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.

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/).

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).

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).

Tropical high altitude and severe asthma in adults: house dust mite sensitization and phenotypic distribution.

BACKGROUND: There is a lack of information on house dust mite (HDM) sensitization and phenotype distribution in patients with severe asthma (SA) living permanently at high-altitude (HA) in tropical regions, which may be different. OBJECTIVE: The aim of this study was to characterize adults with SA in a tropical high altitude city (2,640 m): Bogotá, Colombia. MATERIAL AND METHODS: This observational cross-sectional study included severe asthmatic outpatients (n = 129) referred to the ASMAIRE program of the Fundación Neumológica Colombiana in Bogotá (2,640 m). Clinical history, spirometry, total IgE, blood eosinophils, and skin prick test (SPT), including HDM allergens, were performed. Phenotype definitions: Allergic/atopic (AA): IgE ≥100 IU/mL and/or at least one positive SPT; eosinophilic (EOS): blood eosinophils ≥300 cells/µL; type 2-high: AA and/or EOS phenotype; type 2-low: non-AA/non-EOS phenotype (IgE <100 IU/mL, negative SPT, and blood eosinophils <300 cells/µL). RESULTS: A total of 129 adults with SA were included, 79.8% female. Phenotype distribution: AA: 61.2%; EOS: 37.2%; type 2-high: 72.1%; type 2-low: 27.9%. Among AA patients, HDM sensitization was present in 87% and 34.9% were non-eosinophilic. There was a significant overlap between the phenotypes. CONCLUSIONS: In contrast to non-tropical high-altitude regions, we found a high frequency of HDM sensitization in patients with AA phenotype living in a tropical high-altitude city. We also found a discrete lower frequency of EOS phenotype with no other significant differences in the phenotypic distribution compared to that described at low altitudes. We propose that tropical location may modify the effect of high altitude on HDM concentrations and allergenicity.

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.

Real-world effectiveness of omalizumab for severe allergic asthma treatment in Colombia.

BACKGROUND: The allergic phenotype is responsible for more than 50% of severe asthma cases. In a stepwise approach, add-on treatments such as anti-IgE are used for severe allergic asthma (SAA). This study was aimed to describe the real-world effectiveness of omalizumab in adult and pediatric patients with SAA in Colombia. METHODS: This was an observational, non-interventional, retrospective study. Data from patients with SAA that received at least one month of treatment with omalizumab was obtained from medical records at eight sites in Colombia. Time-zero (t - 0) was defined as the date of initiation of omalizumab, and data was gathered for a 12-month period before t - 0 and a 12-month period after t - 0. Clinical outcomes, including exacerbations, were assessed at 6 and 12 months. Effectiveness of omalizumab was evaluated in terms of the reduction of the risk of exacerbations (annualized rate). RESULTS: We included 143 patients with SAA. There was a decrease of 72.4% of the annualized rate of clinically significant asthma exacerbations during the year after omalizumab (from 1.74 before to 0.48 after) with a substantial reduction of the risk of exacerbations by 56.7% (RR [95% CI] 0.43 [0.30-0.63] p < 0,001). CONCLUSION: The use of omalizumab in Colombia as a treatment for SAA notably reduced the risk of clinically significant exacerbations. This study is the first to evaluate omalizumab real-life effectiveness in pediatric and adult patients in the country.

Effect of pulmonary hypertension on exercise capacity and gas exchange in patients with chronic obstructive pulmonary disease living at high altitude.

BACKGROUND: Pulmonary hypertension (PH) is associated with decreased exercise tolerance in chronic obstructive pulmonary disease (COPD) patients, but in the altitude the response to exercise in those patients is unknown. Our objective was to compare exercise capacity, gas exchange and ventilatory alterations between COPD patients with PH (COPD-PH) and without PH (COPD-nonPH) residents at high altitude (2640 m). METHODS: One hundred thirty-two COPD-nonPH, 82 COPD-PH, and 47 controls were included. Dyspnea by Borg scale, oxygen consumption (VO2), work rate (WR), ventilatory equivalents (VE/VCO2), dead space to tidal volume ratio (VD/VT), alveolar-arterial oxygen tension gradient (AaPO2), and arterial-end-tidal carbon dioxide pressure gradient (Pa-ETCO2) were measurement during a cardiopulmonary exercise test. For comparison of variables between groups, Kruskal-Wallis or one-way ANOVA tests were used, and stepwise regression analysis to test the association between PH and exercise capacity. RESULTS: All COPD patients had a lower exercise capacity and higher PaCO2, A-aPO2 and VD/VT than controls. The VO2 % predicted (61.3 ± 20.6 vs 75.3 ± 17.9; p < 0.001) and WR % predicted (65.3 ± 17.9 vs 75.3 ± 17.9; p < 0.001) were lower in COPD-PH than in COPD-nonPH. At peak exercise, dyspnea was higher in COPD-PH (p = 0.011). During exercise, in COPD-PH, the PaO2 was lower (p < 0.001), and AaPO2 (p < 0.001), Pa-ETCO2 (p = 0.033), VE/VCO2 (p = 0.019), and VD/VT (p = 0.007) were higher than in COPD-nonPH. In the multivariate analysis, PH was significantly associated with lower peak VO2 and WR (p < 0.001). CONCLUSION: In COPD patients residing at high altitude, the presence of PH was an independent factor related to the exercise capacity. Also, in COPD-PH patients there were more dyspnea and alterations in gas exchange during the exercise than in those without PH.

Arterial blood gases and ventilation at rest by age and sex in an adult Andean population resident at high altitude.

PURPOSE: Arterial blood gases (ABG) are influenced by the altitude above sea level, age and sex. Most studies have been conducted at sea level and in small populations ascending to or residents at very high altitudes. Our objective was to evaluate the ventilation and ABG by age and sex in an Andean population resident at high altitude (2640 m). METHODS: Analytical cross-sectional study was done in healthy volunteers. ABG and minute ventilation (VE) were measured. T test and ANOVA for differences by sex and age, and Pearson test for correlations between age, VE and ABG were performed. RESULTS: We included 374 adults, 55% women from 18 to 83 years and hemoglobin of 15.7 ± 1.6 g/dl. There was a significant decrease in PaO2 and SaO2 and an increase in P(A - a)O2 with age (p < 0.001). Unlike men, with age women had a significant increase in PaCO2 and a higher decrease in PaO2. The correlations between age, the decrease in PaO2 and the increase in PaCO2 were greater in women than in men. The VE adjusted to body surface area decreased with age, but this correlation was significantly higher in women. CONCLUSIONS: In this study, with a considerable number of healthy adults living at high altitude (2640 m), we established the physiological impact of altitude, aging and gender in ABG. The PaO2 and PaCO2 were significantly lower and the hemoglobin values slightly higher than described at sea level. In addition to PaO2 decline with age, there was an age-related increase in PaCO2 in women, associated with a greater reduction of VE.

Chronic bronchitis: High prevalence in never smokers and underdiagnosis- A population-based study in Colombia.

The objective of the article was to establish the prevalence, underdiagnosis, and risk factors of chronic bronchitis (CB) in a general population in five Colombian cities. Cross-sectional study using a probabilistic sampling technique in five Colombian cities was adopted. The CB definition was "cough and expectoration for three or more months per year for at least two consecutive years." Underdiagnosis was considered in subjects with clinical definition without previous medical diagnosis. Univariate χ2 or Student's t-test and logistic regression analysis were used. The study included 5539 subjects. The prevalence was 5.5%, the underdiagnosis 50.3%, and 33.7% of the cases were in nonsmokers (53.6% in women vs. 16.9% in men, p < 0.001). The adjusted risk factors were living in Bogota, current smoking, male, age ≥ 64 years, low education, indoor wood smoke exposure, and occupational exposure to vapors, gases, dust, and fumes. CB is a common disease among adults in Colombia. The underdiagnosis was high and there were a large proportion of cases in nonsmokers, particularly in women. Our findings support the association of CB with indoor wood smoke and occupational exposures.

Altitude and COPD prevalence: analysis of the PREPOCOL-PLATINO-BOLD-EPI-SCAN study.

BACKGROUND: COPD prevalence is highly variable and geographical altitude has been linked to it, yet with conflicting results. We aimed to investigate this association, considering well known risk factors. METHODS: A pooled analysis of individual data from the PREPOCOL-PLATINO-BOLD-EPI-SCAN studies was used to disentangle the population effect of geographical altitude on COPD prevalence. Post-bronchodilator FEV1/FVC below the lower limit of normal defined airflow limitation consistent with COPD. High altitude was defined as >1500 m above sea level. Undiagnosed COPD was considered when participants had airflow limitation but did not report a prior diagnosis of COPD. RESULTS: Among 30,874 participants aged 56.1 ± 11.3 years from 44 sites worldwide, 55.8% were women, 49.6% never-smokers, and 12.9% (3978 subjects) were residing above 1500 m. COPD prevalence was significantly lower in participants living at high altitude with a prevalence of 8.5% compared to 9.9%, respectively (p < 0.005). However, known risk factors were significantly less frequent at high altitude. Hence, in the adjusted multivariate analysis, altitude itself had no significant influence on COPD prevalence. Living at high altitude, however, was associated with a significantly increased risk of undiagnosed COPD. Furthermore, subjects with airflow limitation living at high altitude reported significantly less respiratory symptoms compared to subjects residing at lower altitude. CONCLUSION: Living at high altitude is not associated with a difference in COPD prevalence after accounting for individual risk factors. However, high altitude itself was associated with an increased risk of undiagnosed COPD.

Factors Associated With Non-compliance of Asbestos Occupational Standards in Brake Repair Workers.

Asbestos and non-asbestos containing brake products are currently used in low- and middle-income countries like Colombia. Because brake products are distributed detached from their supports, they require manipulation before installation, which release fibers and expose workers. Previous studies of our research group have documented exposures in excess of the widely accepted 0.1 f/cm(3) exposure guideline. The aim of this study is to identify factors associated with non-compliance of the 8-h time weighted average (TWA) 0.1 f/cm(3) asbestos occupational limit among brake mechanics (i.e. riveters). Eighteen brake repair shops (BRS) located in Bogotá (Colombia) were sampled during 3 to 6 consecutive days for the entire work-shift. Personal and short-term personal samples were collected following NIOSH methods 7400 and 7402. Longitudinal based logistic regression models were used to determine the association between the odds of exceeding the 8-h TWA 0.1 f/cm(3) asbestos occupational limit and variables such as type of tasks performed by workers, workload (number of products manipulated daily), years of experience as riveters, and shop characteristics. These models can be used to estimate the odds of being currently or historically overexposed when sampling data do not exist. Since the information required to run the models can vary for both retrospective and current asbestos occupational exposure studies, three models were constructed with different information requirements. The first model evaluated the association between the odds of non-compliance with variables related to the workload, the second model evaluated the association between the odds of non-compliance with variables related to the manipulation tasks, and the third model evaluated the association between the odds of non-compliance with variables related with both the type of tasks performed by workers and the workload. Variables associated with the odds of non-compliance included conducting at least one manipulation activity with beveling and grinding of asbestos and non-asbestos containing brake products during the work shift, the location of the worker in the shop during non-manipulation activities, cleaning activities of the manipulation area, the years of experience working as riveters, and the number of asbestos and non-asbestos containing brake products manipulated daily. These models could be useful for current and retrospective occupational studies, in determining the odds of non-compliance of the asbestos occupational limit among brake mechanics.

Prevalence, risk factors and underdiagnosis of asthma and wheezing in adults 40 years and older: A population-based study.

OBJECTIVE: There are differences in the prevalence and risk factors of asthma around the world. The epidemiological situation of adults 40 years and older is not well established. Our aim was to determine the prevalence, underdiagnosis and risk factors of asthma and wheezing in adults in Colombia. METHODS: A cross-sectional, population-based study including 5539 subjects from 40 to 93 years selected by a probabilistic sampling technique in five cities was conducted. MEASUREMENTS: respiratory symptoms and risk factors questionnaire and spirometry. DEFINITIONS: (a) Wheezing: Affirmative answer to the question "have you ever had two or more attacks of "wheezes" causing you to feel short of breath?" (b) Asthma: Wheezing definition and FEV1/FVC post-bronchodilator ≥ 70%. (c) Underdiagnosis: Asthma definition without a physician-diagnosis. Logistic regression was used for exploring risk factors. RESULTS: Prevalence of asthma was 9.0% (95% CI: 8.3-9.8) and wheezing 11.9% (95% CI: 11.0-12.8). Asthma underdiagnosis was 69.9% and increased to 79.0% in subjects 64 years or older. The risk factors related to asthma and/or wheezing were: living in Bogota or Medellin, female gender, first degree relative with asthma, respiratory disease before 16 years of age, obesity, no education, indoor wood smoke exposure and occupational exposure to dust particles, gases or fumes. CONCLUSION: We described the epidemiologic situation of asthma in adults 40 years and older in Colombia. In addition to some recognized risk factors, our data supports the association of indoor wood smoke and occupational exposures with asthma and wheezing. Underdiagnosis of asthma in adults was high, particularly in older subjects.

Cost-effectiveness analysis of dupilumab versus omalizumab, mepolizumab, and benralizumab added to the standard of care in adults with severe asthma in Colombia.

BACKGROUND: Cost-effectiveness studies evaluate health technologies and help choose treatments. The current study compared dupilumab to omalizumab, mepolizumab, and benralizumab in Colombian adults with severe uncontrolled type 2 asthma. METHODS: Over a 5-year period, a Markov model was utilized to assess the costs of biological treatments and management of exacerbations, comparing various doses of exacerbations, comparing various doses of dupilumab, omalizumab, mepolizumab, and benralizumab as add-on treatments. It included a 5% annual discount rate per local HTA, and set willingness-to-pay at three times GDP per capita per quality-adjusted life year (QALY) in Colombia. RESULTS: Dupilumab (200 mg) exhibited greater QALYs and reduced overall costs compared to mepolizumab (100 mg), benralizumab (30 mg), and omalizumab (450 mg and 600 mg), with the incremental cost-effectiveness ratio (ICER) per QALYgained being -$5.429, -$6.269, -$196.567 and -$991.007, respectively. Dupilumab had greater QALYs and costs versus omalizumab 300 mg (ICERof $200.653 per QALY, above the willingness-to-pay threshold of 3 × GDP per capita). Sensitivity analyses were consistent with base case results. CONCLUSIONS: Dupilumab 200 mg was strongly dominant versus omalizumab 450 mg and 600 mg, mepolizumab 100 mg, and benralizumab 30 mg; however, cost-effectiveness was not demonstrated versus omalizumab 300 mg. These results could assist healthcare professionals in choosing an appropriate biologic for treating severe type 2 asthma.

Sputum Biomarkers in Wood and Tobacco Smoke Etiotypes of Chronic Obstructive Pulmonary Disease.

Introduction: There is a need to better understand the etiotypes of chronic obstructive pulmonary disease (COPD) beyond the tobacco-smoke (TS-COPD). Wood smoke COPD (WS-COPD) is characterized by greater airway compromise, milder emphysema, and slower rate of lung function decline than TS-COPD. However, it is unclear if these two etiotypes of COPD have differences in sputum biomarker concentrations. Objective was to compare sputum levels of selected sputum biomarkers between WS-COPD and TS-COPD, and healthy controls. Methods: Eighty-eight women (69±12 years) were recruited and classified into: WS-COPD (n=31), TS-COPD (n=29) and controls (n=28). Using ELISA, we determined induced sputum levels of metalloproteinase 9 (MMP-9), chemokine ligand 5 (CCL5), interleukin-8 (IL-8), chemokine ligand 16 (CCL16/HCC-4) and vascular endothelial growth factor (VEGF-1). Differences were analyzed by Kruskal-Wallis and Mann-Whitney-U tests and correlation between airflow limitation and biomarkers by Spearman's test. Results: At similar degree of airflow obstruction, anthropometrics and medications use, the level of sputum CCL5 was higher in TS-COPD than WS-COPD (p=0.03) without differences in MMP-9, IL-8, CCL16/HCC-4, and VEGF-1. Women with WS-COPD and TS-COPD showed significantly higher sputum levels of MMP-9, IL-8 and CCL5 compared with controls (p<0.001). FEV1% predicted correlated negatively with levels of MMP-9 (rho:-0.26; P=0.016), CCL5 (rho:-0.37; P=0.001), IL-8 (rho:-0.42; P<0.001) and VEGF (rho:-0.22; P=0.04). Conclusion: While sputum concentrations of MMP-9, IL-8, and CCL5 were higher in COPD women compared with controls, women with TS-COPD had higher levels of CCL5 compared with those with WS-COPD. Whether this finding relates to differences in pathobiological pathways remains to be determined.

Delphi Consensus on Clinical Applications of GOLD 2023 Recommendations in COPD Management: How Aligned are Recommendations with Clinical Practice?

INTRODUCTION: The objective of this Delphi study was to understand and assess the level of consensus among respiratory experts on the clinical application of GOLD 2023 recommendations in management of patients with chronic obstructive pulmonary disease (COPD). METHODS: The study comprised two online surveys and a participant meeting with 34 respiratory experts from 16 countries. Responses of 73 questions were recorded using a Likert scale ranging from 0 (disagreement) to 9 (agreement). The consensus threshold was 75%. RESULTS: Survey 1 and survey 2 had 34 and 32 participants, respectively; and 25 attended the participant meeting. Consensus was reached on survey 1: 28/42; survey 2: 18/30 close-ended questions. A consensus was reached on the clinical relevance of most updates in definitions and diagnosis of COPD. Mixed results for the treatment recommendations by GOLD were noted: 74% agreed with the recommendation to initiate treatment with dual bronchodilators for group E patients; 63% agreed for including inhaled corticosteroids (ICS)/long-acting ß2 agonist(LABA)/ Long-acting muscarinic receptor antagonists (LAMA) as a treatment option for GOLD B patients. Also, consensus lacked on removing ICS + LABA as an initial therapeutic option, in countries with challenges in access to other treatment option;. 88% agreed that they use GOLD recommendations in their daily clinical practice. CONCLUSIONS: This Delphi study demonstrated a high level of consensus regarding key concepts of GOLD 2023 report, with most participants favoring recent updates in definitions, diagnosis, management, and prevention of COPD. More evidence on the etiotype based management and treatment options for group B and E are required which could further strengthen clinical application of the GOLD report.

The goal of this Delphi study was to understand and assess the level of alignment among the respiratory experts on the application of key changes and recommendations proposed by the GOLD 2023 report in their routine clinical practice for the management of patients with chronic obstructive pulmonary disease (COPD). There were two online surveys in this study, and experts from 16 countries (primarily focused on developing countries) were invited to participate. Using the Delphi method, expert representatives shared their insights with the aim of optimizing patient care. The alignment was assessed in six well-defined themes: 1) Overall view on GOLD/other recommendations; 2) Assessing patients with COPD; 3) Initial pharmacological treatment in patients with COPD; 4) Vaccination for patients with COPD; 5) Follow-up pharmacological treatment in patients with COPD; and 6) Survival evidence in patients with COPD. Participants expressed a high level of agreement regarding key concepts of the GOLD 2023 report, with most of them agreeing with recent updates in definitions, diagnosis, management, and prevention of COPD. The results also highlighted the need to publish GOLD reports in multiple languages and in a shorter, pocket-sized format to increase awareness and adaptation among healthcare providers.

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.

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.

Toward a better understanding of severe asthma phenotypes in Latin America: results from the PREPARE study.

OBJECTIVE: Data on severe asthma phenotypes in Latin America are lacking. The PREPARE study describes the prevalence of certain determinants of severe asthma among patients in 5 Latin American countries with blood eosinophil counts (BEC) ≥300 cells/mm3 and serum immunoglobulin E (IgE) concentrations >100 IU/mL. METHODS: In this cross-sectional study, information on demographics, disease characteristics, and asthma treatments were extracted from the existing medical records of patients aged ≥12 years attending centers specialized in severe asthma management. Medical record data were transcribed onto electronic case report forms. Blood eosinophil counts and IgE concentrations were assayed from specimens obtained at study visit. Data were analyzed with descriptive statistics. RESULTS: Data from 461 patients with severe asthma (mean age, 50.5 years) were analyzed. Most patients were female (73%), had a body mass index of ≥25 kg/m2 (77%), and received full healthcare reimbursement (63%). In the previous 12 months, 52% of patients experienced ≥1 severe exacerbation and 44% received oral corticosteroid burst therapy. Blood eosinophil counts ≥300 cells/mm3 and ≥150 cells/mm3 were reported in 44% and 76% of patients, respectively. In 58% of patients, serum IgE concentrations exceeded 100 IU/mL. Uncontrolled asthma was documented in 50% (n = 230) of patients. CONCLUSIONS: The PREPARE study provides useful insights about the prevalence of eosinophilic and atopic phenotypes in patients with severe asthma in Latin America, thereby paving the way for a more personalized approach to managing severe asthma. Notwithstanding the treatment at specialized medical centers, disease burden remained high in this study population.