Biologic initiation was associated with a 72.9% reduction in the average number of exacerbations per year versus noninitiators (0.64 vs 2.06; rate ratio, 0.27 [95% CI, 0.10-0.71]). Biologic initiators were 2.2 times more likely than noninitiators to take a daily long-term OCS dose of less than 5 mg (risk probability, 49.6% vs 22.5%; P = .002) and had a lower risk of asthma-related emergency department visits (relative risk, 0.35 [95% CI, 0.21-0.58]; rate ratio, 0.26 [0.14-0.48]) and hospitalizations (relative risk, 0.31 [95% CI, 0.18-0.52]; rate ratio, 0.25 [0.13-0.48]). CONCLUSIONS: In a real-world setting, including patients with severe asthma and HOCS from 19 countries, and within an environment of clinical improvement, initiation of biologics was associated with further improvements across multiple asthma outcomes, including exacerbation rate, OCS exposure, and health care resource utilization.

Prevalence and management of severe asthma in the Nordic countries: findings from the NORDSTAR cohort.

Background: Real-life evidence on prevalence and management of severe asthma is limited. Nationwide population registries across the Nordic countries provide unique opportunities to describe prevalence and management patterns of severe asthma at population level. In nationwide register data from Sweden, Norway and Finland, we examined the prevalence of severe asthma and the proportion of severe asthma patients being managed in specialist care. Methods: This is a cross-sectional study based on the Nordic Dataset for Asthma Research (NORDSTAR) research collaboration platform. We identified patients with severe asthma in adults (aged ≥18 years) and in children (aged 6-17 years) in 2018 according to the European Respiratory Society/American Thoracic Society definition. Patients managed in specialist care were those with an asthma-related specialist outpatient contact (only available in Sweden and Finland). Results: Overall, we identified 598 242 patients with current asthma in Sweden, Norway and Finland in 2018. Among those, the prevalence of severe asthma was 3.5%, 5.4% and 5.2% in adults and 0.4%, 1.0%, and 0.3% in children in Sweden, Norway and Finland, respectively. In Sweden and Finland, 37% and 40% of adult patients with severe asthma and two or more exacerbations, respectively, were managed in specialist care; in children the numbers were 56% and 41%, respectively. Conclusion: In three Nordic countries, population-based nationwide data demonstrated similar prevalence of severe asthma. In children, severe asthma was a rare condition. Notably, a large proportion of patients with severe asthma were not managed by a respiratory specialist, suggesting the need for increased recognition of severe asthma in primary care.

Complete response to anti-interleukin-5 biologics in a real-life setting: results from the nationwide Danish Severe Asthma Register.

Background: Phase III regulatory trials show that anti-interleukin (IL)-5 biologics efficiently reduce exacerbations and the use of maintenance oral corticosteroids (mOCS) in patients with severe eosinophilic asthma. However, patients eligible for these trials differ significantly compared with real-life severe asthma populations. Therefore, our aim was to explore efficacy in a real-life setting. The Danish Severe Asthma Register (DSAR) is a complete, nationwide register that comprises all Danish patients on biological therapy for severe asthma. Methods: This prospective study identified patients in the DSAR who were complete responders to anti-IL-5 biologics after 1 year of treatment. A complete response was defined as resolution of the parameter setting the indication, i.e. recurrent exacerbations and/or use of mOCS. Results: A total of 289 out of 502 (58%) patients were complete responders to anti-IL-5 biologics after 12 months. Complete responders had greater improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire (ACQ) score compared with noncomplete responders (Δ 210 versus 30 mL; p<0.0001 and Δ -1.04 versus -0.68; p=0.016, respectively). A complete response was predicted by age at onset, less severe disease at baseline (i.e. no mOCS and lower ACQ score) and higher blood eosinophils. Conclusions: More than half of Danish patients treated with anti-IL-5 biologics for severe asthma achieve a complete response to treatment, thereby becoming free from asthma exacerbations and the need for mOCS. Complete responders also achieved superior effects on lung function and symptoms compared with noncomplete responders.

Characterization of Patients in the International Severe Asthma Registry with High Steroid Exposure Who Did or Did Not Initiate Biologic Therapy.

Background: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics. Methods: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson's chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons. Results: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/µL, p=0.003), serious infections (49.0% vs 13.3%, p<0.001), nasal polyps (35.2% vs 23.6%, p<0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147). Conclusion: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use.

Allergen immunotherapy effectively reduces the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma: a nationwide epidemiological study.

BACKGROUND: Allergic asthma is associated with increased risk of respiratory tract infections and exacerbations. It remains unclear whether this susceptibility is conditioned by seasonal or by perennial allergy. AIM: To investigate perennial allergy compared with seasonal allergy as a risk factor for lower respiratory tract infections and exacerbations in asthma and whether this risk can be reduced by allergen immunotherapy (AIT). METHODOLOGY: This is a prospective register-based nationwide study of 18-44-year-olds treated with AIT during 1995-2014. Based on the type of AIT and use of anti-asthmatic drugs, patients were subdivided into two groups: perennial allergic asthma (PAA) versus seasonal allergic asthma (SAA). Data on antibiotics against lower respiratory tract infections (LRTI) and oral corticosteroids for exacerbations were analysed before starting AIT (baseline) and 3 years after completing AIT (follow-up). RESULTS: We identified 2688 patients with asthma treated with AIT, of whom 1249 had PAA and 1439 had SAA. At baseline, patients with SAA had more exacerbations (23.8% versus 16.5%, p≤0.001), but there were no differences in LRTI. During the 3-year follow-up, we observed a highly significant reduction of exacerbations with an average decrease of 57% in PAA and 74% in SAA. In addition, we observed a significant reduction of LRTI in both PAA and SAA: 17% and 20% decrease, respectively. CONCLUSION: AIT effectively reduced the risk of exacerbations and lower respiratory tract infections in both seasonal and perennial allergic asthma. Perennial allergy is seemingly not a stronger risk factor for respiratory infections and exacerbations than seasonal allergy.

Impact of former smoking exposure on airway eosinophilic activation and autoimmunity in patients with severe asthma.

INTRODUCTION: Severe eosinophilic asthma is characterised by frequent exacerbations and a relative insensitivity to steroids. Experimentally, smoking may induce eosinophilic airway inflammation, but the impact in patients with severe asthma is not clear. OBJECTIVE: To investigate the association between smoking exposure in patients with severe asthma, and eosinophilic inflammation and activation, as well as airway autoimmunity and steroid responsiveness. METHODS: Patients with severe asthma according to European Respiratory Society/American Thoracic Society criteria were assessed with sputum samples, analysed by cell differential count, and for the presence of free eosinophil granules (FEGs), autoantibodies against eosinophil peroxidase (EPX) and macrophage receptor with collagenous structure (MARCO). A subgroup of patients with eosinophilic airway inflammation was re-assessed after a 2-week course of prednisolone. RESULTS: 132 severe asthmatics were included in the study. 39 (29.5%) patients had ≥10 pack-years of smoking history: 36 (27.3%) were former smokers and three (2.3%) current smokers; and 93 (70.5%) had <10 pack-years exposure. Eosinophilic airway inflammation was more prevalent among patients with ≥10 pack-years (66.7%), compared to patients with <10 pack-years (38.7%, p=0.03), as was the level of FEGs (p=0.001) and both anti-EPX and anti-MARCO (p<0.05 and p<0.0001, respectively). Omitting current smokers did not affect these associations. Furthermore, prednisolone reduced, but did not normalise, sputum eosinophils in patients with a ≥10 pack-year smoking history. CONCLUSION: In patients with severe asthma, a former smoking history is associated with eosinophilic airway inflammation and activation and relative insensitivity to steroids, as well as airway autoimmunity.

Real World Biologic Use and Switch Patterns in Severe Asthma: Data from the International Severe Asthma Registry and the US CHRONICLE Study.

INTRODUCTION: International registries provide opportunities to describe use of biologics for treating severe asthma in current clinical practice. Our aims were to describe real-life global patterns of biologic use (continuation, switches, and discontinuations) for severe asthma, elucidate reasons underlying these patterns, and examine associated patient-level factors. METHODS: This was a historical cohort study including adults with severe asthma enrolled into the International Severe Asthma Registry (ISAR; http://isaregistries.org, 2015-2020) or the CHRONICLE Study (2018-2020) and treated with a biologic. Eleven countries were included (Bulgaria, Canada, Denmark, Greece, Italy, Japan, Kuwait, South Korea, Spain, UK, and USA). Biologic utilization patterns were defined: 1) continuing initial biologic; 2) stopping biologic treatment; or 3) switching to another biologic. Reasons for discontinuation/switching were recorded and comparisons drawn between groups. RESULTS: A total of 3531 patients were included. Omalizumab was the most common initial biologic in 2015 (88.2%) and benralizumab in 2019 (29.6%). Most patients (79%; 2791/3531) continued their first biologic; 10.2% (356/3531) stopped; 10.8% (384/3531) switched. The most frequent first switch was from omalizumab to an anti-IL-5/5R (49.6%; 187/377). The most common subsequent switch was from one anti-IL-5/5R to another (44.4%; 20/45). Insufficient efficacy and/or adverse effects were the most frequent reasons for stopping/switching. Patients who stopped/switched were more likely to have a higher baseline blood eosinophil count and exacerbation rate, lower lung function, and greater health care resource utilization. CONCLUSION: The description of real-life patterns of continuing, stopping, or switching biologics enhances our understanding of global biologic use. Prospective studies involving structured switching criteria could ascertain optimal strategies to identify patients who may benefit from switching.

Airway gene expression identifies subtypes of type 2 inflammation in severe asthma.

BACKGROUND: Type 2 inflammation is characterized by enhanced activity of interleukin (IL)-4, -5 and -13, and treatments targeting these pathways are available for treatment of severe asthma. At present, the pattern of pathway activity and the implications overlapping of pathway activity are unknown. OBJECTIVE: We hypothesized that clustering of airway mRNA expression would identify distinct molecular subtypes of severe asthma and thereby uncover the prevalence and overlap of pathway activity. METHODS: Sputum mRNA expression of genes related to expression of IL-5(CLC, CPA3 and DNASE1L3), IL-13(IL13Ra1, TNFSF14 and SERPINB2), T1/Th17 activity(IL1B, ALPL and CXCR2) and in vitro response to corticosteroids (FKBP512) and mepolizumab (ARAP3) was analysed in patients (n = 109) with severe asthma and healthy controls (n = 22). A cluster analysis of gene expression was performed. The response to a short course of OCS was assessed in a subset of patients (n = 29). RESULTS: Five molecular clusters were identified. Three had abundant T2 gene expression of which two (n = 39 and n = 9) were characterized by abundant expression of both IL-13- and IL-5-related genes. The last (n = 6) had only abundant IL-5-related gene expression. These T2-high molecular clusters could not be distinguished using T2 biomarkers. T2- and Th1/Th17-related mRNA expression were co-expressed across all clusters. OCS significantly reduced T2 gene expression (CLC, IL13Ra1, SERPINB2 and ARAP3) and significantly increase expression of Th1/Th17-related genes (ALPL and CXCR2). CONCLUSIONS AND CLINICAL RELEVANCE: Clustering of airway mRNA expression identified five molecular clusters of severe asthma of which three were considered T2 high. Co-expression of IL-5- and IL-13-related genes at moderate levels was present in almost half of patients, while marked elevated expression of both was rare. In contrast to IL-5, clusters with isolated IL-13- and Th1/Th17-related gene expression were not identified.

Airway Hyperresponsiveness to Inhaled Mannitol Identifies a Cluster of Noneosinophilic Asthma Patients with High Symptom Burden.

BACKGROUND: Patients with asthma are heterogeneous in clinical presentation and in response to treatment. Despite this, tools to guide treatment are limited and include mainly measures of eosinophilic inflammation and symptoms. Airway hyperresponsiveness (AHR) to mannitol is present in patients across inflammatory phenotypes and improve with inhaled corticosteroids. OBJECTIVE: To investigate whether measuring AHR to mannitol in addition to eosinophilic inflammation and symptoms adds information to the phenotypic characterization of patients with asthma. METHODS: A total of 317 patients with asthma from 6 different cohorts were included in the analysis. All patients had measures of AHR to mannitol, blood eosinophils, and Asthma Control Questionnaire 5 available. A cluster analysis using Ward minimum variance method was performed. The distribution of fraction of exhaled nitric oxide, immunoglobulin E, lung function, induced sputum inflammatory cell count, age of onset, and severity of disease was compared between clusters. RESULTS: Four clusters were identified. Three of the clusters had proportionate levels of AHR, eosinophilic inflammation, and symptoms, but 1 cluster presented with low levels of eosinophilic inflammation and a significant symptom burden. Half of the subjects in this cluster presented with AHR to inhaled mannitol. Lung function, fraction of exhaled nitric oxide, body mass index, and immunoglobulin E were normal. CONCLUSIONS: Information on AHR to mannitol in addition to blood eosinophils and symptoms identifies a subgroup of asthma patients with symptomatic, noneosinophilic disease. Airway hyperresponsiveness to mannitol may provide a treatable trait in a subgroup of patients with noneosinophilic asthma.

The Prevalence of Subtypes of Type 2 Inflammation in an Unselected Population of Patients with Severe Asthma.

BACKGROUND: With the introduction of different targeted therapies for type 2 (T2)-high asthma, there is an urgent need for markers to guide the choice of treatment. T2-high asthma includes different clinical phenotypes of asthma, but the prevalence and impact of activation of different T2 inflammatory pathways is unknown. OBJECTIVE: To describe the level of coexpression of clinically available T2 inflammatory markers in patients with severe asthma, and the relationship with clinical characteristics and comorbidities. METHODS: Patients with severe asthma according to European Respiratory Society/American Thoracic Society guidelines were examined prospectively including sputum induction and grouped according to T2 biomarkers: blood eosinophilia (≥0.3 × 109/L), total IgE (≥150 U/mL), and fractional exhaled nitric oxide (≥25 parts per billion). RESULTS: We found 116 (70%) of the 166 patients to have at least 1 T2 biomarker elevated: 39% had 2 or more elevated biomarkers, whereas 31% had only 1 biomarker elevated. Concomitant airway and systemic eosinophilia was present in 28% of all patients, corresponding to half (53%) of the patients with either. Expression patterns of the T2 biomarkers were associated with differences in allergic sensitization and the coexistence of nasal polyposis. CONCLUSIONS: Most patients with severe asthma showed at least 1 T2 inflammatory trait. Coexpression of T2 biomarkers was highly heterogeneous, and different expression patterns were associated with distinct clinical characteristics.

Depressive symptoms among patients with COPD according to smoking status: a Danish nationwide case-control study of 21 184 patients.

INTRODUCTION: Depressive symptoms appear more often among patients with COPD and are associated with reduced disease control and increased mortality. Both smoking and COPD increase the risk of depressive symptoms. Whether smoking cessation among COPD patients affects the occurrence of depressive symptoms is unknown. We hypothesised that smoking cessation in patients with COPD leads to reduced use of antidepressants and fewer admissions to psychiatric hospitals with depression, anxiety or bipolar disorder. METHODS: We conducted a nationwide retrospective case-control study, in patients from The Danish Register for COPD with spirometry-verified COPD, age ≥40 years, a history of smoking and absence of cancer. Consistent smokers were matched 1:1 with ex-smokers using a propensity score model. Prescription fillings of antidepressants and risk of admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder both descriptively was assessed by Cox proportional hazard models. RESULTS: We included 21 184 patients. A total of 2011 consistent smokers collected antidepressant prescriptions compared with 1821 ex-smokers. Consistent smoking was associated with increased risk of filling prescription on antidepressants (HR 1.4, 95% CI 1.3-1.5, p<0.0001) and with increased risk of psychiatric hospital admission with either depression, anxiety or bipolar disorder (HR 2.0, 95% CI 1.6-2.5). The associations persisted after adjustment for former use of antidepressants. CONCLUSION: Consistent smoking among COPD patients was associated with increased use of antidepressants and admissions to psychiatric hospitals with either depression, anxiety or bipolar disorder, compared to smoking cessation.