Real-world biologics response and super-response in the International Severe Asthma Registry cohort.

BACKGROUND: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma. METHODS: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13). Treatment responses were examined across four domains: forced expiratory volume in 1 second (FEV1) increase by ≥100 mL, improved asthma control, annualized exacerbation rate (AER) reduction ≥50%, and any LTOCS dose reduction. Super-response criteria were: FEV1 increase by ≥500 mL, new well-controlled asthma, no exacerbations, and LTOCS cessation or tapering to ≤5 mg/day. RESULTS: 5.3% of ISAR patients met basic RCT inclusion criteria; 2116/8451 started biologics. Biologic initiators had worse baseline impairment than non-initiators, despite having similar biomarker levels. Half or more of initiators had treatment responses: 59% AER reduction, 54% FEV1 increase, 49% improved control, 49% reduced LTOCS, of which 32%, 19%, 30%, and 39%, respectively, were super-responses. Responses/super-responses were more frequent in biologic initiators than in non-initiators; nevertheless, ~40-50% of initiators did not meet response criteria. CONCLUSIONS: Most patients with severe asthma are ineligible for RCTs of biologic therapies. Biologics are initiated in patients who have worse baseline impairments than non-initiators despite similar biomarker levels. Although biologic initiators exhibited clinical responses and super-responses in all outcome domains, 40-50% did not meet the response criteria.

Basic host response parameters to classify mortality risk in COVID-19 and community-acquired pneumonia.

Improved phenotyping in pneumonia is necessary to strengthen risk assessment. Via a feasible and multidimensional approach with basic parameters, we aimed to evaluate the effect of host response at admission on severity stratification in COVID-19 and community-acquired pneumonia (CAP). Three COVID-19 and one CAP multicenter cohorts including hospitalized patients were recruited. Three easily available variables reflecting different pathophysiologic mechanisms-immune, inflammation, and respiratory-were selected (absolute lymphocyte count [ALC], C-reactive protein [CRP] and, SpO2/FiO2). In-hospital mortality and intensive care unit (ICU) admission were analyzed as outcomes. A multivariable, penalized maximum likelihood logistic regression was performed with ALC (< 724 lymphocytes/mm3), CRP (> 60 mg/L), and, SpO2/FiO2 (< 450). A total of 1452, 1222 and 462 patients were included in the three COVID-19 and 1292 in the CAP cohort for the analysis. Mortality ranged between 4 and 32% (0 to 3 abnormal biomarkers) and 0-9% in SARS-CoV-2 pneumonia and CAP, respectively. In the first COVID-19 cohort, adjusted for age and sex, we observed an increased odds ratio for in-hospital mortality in COVID-19 with elevated biomarkers altered (OR 1.8, 3, and 6.3 with 1, 2, and 3 abnormal biomarkers, respectively). The model had an AUROC of 0.83. Comparable findings were found for ICU admission, with an AUROC of 0.76. These results were confirmed in the other COVID-19 cohorts Similar OR trends were reported in the CAP cohort; however, results were not statistically significant. Assessing the host response via accessible biomarkers is a simple and rapidly applicable approach for pneumonia.

Exploring Definitions and Predictors of Response to Biologics for Severe Asthma.

BACKGROUND: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging. OBJECTIVE: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response. METHODS: This was a longitudinal cohort study using data from 21 countries, which shared data with the International Severe Asthma Registry. Changes in four asthma outcome domains were assessed in the 1-year period before and after biologic initiation in patients with a predefined level of prebiologic impairment. Responder cutoffs were 50% or greater reduction in exacerbation rate, 50% or greater reduction in long-term oral corticosteroid daily dose, improvement in one or more category in asthma control, and 100 mL or greater improvement in FEV1. Responders were defined using single and multiple domains. The association between prebiologic characteristics and postbiologic initiation response was examined by multivariable analysis. RESULTS: A total of 2,210 patients were included. Responder rate ranged from 80.7% (n = 566 of 701) for exacerbation response to 10.6% (n = 9 of 85) for a four-domain response. Many responders still exhibited significant impairment after biologic initiation: 46.7% (n = 206 of 441) of asthma control responders with uncontrolled asthma before the biologic still had incompletely controlled disease postbiologic initiation. Predictors of response were outcome-dependent. Lung function responders were more likely to have higher prebiologic FeNO (odds ratio = 1.20 for every 25-parts per billion increase), and shorter asthma duration (odds ratio = 0.81 for every 10-year increase in duration). Higher blood eosinophil count and the presence of type 2-related comorbidities were positively associated with higher odds of meeting long-term oral corticosteroid, control, and lung function responder criteria. CONCLUSIONS: Our findings underscore the multimodal nature of response, showing that many responders experience residual symptoms after biologic initiation and that predictors of response vary according to the outcome assessed.

Exploring Definitions and Predictors of Severe Asthma Clinical Remission Post-Biologic in Adults.

RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

International Variation in Severe Exacerbation Rates in Patients With Severe Asthma.

BACKGROUND: Exacerbation frequency strongly influences treatment choices in patients with severe asthma. RESEARCH QUESTION: What is the extent of the variability of exacerbation rate across countries and its implications in disease management? STUDY DESIGN AND METHODS: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit. A severe exacerbation was defined as the use of oral corticosteroids for ≥ 3 days or asthma-related hospitalization/ED visit. A series of negative binomial models were applied to estimate country-specific severe exacerbation rates during 365 days of follow-up, starting from a naive model with country as the only variable to an adjusted model with country as a random-effect term and patient and disease characteristics as independent variables. RESULTS: The final sample included 7,510 patients from 17 countries (56% from the United States), contributing to 1,939 severe exacerbations (0.27/person-year). There was large between-country variation in observed severe exacerbation rate (minimum, 0.04 [Argentina]; maximum, 0.88 [Saudi Arabia]; interquartile range, 0.13-0.54), which remained substantial after adjusting for patient characteristics and sampling variability (interquartile range, 0.16-0.39). INTERPRETATION: Individuals with similar patient characteristics but coming from different jurisdictions have varied severe exacerbation risks, even after controlling for patient and disease characteristics. This suggests unknown patient factors or system-level variations at play. Disease management guidelines should recognize such between-country variability. Risk prediction models that are calibrated for each jurisdiction will be needed to optimize treatment strategies.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR 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 (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 (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

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.

Evaluation of real-world mepolizumab use in severe asthma across Europe: the SHARP experience with privacy-preserving federated analysis.

Background: An objective of the Severe Heterogeneous Asthma Registry, Patient-centered (SHARP) is to produce real-world evidence on a pan-European scale by linking nonstandardised, patient-level registry data. Mepolizumab has shown clinical efficacy in randomised controlled trials and prospective real-world studies and could therefore serve as a proof of principle for this novel approach. The aim of the present study was to harmonise data from 10 national severe asthma registries and characterise patients receiving mepolizumab, assess its effectiveness on annual exacerbations and maintenance oral glucocorticoid (OCS) use, and evaluate treatment patterns. Methods: In this observational cohort study, registry data (5871 patients) were extracted for harmonisation. Where harmonisation was possible, patients who initiated mepolizumab between 1 January 2016 and 31 December 2021 were examined. Changes of a 12-month (range 11-18 months) period in frequent (two or more) exacerbations, maintenance OCS use and dose were analysed in a privacy-preserving manner using meta-analysis of generalised estimating equation parameters. Periods before and during the coronavirus disease 2019 pandemic were analysed separately. Results: In 912 patients who fulfilled selection criteria, mepolizumab significantly reduced frequent exacerbations (OR 0.18, 95% CI 0.13-0.25), maintenance OCS use (OR 0.75, 95% CI 0.61-0.92) and dose (mean -3.93 mg·day-1, 95% CI -5.24-2.62 mg·day-1) in the pre-pandemic group, with similar trends in the pandemic group. Marked heterogeneity was observed between registries in patient characteristics and mepolizumab treatment patterns. Conclusions: By harmonising patient-level registry data and applying federated analysis, SHARP demonstrated the real-world effectiveness of mepolizumab on asthma exacerbations and maintenance OCS use in severe asthma patients across Europe, consistent with previous evidence. This paves the way for future pan-European real-world severe asthma studies using patient-level data in a privacy-proof manner.

Comparative effectiveness of anti-IL5 and anti-IgE biologic classes in patients with severe asthma eligible for both.

BACKGROUND: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. METHODS: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. RESULTS: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). CONCLUSIONS: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

Redefining the Role of Bronchoscopy in the Workup of Severe Uncontrolled Asthma in the Era of Biologics: A Prospective Study.

BACKGROUND: Severe uncontrolled asthma (SUA) is frequently treated with biologic therapy if a T2 phenotype is found. Bronchoscopy is not routinely recommended in these patients unless a specific indication to rule out comorbidities is present. RESEARCH QUESTION: Is routine bronchoscopy safe and useful in phenotyping and endotyping patients with SUA before the indication of a biologic therapy? STUDY DESIGN AND METHODS: Prospective study of consecutive patients with SUA who were referred to a specialized asthma clinic to assess the indication of a biologic therapy. Patients were clinically phenotyped as T2-allergic, T2-eosinophilic, and non-T2. All patients underwent bronchoscopy, and systematic data collection of endoscopic findings, microbiology of bronchial aspirate, and presence of eosinophils in bronchial biopsy were recorded and compared between asthma phenotypes. Cluster analysis was performed accordingly. RESULTS: One hundred patients were recruited and classified as T2-allergic (28%), T2-eosinophilic (64%), and non-T2 (8%). On bronchoscopy, signs of gastroesophageal reflux disease were detected in 21%, vocal cord dysfunction in 5%, and tracheal abnormalities in 3%. Bronchial aspirate culture isolated bacteria in 27% of patients and fungi in 14%. Three clusters were identified: nonspecific, upper airway, and infection, the latter being less frequently associated with submucosal eosinophilia. Eosinophils were detected in 91% of bronchial biopsies. Despite a correlation to blood eosinophils, five patients with T2-phenotypes showed no eosinophils in bronchial biopsy, and three patients with non-T2 showed eosinophils in bronchial biopsy. Only one patient had moderate bleeding. INTERPRETATION: Routine bronchoscopy in SUA eligible for biologic therapy is a safe procedure that can help to better phenotype and personalize asthma management.

Incidence and profile of severe exacerbations of chronic obstructive pulmonary disease due to biomass smoke or tobacco.

INTRODUCTION AND OBJECTIVES: Stable chronic obstructive pulmonary disease (COPD) caused by biomass smoke (B-COPD) has some differences from tobacco-induced-COPD (T-COPD), but acute exacerbations (AECOPD) have not been well characterized in B-COPD. OBJECTIVE: To compare the incidence, characteristics and outcomes of AECOPD in B-COPD with those of T-COPD. METHODS: A retrospective observational study that included consecutive patients seen at a specialized COPD clinic (2008-2021). The incidence of severe AECOPD that required hospital admission was studied. For the first AECOPD, the following variables were recorded: fever, coexistence of pneumonia, purulent sputum, eosinophil count, neutrophil to lymphocyte ratio, hypercapnia, and respiratory acidosis. Outcome variables were intensive care unit (ICU) admission, length of hospital stay, and mortality within 1 month of hospital admission. RESULTS: Of 1060 subjects, 195 (18.4%) belonged to the B-COPD group and 865 (81.6%) to the T-COPD group. During a follow-up of 67.9 (37.8-98.8) months, 75 (38.4%) patients in the B-COPD group and 319 (36.8%) in the T-COPD group suffered at least one severe AECOPD. The only difference between groups was in a higher risk of ICU admission for the T-COPD group. The incidence, characteristics, and the rest of the outcomes of AECOPD were similar for both groups. CONCLUSION: AECOPD are similar events for B-COPD and T-COPD and should be managed similarly.