Reduction In Exacerbations Research Articles

Short-term Tezepelumab effectiveness in patients with severe asthma: a multicenter study

Objective Severe asthma presents significant management challenges, often requiring advanced treatments to control symptoms and reduce exacerbations. The use of monoclonal antibodies has revolutionized the clinical course of patients with severe asthma, showing a significant impact on exacerbations reduction, oral corticosteroids (OCS) cessation and on the improvement of lung function and quality of life. Tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) monoclonal antibody, has emerged as a potential therapeutic option for these patients. Methods We conducted an observational, prospective, multicenter study including 20 patients with confirmed severe asthma according to ERS guidelines and GINA recommendations. Patients received Tezepelumab 210 mg every 4 wk due to uncontrolled asthma despite maximal inhalation treatment with ICS/LABA. Data were collected before treatment initiation (T0) and after three months from the first administration (T3). Results After three months of Tezepelumab treatment, we reported significant improvements in asthma symptoms and quality of life, as well as a consistent reduction in exacerbations and OCS use. We found no statistically meaningful differences among main clinical and functional outcomes according to inflammatory biomarkers, while lung function improved significantly in patients with less allergic sensitization. No serious adverse event was reported during the follow up, while the rates of mild adverse effects were comparable to those from registration trials. Conclusion Tezepelumab demonstrated short-term efficacy in improving asthma control and quality of life, showing a favorable safety profile. Further studies with larger sample sizes and longer follow-up would confirm these findings and identify predictors of response to Tezepelumab.

Clinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies.

In asthma, clinical response is characterized by disease improvement with treatment, whereas clinical remission is characterized by long-term disease stabilization with or without ongoing treatment. The proportion of patients receiving tezepelumab who responded to treatment and those who achieved on-treatment clinical remission was assessed in the NAVIGATOR (NCT03347279) and DESTINATION (NCT03706079) studies of severe, uncontrolled asthma. NAVIGATOR and DESTINATION were phase 3, randomized, double-blind, placebo-controlled studies; DESTINATION was an extension of NAVIGATOR. Complete clinical response was defined as achieving all of the following: ≥50% reduction in exacerbations versus the previous year, improvements in pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) of ≥100 mL or ≥5%, improvements in Asthma Control Questionnaire (ACQ)-6 score of ≥0.5 and physicians' assessment of asthma improvement. On-treatment clinical remission was defined as an ACQ-6 total score ≤1.5, stable lung function (pre-BD FEV1 >95% of baseline) and no exacerbations or use of oral corticosteroids during the time periods assessed. Higher proportions of tezepelumab than placebo recipients achieved complete clinical response over weeks 0-52 (46% versus 24%; OR: 2.83 [95% CI: 2.10-3.82]), and on-treatment clinical remission over weeks 0-52 (28.5% versus 21.9%; OR: 1.44 [95% CI: 0.95-2.19]) and weeks >52-104 (33.5% versus 26.7%; OR: 1.44 [95% CI: 0.97-2.14]). Tezepelumab recipients who achieved on-treatment clinical remission versus complete clinical response at week 52 had better preserved lung function and lower inflammatory biomarkers at baseline, and fewer exacerbations in the 12 months before the study. Among patients with severe, uncontrolled asthma, tezepelumab treatment was associated with an increased likelihood of achieving complete clinical response and on-treatment clinical remission compared with placebo. Both are clinically important outcomes but may be driven by different patient characteristics.

Effectiveness of anti-IL5/5Rα biologics in severe asthma in real world studies: a systematic review and meta-analysis

BackgroundThree biologics targeting interleukin 5 (anti-IL5) or its receptor-α (anti-IL5Ra) are approved for patients with severe asthma.MethodsWe conducted a systematic search until May 1, 2023, to identify observational studies and non-randomised trials that assess the response to anti-IL5/5Rα of real-life patients with severe eosinophilic asthma in MEDLINE and EMBASE. We performed random-effects meta-analyses.ResultsWe identified 6,401 studies of which 92 with 9546 patients were analysed. Biologics use was associated with 62% reduction in severe exacerbations (risk ratio, RR, 0.38, 95%CI 0.29 to 0.50) and 54% reduction in hospitalisations (RR 0.46, 95%CI 0.35 to 0.61) at 12 months of treatment, compared to pre-treatment. Biologics improved asthma control [decrease in asthma control questionnaire (ACQ) by 1.11 points (95%CI −1.29 to −0.94) and increase in asthma control test (ACT) by 6.41 points (95%CI 5.66 to 7.16)], and increased the asthma quality of life questionnaire (AQLQ) by 1.08 points (95%CI 0.88 to 1.28) and forced expiratory volume in 1 s (FEV1) by 0.21 L (95% CI 0.15 to 0.27) at 12 months. There was a significant reduction in oral corticosteroids use by 51% (RR 0.49, 95%CI 0.42 to 0.56), with a mean dose reduction of 6.01 mg/d (95%CI −7.55 to −4.48) at 12 months of treatment. Similar findings were observed at 3–4, 6 and 24 months. Biomarker-related response to treatment was also noted.ConclusionsThis comprehensive meta-analysis summarises the significant clinical response to anti-IL5/5Rα biologics in real-life studies, providing important insights for clinical practice use of these agents.

Prospective REALITI-A Study: 2-Year Real-World Benefits of Mepolizumab in Severe Asthma

BackgroundMepolizumab, a monoclonal antibody targeting interleukin-5, is of proven clinical benefit in severe asthma; prospective, long-term, real-world data in severe asthma are required. Research QuestionThis study aimed to assess the real-world benefit of 2 years’ mepolizumab treatment in severe asthma. Study Design and MethodsREALITI-A was a 2-year, international, prospective study enrolling adults with asthma, newly initiating mepolizumab 100 mg subcutaneously (physician decision). Outcomes in the 1-year pre-mepolizumab versus 2-year follow-up periods included rates of clinically significant asthma exacerbations (CSE; deterioration requiring systemic corticosteroids and/or emergency department [ED] visit/hospitalisation), exacerbations requiring ED visit/hospitalisation, exacerbations requiring hospitalisation, proportion of patients with no exacerbations, median daily maintenance oral corticosteroid (mOCS) dose, proportion of patients discontinuing mOCS completely, asthma control questionnaire (ACQ)-5 score, forced expiratory volume in 1s (FEV1) and adverse events (AEs). ResultsAfter 2 years’ follow-up, 73% of patients (n=599/822) had no record of mepolizumab discontinuation. During the 2-year follow-up versus pre-mepolizumab period (N=822), rates of CSEs, exacerbations requiring ED visit/hospitalisation, or hospitalisation only were reduced by 74%, 79% and 73%, respectively (odds ratio for no CSEs: 10.0; 95% confidence interval: 7.55, 13.25). Median (Q1, Q3) daily mOCS dose decreased from 10.0 (5.0, 14.7) mg at Week 0 (n=297) to 0.0 (0.0, 5.0) mg at Weeks 101–104 (n=168), and the proportion of patients discontinuing mOCS increased progressively to 43% at 1 year and 57% at 2 years. There was a 1.53-point reduction in ACQ-5 scores from baseline at 2 years. At Months 21–24, least square mean FEV1 improved by 142 mL from baseline. Ninety (11%) and 7 (<1%) patients experienced mepolizumab-related AEs and serious AEs during the follow-up period, respectively. InterpretationIn patients with severe asthma, real-world mepolizumab treatment for 2 years was well-tolerated, and was associated with sustained reductions in exacerbations and progressive reductions in mOCS use.

Assessing the environmental justice implications of decarbonizing the US electric grid: estimating changes in asthma exacerbation by race and income

Abstract This paper examines how air quality improvements due to the 100% decarbonization of the US power sector in 2040 can reduce asthma exacerbation among children disaggregated by poverty status, race, and geography. Using spatial datasets that differentiate asthma prevalence by income, race, and state, we find that children living in households with income below the poverty line receive a disproportionate share of the benefits. To obtain these results, we employ several different federally administered datasets: American Community Survey, Behavioral Risk Factor Surveillance System (BRFSS), and Poverty Thresholds as provided by the US Census. We find that Black children and poor children, on average, have higher reductions in exposure to PM2.5. Nationally, close to 235 372 asthma exacerbation cases will be averted in 2040 under the decarbonization policy compared with Business-as-Usual. States with significant gains in asthma cases averted per 100 000 are Indiana, Kentucky, Ohio, Missouri, Pennsylvania, Texas, and Wisconsin. Furthermore, since the asthma portion of the BRFSS is not conducted in South Carolina, Colorado, Arkansas, and South Dakota, these states were omitted from the analysis. Across all states with significant gains, children living below the poverty line have larger health benefits than children above the poverty line. Households with child poverty have 50% larger reductions in asthma exacerbations than households without childhood poverty. Black children below the poverty line experience 33% higher health gains compared to Black children per 100 000 above the poverty line, 50% higher health gains compared to White children below the poverty line, and 159% higher than White children above the poverty line. We also provide general methodological insights for quantifying the environmental justice impacts of regulatory policies. We demonstrate why using race and poverty status-based prevalence rates is critical for understanding the distribution of health improvements and evaluating whether policies contribute to environmental justice goals.

Comparative effectiveness of dupilumab and omalizumab on asthma exacerbations and systemic corticosteroid prescriptions: Real-world US ADVANTAGE study

In the United States, dupilumab is approved for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma, and omalizumab is approved for managing moderate-to-severe allergic asthma uncontrolled by inhaled corticosteroids. However, limited comparative effectiveness data exist for these biologics due to differing patient characteristics and treatment histories. This study assessed the real-world effectiveness of dupilumab and omalizumab for asthma in patients in the United States. In this retrospective observational study, TriNetX Dataworks electronic medical record data were used to identify patients with asthma age ≥12 years who initiated (index) dupilumab or omalizumab between November 2018 and September 2020 and who had at least 12 months of pre- and post-index clinical information. Inverse probability of treatment weighting was applied to balance potential confounding in treatment groups. Asthma exacerbation rates and systemic corticosteroid (SCS) prescriptions were compared using a doubly robust negative binomial regression model, adjusting for baseline exacerbation/SCS rates and patient characteristics with ≥10% standardized differences after inverse probability of treatment weighting. All inclusion and exclusion criteria were met by 2138 dupilumab patients and 1313 omalizumab patients. After weighting, the majority of baseline characteristics were balanced (standard difference <10%) between the 2 groups. Dupilumab was associated with a 44% lower asthma exacerbation rate (P< .0001) versus omalizumab. Additionally, dupilumab treatment significantly (P< .05) reduced SCS prescriptions by 28% during the follow-up period compared with omalizumab treatment. The US ADVANTAGE real-world study demonstrated a significant reduction in severe asthma exacerbations and SCS prescriptions for patients prescribed dupilumab compared with patients prescribed omalizumab during 12 months of follow-up.

Therapeutic relevance of eosinophilic inflammation and airway viral interactions in severe asthma.

The role of eosinophils in airway inflammation and asthma pathogenesis is well established, with raised eosinophil counts in blood and sputum associated with increased disease severity and risk of asthma exacerbation. Conversely, there is also preliminary evidence suggesting antiviral properties of eosinophils in the airways. These dual roles for eosinophils are particularly pertinent as respiratory virus infections contribute to asthma exacerbations. Biologic therapies targeting key molecules implicated in eosinophil-associated pathologies have been approved in patients with severe asthma and, therefore, the effects of depleting eosinophils in a clinical setting are of considerable interest. This review discusses the pathological and antiviral roles of eosinophils in asthma and exacerbations. We also highlight the significant reduction in asthma exacerbations seen with biologic therapies, even at the height of the respiratory virus season. Furthermore, we discuss the implications of these findings in relation to the role of eosinophils in inflammation and antiviral responses to respiratory virus infection in asthma.

WPŁYW ADENOTONSILLEKTOMII NA KONTROLĘ ASTMY U PACJENTÓW PEDIATRYCZNYCH – PRZEGLĄD SYSTEMATYCZNY

IntroductionThis systematic review investigates the influence of adenotonsillectomy (AT) on asthma control in pediatric patients.Material and methodsA literature review from 2000 to 2023 based on the databases PubMed, the Cochrane Library, and Web of Science. The analysis is distilled down to four studies that revealed positive outcomes in asthma control as gauged by the Asthma Control Test (ACT), the Childhood Asthma Control Test (C-ACT), clinical outcomes, and asthma-related chitinase levels.ResultsThe four studies consistently demonstrated improved asthma control postoperatively in terms of improved ACT scores, reductions in acute asthma exacerbations, emergency room visits, hospitalisations, and medication usage. Notably, the correlation between improved asthma control and decreased chitinase activity suggests that AT has an impact on molecular markers associated with asthma.ConclusionsThe findings underline the potential benefits of AT in pediatric asthma management. However, the limitations of this study include a small number of studies and potential biases related to asthma’s natural course and seasonal variations. While the review provides evidence for the positive impact of AT on asthma control, further research with longer follow-up periods, case-matched controls, and consideration of seasonal factors is recommended.

Patient and clinician preferences for biologic treatments for severe uncontrolled asthma: a discrete choice experiment (DCE)

Objectives To estimate the preferences of patients with asthma and asthma-treating clinicians for attributes of biologic treatments, to compare patients’ and clinicians’ preferences, and to better understand the reasons for their preferences. Methods Adults with moderate-to-severe asthma and clinicians who treat asthma in the US completed a cross-sectional, online survey including a discrete choice experiment (DCE) that consisted of seven attributes spanning treatment efficacy, risk and convenience. Marginal utilities were estimated using a mixed logit model, and relative attribute importance scores calculated. Clinicians were also asked about the value of biomarker agnostic biologic treatments. The survey was followed by qualitative interviews targeting a sub-sample of survey participants, in which the rationale behind their survey responses was discussed. Results In the DCE, both patients and clinicians placed the most importance on exacerbation and hospitalization rate reduction, and risk of injection site reaction. Patients valued location of administration more than clinicians. Rationale for individual-level preferences varied, with patients and clinicians reporting their preference depended on event frequency and anticipated quality of life impacts. Clinicians mentioned compliance and financial impacts, while patients mentioned personal experience, particularly around site reactions. Most patients and clinicians would value a biomarker agnostic asthma treatment. Conclusions Asthma treatment preferences are largely driven by treatment efficacy and minimizing the risk of site reactions, although preferences differ between patients and clinicians across other attributes, highlighting the need for shared decision-making and individualized care.

Impact of elexacaftor/tezacaftor/ivacaftor CFTR modulator therapy on rates of endoscopic sinus surgery in cystic fibrosis.

Elexacaftor/tezacaftor/ivacaftor (ETI), a combination cystic fibrosis transmembrane receptor (CFTR) modulator, has demonstrated improved pulmonary outcomes in individuals with cystic fibrosis (CF). However, ETI's impact on functional endoscopic sinus surgery (FESS) remains unclear. The TriNetX Analytics Research Network, consisting of 120 million global de-identified electronic medical records, was queried from 2012 to 2023 for subjects with CF who underwent sinus surgery.1 Patients on ETI prior to FESS (n=6,056) were propensity score matched to control individuals with CF not on CFTR modulators (n=37,906) and those on other FDA-approved CFTR modulators (tezacaftor/ivacaftor, lumacaftor/ivacaftor, and ivacaftor) (n=2437) based on relevant factors. The primary outcome was the absolute risk reduction (ARR) of undergoing FESS. Secondary outcomes included ARR of CF-related pulmonary exacerbations and hospital admission from 0 to 6, 6 to 12, and 12 to 24 months following FESS. ETI use demonstrated a significant ARR for FESS when compared to CF patients not on CFTR modulators (2.12%; 95% confidence interval [CI] 1.5-2.75; p-value<0.0001) and those on other CFTR modulators (4.7%; 95% CI 3.54-5.85; p-value<0.0001). No significant differences occurred in secondary outcomes between ETI and non-CFTR modulator groups, except for reduced CF-related pulmonary exacerbations from 0 to 6 months post-FESS. Additionally, a significant reduction in pulmonary exacerbations was observed at all time points and hospital admissions within 6 months following FESS compared to those using other CFTR modulators. In a large dataset, CF patients on ETI demonstrated significantly reduced risk of FESS, pulmonary exacerbations, and hospital admission compared to patients not on CFTR modulators or those on other CFTR modulators, suggesting improved sinonasal disease and overall health status in CF.

Efficacy of Tezepelumab in Patients with Severe, Uncontrolled Asthma Across Multiple Clinically Relevant Subgroups in the NAVIGATOR Study.

Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR. NAVIGATOR was a phase 3, multicentre, randomized, double-blind, placebo-controlled study. Participants (12-80years old) with severe, uncontrolled asthma were randomized 1:1 to receive tezepelumab 210mg or placebo subcutaneously every 4weeks for 52weeks. Pre-specified and post hoc analyses were performed to evaluate the annualized asthma exacerbation rate (AAER) over 52weeks in clinically relevant subgroups of patients defined by baseline patient characteristics, medical history, exacerbation triggers, medication eligibility and medication use before and during the study. Tezepelumab reduced the AAER over 52weeks compared with placebo across a wide range of patient subgroups assessed. Reductions in exacerbations were similar across subgroups defined by baseline patient characteristics, ranging from 48% (95% confidence interval [CI]: 21, 65) to 60% (95% CI: 44, 71) in subgroups analysed by sex, smoking history and body mass index. Among the asthma-related comorbidity subgroups investigated, patients with aspirin or NSAID sensitivity had the greatest reductions in AAER with tezepelumab compared with placebo (83%; 95% CI: 66, 91). In patients eligible to receive dupilumab, tezepelumab reduced exacerbations compared with placebo by 64% (95% CI: 54, 71). Reductions in the AAER with tezepelumab compared with placebo were also observed irrespective of exacerbation trigger category and the number of asthma controller medications patients were receiving at baseline. These findings further support the benefits of tezepelumab in patients with severe, uncontrolled asthma and can help to inform healthcare providers' treatment decisions. NAVIGATOR (NCT03347279).

Real-world effectiveness of dupilumab versus benralizumab and mepolizumab.

Introduction: In the United States, this real-world study compared the effectiveness of dupilumab, benralizumab, and mepolizumab in reducing exacerbations and systemic corticosteroid (SCS) prescriptions among patients with asthma. Methods: Patients (≥12 years old) who initiated dupilumab, benralizumab, or mepolizumab (index) between November 2018 and September 2020 were identified by using electronic medical record data. Subjects were included if they had ≥ 12 months of data before and after the index date and two or more severe asthma-related exacerbations before the index date. Differences in baseline characteristics were addressed by using inverse probability treatment weighting (IPTW). Pairwise comparisons between dupilumab and benralizumab, or mepolizumab were conducted by using negative binomial regression, adjusting for baseline rates and unbalance characteristics (≥10% standardized differences) after IPTW. Results: Overall, a total of 1737 subjects met all criteria: 825 dupilumab, 461 benralizumab, and 451 mepolizumab initiators. In the postindex period, dupilumab was associated with a 24% and 28% significant reduction in the risk of severe asthma exacerbations versus benralizumab (incidence rate ratio [IRR] 0.76 [95% confidence interval {CI}, 0.67-0.86)] and mepolizumab (IRR 0.72 [95% CI, 0.63-0.82]), respectively. In addition, dupilumab treatment significantly reduced SCS prescriptions by 16% and 25% versus benralizumab and mepolizumab, respectively (p < 0.05). Conclusion: This study represents one of the largest real-world comparisons of biologics (dupilumab, benralizumab, and mepolizumab) for asthma in the United States to date. This analysis shows that the use of dupilumab was associated with a significantly greater reduction in both severe asthma exacerbations and SCS prescriptions compared with benralizumab and mepolizumab.

APPaRENT 3: Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma in Seven Countries.

Asthma management is strongly dependent on physician and patient beliefs and perceptions about the disease and its long-term treatment. The APPaRENT 3 study was conducted to explore factors influencing treatment choice and to understand patients' and physicians' attitudes and perspectives on the use of controller inhalers in regular versus flexible dosing for asthma management. This cross-sectional survey of patients with asthma and treating physicians was conducted in seven countries: Indonesia, Malaysia, Philippines, Thailand, Vietnam (patient survey only), Saudi Arabia, and the United Arab Emirates. Assessment was carried out through an online/face-to-face questionnaire, where patients' viewpoints were focused on their attitudes and beliefs about asthma and treatment adherence, whereas physicians' viewpoints were gathered on their attitudes and beliefs about asthma management, knowledge of and adherence to asthma treatment guidelines, and asthma treatment regimens. Overall, 1400 patients (mean age, 34years) and 599 physicians (mean age, 43years) were included in the survey. Physicians similarly prioritised symptom control (39%) and exacerbation reduction (40%) in moderate asthma, whereas patients prioritised symptom control (41%) over exacerbation reduction (22%). Although both groups (physicians, 86%; patients, 84%) perceived asthma as well-controlled, poor management was evident based on Asthma Control Test (ACT) scores (mean, 15.7; standard deviation, 4.14; 82% had an ACT score<20) and high symptom burden (39% reported nighttime awakenings or early mornings≥2 nights/week). Most patients (76%) with moderate asthma were prescribed regular dosing, with the most common treatment being inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) with as-needed inhaled short-acting β2-agonist (SABA; 20%). Among patients on maintenance and reliever therapy, 93% of patients received a separate inhaled reliever. Despite high symptom burden, patients overestimated their level of asthma control. Physicians prioritised controlling symptoms and reducing exacerbations as treatment goals for moderate asthma, often prescribing regular dosing with ICS/LABA with as-needed inhaled SABA.

How to implement the anti-inflammatory reliever treatment proposed by the Global Initiative for Asthma in low- and middle-income countries

There are no plausible arguments to consider that the best evidence-based asthma treatment should be different in low- and middle-income countries (LMICs). A few decades ago, the recognition of asthma as an inflammatory disease of the airways positioned the inhaled corticosteroids (ICS) as the cornerstone of the treatment of this disease, maintaining bronchodilators, especially the short-acting beta-agonists (SABA), as symptom-reliever medications for use as needed. However, adherence to regular use of ICS is very low, especially in LMICs, favoring the overuse of SABA, which has been related to an excess of exacerbations and mortality. Recently, the Global Initiative for Asthma (GINA) strategy has recommended the mandatory use of ICS every time a bronchodilator is used as needed (for symptoms relief), whether only as needed or with a background of regular dose of ICS, and has named it: anti-inflammatory reliever (AIR) therapy. This form of therapy, which has been related to a significant reduction of asthma exacerbations, is very attractive for LMICs where patients do not have guaranteed a proper medical follow-up and the access to on-the-counter medications is high. However, the implementation of AIR therapy in LMICs will face many of the already recognized barriers for the diagnosis and treatment of asthma in these countries, especially related to limited access to care in very different health systems, low education level of patients and communities, insufficient health personnel training in asthma in primary care, the unfordable cost of medications, and the lack of political commitment. This review analyzes some of these challenges and strategies for facing them in LMICs.

Impact of comorbidities on EQ-5D quality-of-life index in severe asthma

BackgroundSevere asthma pathology encompasses a wide range of pulmonary and extra-pulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health related quality of life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. ObjectiveTo examine the impact of pulmonary and extra-pulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centres. MethodsPatients characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. ResultsPatients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extra-pulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms and requirement for maintenance oral corticosteroids (OCS) was observed. ConclusionBoth pulmonary and extra-pulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasising the importance of early identification and management of severe asthma before comorbidities develop.

Towards precision medicine in COPD: Targeting type 2 cytokines and alarmins

Chronic obstructive pulmonary disease (COPD) is a main global epidemic increasing as population age and affecting approximately 10% of subjects over 45 years. COPD is a heterogeneous inflammatory disease with several endo-phenotypes and clinical presentations. Although neutrophilic inflammation is canonically considered a hallmark of COPD, eosinophilic inflammation can also be present in a subgroup of patients. Several other immune cells and cytokines play a key role in orchestrating and perpetuating the inflammatory pathways in COPD, making them attractive targets for treating this disorder. Recent studies have started to evaluate the possible role of type 2 (T2) inflammation and epithelial-derived alarmins (TSLP and IL-33) in COPD. Two phase III randomized clinical trials (RCTs) showed a modest reduction in exacerbations in COPD patients with eosinophilic phenotype treated with mepolizumab (anti-IL-5) or benralizumab (anti-IL-5Rα). A phase III RCT showed a 30% reduction in exacerbations in COPD patients with ≥ 300 eosinophils/μL treated with dupilumab (anti-IL-4Rα). These results suggest that blocking a single cytokine (e.g., IL-5) or its main target (i.e., IL-5Rα) is less promising than blocking a wider spectrum of cytokines (i.e., IL-4 and IL-13) in COPD. TSLP and IL-33 are upstream regulators of T2-high and T2-low immune responses in airway inflammation. Several ongoing RCTs are evaluating the efficacy and safety of anti-TSLP (tezepelumab), anti-IL-33 (itepekimab, tozorakimab), and anti-ST2 (astegolimab) in patients with COPD, who experience exacerbations. In conclusion, targeting T2 inflammation or epithelial-derived alarmins might represent a step forward in precision medicine for the treatment of a subset of COPD.

Statins did not reduce the frequency of exacerbations in individuals with COPD and cardiovascular comorbidities in the COSYCONET cohort

BackgroundThe evidence regarding effects of statins on exacerbation risk in COPD remains controversial. Previous studies often excluded patients with cardiovascular comorbidities despite their high prevalence in COPD and role for exacerbations. Based on the cardioprotective properties of statins, we hypothesised that statins may reduce the risk of exacerbations especially in patients with cardiovascular comorbidities.MethodsOne thousand eight hundred eighty seven patients of the German COPD cohort COSYCONET (COPD and Systemic Consequences Comorbidities Network) of GOLD grades 1–4 (37.8% female, mean age 64.78 ± 8.3) were examined at baseline and over a period of 4.5 years for the occurrence of at least one exacerbation or severe exacerbation per year in cross-sectional and longitudinal analyses adjusted for age, gender, BMI, GOLD grade and pack-years. Due to their collinearity, various cardiovascular diseases were tested in separate analyses, whereby the potential effect of statins in the presence of a specific comorbidity was tested as interaction between statins and comorbidity. We also identified patients who never took statins, always took statins, or initiated statin intake during the follow-up.ResultsOne thousand three hundred six patients never took statins, 31.6% were statin user, and 12.9% initiated statins during the follow-up. Most cardiovascular diseases were significantly (p < 0.05)may associated with an increased risk of COPD exacerbations, but in none of them the intake of statins was a significant attenuating factor, neither overall nor in modulating the increased risk linked to the specific comorbidities. The results of the cross-sectional and longitudinal analyses were consistent with each other, also those regarding at least 1 exacerbation or at least 1 severe exacerbation per year.ConclusionThese findings complement the existing literature and may suggest that even in patients with COPD, cardiovascular comorbidities and a statin therapy that targets these comorbidities, the effects of statins on exacerbation risk are either negligible or more subtle than a reduction in exacerbation frequency.Trial registrationTrial registration ClinicalTrials.gov, Identifier: NCT01245933.Other Study ID (BMBF grant): 01GI0881, registered 18 November 2010, study start 2010–11, primary completion 2013–12, study completion 2023–09.https://clinicaltrials.gov/study/NCT01245933?cond=COPD&term=COSYCONET&rank=3

HLA-DRB5 Overexpression Promotes Platelet Reduction in Immune Thrombocytopenia Mice Model by Facilitating MHC-II-Mediated Antigen Presentation

Introduction: Major histocompatibility complex II (MHC-II)-mediated antigen presentation contributes to the pathogenesis of immune thrombocytopenia (ITP). Human leukocyte antigen (HLA)-DRB5 is an MHC-II molecule and this study aims to investigate its role and mechanisms in ITP development. Methods: Guinea pig anti-mouse platelet (PLT) serum-induced ITP mice received tail vein injection of HLA-DRB5 overexpressing adenoviral vector/immune receptor expressed on myeloid cells-1 (IREM-1) monoclonal antibody (mAb). PLT count changes in mice blood were assessed by a hematology analyzer. MHC-II/CD80/CD86 expression in mice blood was measured by quantitative real-time-PCR and immunofluorescence assay. CD8+ T-cell proportion in mice blood was detected by flow cytometry. Results: HLA-DRB5 overexpression exacerbated PLT reduction since the 5th day of the establishment of ITP mice model and enhanced MHC-II/CD80/CD86 expression upregulation as well as CD8+ T-cell ratio elevation in the blood of ITP mice, while its effects were reversed by IREM-1 mAb. Conclusion: HLA-DRB5 overexpression upregulates MHC-II-mediated antigen presentation to CD8+ T cells, thus lowering PLT count in the ITP mice model.

Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic Omalizumab in Severe Asthma in Adults: Results of the SoMOSA Study.

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting β-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-β-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

Effectiveness and safety of biological therapy in patients with severe asthma in a real clinical practice

To assess effectiveness and safety of biological therapy in patients with severe asthma during 5 yr follow-up. We recruited 129 adult outpatients (29% males) aged 18-81 yrs with severe asthma were followed up during 5 yrs and were examined for every 3-6 months. Eighty five patients were treated by conventional therapy (ICS/LABA ± tiotropium, montelukast, OCS) only and 44 pts additionally received biologicals (оmalizumab - 9 pts, мepolizumab - 8 pts, benralizumab - 11 pts, dupilumab - 16 pts). Pulmonary function tests were measured by dry spirometer (2120, Vitalograph Ltd., UK). Eosinophil count in blood was assessed by automatic haemoanalyser. Fraction of exhaled nitric oxide was measured by a chemiluminescence analyzer (LR4100; Logan Research, UK). Asthma control and quality of life were assessed by using Russian versions of ACQ-5 and SGRQ. The use of biologicals led to a more significant reduction of exacerbations and OCS use, improvement of lung function, asthma control and quality of life, decrease of eosinophil and fraction of exhaled nitric oxide than conventional therapy of severe asthma (p<0.05). Systemic side effects were not registered, frequency of local adverse reactions (edema, hyperemia and itching at injection site) was 14%. Long-term use of biologicals added to conventional therapy in patients with severe asthma is characterized by high effectiveness and favorable safety profile.