Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma.

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels.Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels.Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

An epithelial gene signature of trans-IL-6 signaling defines a subgroup of type 2-low asthma.

BACKGROUND: Asthma is stratified into type 2-high and type 2-low inflammatory phenotypes. Limited success has been achieved in developing drugs that target type 2-low inflammation. Previous studies have linked IL-6 signaling to severe asthma. IL-6 cooperates with soluble-IL-6Rα to activate cell signaling in airway epithelium. OBJECTIVE: We sought to study the role of sIL-6Rα amplified IL-6 signaling in airway epithelium and to develop an IL-6+ sIL-6Rα gene signature that may be used to select asthma patients who potentially respond to anti-IL-6 therapy. METHODS: Human airway epithelial cells were stimulated with combinations of IL-6, sIL-6Rα, and inhibitors, sgp130 (Olamkicept), and anti-IL-6R (Tocilizumab), to assess effects on pathway activation, epithelial barrier integrity, and gene expression. A gene signature was generated to identify IL-6 high patients using bronchial biopsies and nasal brushes. RESULTS: Soluble-IL-6Rα amplified the activation of the IL-6 pathway, shown by the increase of STAT3 phosphorylation and stronger gene induction in airway epithelial cells compared to IL-6 alone. Olamkicept and Tocilizumab inhibited the effect of IL-6 + sIL-6Rα on gene expression. We developed an IL-6 + sIL-6Rα gene signature and observed enrichment of this signature in bronchial biopsies but not nasal brushes from asthma patients compared to healthy controls. An IL-6 + sIL-6Rα gene signature score was associated with lower levels of sputum eosinophils in asthma. CONCLUSION: sIL-6Rα amplifies IL-6 signaling in bronchial epithelial cells. Higher local airway IL-6 + sIL-6Rα signaling is observed in asthma patients with low sputum eosinophils.

Characteristics of Current Smokers versus Former Smokers with COPD and Their Associations with Smoking Cessation Within 4.5 Years: Results from COSYCONET.

Background: Many patients with chronic obstructive pulmonary disease (COPD) continue smoking. We used data from the "real-life" COSYCONET COPD cohort to evaluate whether these patients differed from patients with COPD who either had ceased smoking prior to inclusion or ceased during the follow-up time of the study. Methods: The analysis was based on data from visits 1-5 (covering 4.5 years), including all patients with the diagnosis of COPD who were either ex-smokers or smokers and categorized as GOLD 1-4 or the former GOLD 0 category. We compared the characteristics of smokers and ex-smokers at baseline (visit 1), as well as the course of lung function in the follow-up of permanent ex-smokers, permanent smokers and incident ex-smokers (smokers at visit 1 who ceased smoking before visit 5). We also identified baseline factors associated with subsequent smoking cessation. Results: Among 2500 patients who were ever-smokers, 660 were current smokers and 1840 ex-smokers at baseline. Smokers were younger than ex-smokers (mean 61.5 vs 66.0 y), had a longer duration of smoking but fewer pack-years, a lower frequency of asthma, higher forced expiratory volume in 1 sec (FEV1, 59.4 vs 55.2% predicted) and higher functional residual capacity (FRC, 147.7 vs 144.3% predicted). Similar results were obtained for the longitudinal subpopulation, comprising 713 permanent ex-smokers, 175 permanent smokers, and 55 incident ex-smokers. When analyzing the time course of lung function, higher FRC, lower FEV1 and the presence of asthma (p < 0.05 each) were associated with incident cessation prior to visit 5, while less airway obstruction was associated with smoking continuation. Conclusion: These findings, which were consistent in the cross-sectional and longitudinal analyses, suggest that lung hyperinflation was associated with being or becoming ex-smoker. Possibly, it is perceived by patients as one of the factors motivating their attempts to quit smoking, independent from airway obstruction.

Rapid Remote Online Evaluation in Endoscopic Diagnostics: An Analysis of Biopsy-Proven Respiratory Cytopathology.

BACKGROUND: This prospective study assesses the use of rapid remote online cytological evaluation for diagnosing endoscopical achieved biopsies. It focuses on its effectiveness in identifying benign and malignant conditions using digital image processing. METHODS: The study was conducted between April 2021 and September 2022 and involved analyses of 314 Rapid Remote Online Cytological Evaluations in total (154 imprint cytologies, 143 fine needle aspirations and 17 brush cytologies) performed on 239 patients at the LungenClinic Grosshansdorf. During on-site evaluation via telecytology, the time requirement was recorded and the findings were compared with the cyto-/histological and final diagnoses. RESULTS: By means of rapid remote online evaluation, findings of 86 cytological benign, 190 malignant and 38 unclear diagnoses were recorded (Ø assessment time, 100 s; range, 11-370 s). In 27 of the 37 specimens with unclear diagnoses, the final findings were malignant tumours and only 6 were benign changes. The diagnosis of another 4 of these 37 findings remained unclear. Excluding these 37 specimens, rapid remote online evaluation achieved a sensitivity of 90.5% with a specificity of 98.5% and a correct classification rate of 92.4% with regard to the final diagnosis of all cases. As expected, an increase in the sensitivity rate for the cytological detection of malignant tumours (76.1% vs. 92.5%) was found especially in fine-needle aspirations. CONCLUSIONS: Rapid remote online analysis allows the fast quantitative and qualitative evaluation of clinically obtained cytological specimens. With a correct classification rate of more than 93%, sampling deficiencies can be corrected promptly and diagnostic and therapeutic approaches can be derived.

Long-term efficacy of dupilumab in severe asthma by baseline oral corticosteroid dose.

Background: Dupilumab has been shown to improve clinical outcomes long term while reducing oral corticosteroid (OCS) dose in patients with severe OCS-dependent asthma. This post hoc analysis assesses the impact of OCS dose at baseline (≤10 or >10 mg·day-1) on long-term outcomes of dupilumab treatment. Methods: Annualised severe asthma exacerbation rates, forced expiratory volume in 1 s (FEV1), measures of asthma control and quality of life, and OCS dose were evaluated in patients from the phase 3 VENTURE trial with severe OCS-dependent asthma, further categorised by OCS dose ≤10 or >10 mg·day-1 at parent study baseline (PSBL), who enrolled in TRAVERSE. Results: Dupilumab reduced the annualised exacerbation rate in VENTURE, and it remained low throughout TRAVERSE (0.202-0.265 (OCS ≤10 mg·day-1 at PSBL) and 0.221-0.366 (OCS >10 mg·day-1 at PSBL)). Improvements in pre-bronchodilator FEV1, asthma control and quality of life observed in VENTURE dupilumab patients were sustained throughout TRAVERSE. Patients on placebo during VENTURE showed rapid improvements in FEV1 upon initiating dupilumab in TRAVERSE, which were sustained to the end of TRAVERSE. Reductions in OCS dose observed in VENTURE were maintained throughout TRAVERSE, with more than two-thirds of patients achieving reductions in OCS doses to ≤5 mg·day-1 by TRAVERSE week 48. Conclusions: Improvements in clinical outcomes and reductions in OCS dose with dupilumab observed in VENTURE were maintained throughout TRAVERSE, regardless of baseline disease severity. Patients who switched from placebo in VENTURE to dupilumab in TRAVERSE had improved clinical outcomes and reductions in OCS dose comparable to those given dupilumab in VENTURE.

Clinical factors linked to the type of respiratory medication in COPD: results from the COSYCONET cohort.

BACKGROUND: The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations. OBJECTIVES: We used the COSYCONET (COPD and Systemic Consequences - Comorbidities Network) cohort to analyze factors linked to the use of COPD drugs under non-interventional circumstances. DESIGN: COSYCONET is an ongoing, multi-center, non-interventional cohort of patients with COPD. METHODS: Patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 0-4 participating in visits 1-5 were included. Data covered the period from 2010 to 2018. Generalized linear models were used to examine the relation of COPD characteristics to different types of respiratory medication. RESULTS: A total of 1043 patients were included. The duration of observation was 4.5 years. Use of respiratory medication depended on GOLD grades 0-4 and groups A-D. Long-acting muscarinic antagonist therapy increased over time, and was associated with low carbon monoxide (CO) diffusing capacity, while inhaled corticosteroid (ICS) use decreased. Active smoking was associated with less maintenance therapy in general, and female sex with less ICS use. From the eight items of the COPD Assessment Test, only hill and stair climbing were consistently linked to treatment. CONCLUSION: Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT01245933.

Causes and Risk Factors for Absenteeism among Medical Staff in German Specialized Lung Clinics during the COVID Pandemic.

BACKGROUND: Staff shortages pose a major challenge to the health system. OBJECTIVES: The objective of this study was to clarify the role of different causative factors we investigated on staff absenteeism during the COVID pandemic. METHODS: The prospective multicentre cohort study assessed the private and professional impact of the pandemic on health care workers (HCWs) using a specially developed questionnaire. HCWs from 7 specialist lung clinics throughout Germany were surveyed from December 1 to December 23, 2021. The current analysis addresses pandemic-related absenteeism. RESULTS: 1,134 HCW (55% female; 18.4% male, 26.3% not willing to provide information on age or gender) participated. 72.8% had received at least one vaccination dose at the time of the survey, and 9.4% reported a COVID infection. Of those with positive tests, 98% reported home quarantine for median (IQR) 14 (12-17) days; 10.3% of those who ultimately tested negative also reported quarantine periods of 14 (7-14) days. 32.2% of vaccinated respondents reported absenteeism due to vaccine reactions of 2 (1-3) days. Overall, 37% (n = 420) of HCW reported pandemic-related absenteeism, with 3,524 total days of absenteeism, of which 2,828 were due to illness/quarantine and 696 to vaccination effects. Independent risk factors for COVID-related absenteeism ≥5 days included already having COVID, but also concern about long-term effects of COVID (OR 1,782, p = 0.014); risk factors for vaccine-related absenteeism ≥2 days included concerns of late effects of vaccination (OR 2.2, 95% CI: 1.4-3.1, p < 0.000). CONCLUSION: Staff shortages due to quarantine or infections and vaccine reactogenicity have put a strain on German respiratory specialists. The fact that staff concerns also contributed to absenteeism may be helpful in managing future pandemic events to minimize staff absenteeism.

[Diagnosis and treatment of asthma: a guideline for respiratory specialists 2023 - published by the German Respiratory Society (DGP) e. V.] / S2k-Leitlinie zur fachärztlichen Diagnostik und Therapie von Asthma 2023.

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma.

Early Detection of Lung Cancer Using Small RNAs.

INTRODUCTION: Lung cancer remains the deadliest cancer in the world, and lung cancer survival is heavily dependent on tumor stage at the time of detection. Low-dose computed tomography screening can reduce mortality; however, annual screening is limited by low adherence in the United States of America and still not broadly implemented in Europe. As a result, less than 10% of lung cancers are detected through existing programs. Thus, there is a great need for additional screening tests, such as a blood test, that could be deployed in the primary care setting. METHODS: We prospectively recruited 1384 individuals meeting the National Lung Screening Trial demographic eligibility criteria for lung cancer and collected stabilized whole blood to enable the pipetting-free collection of material, thus minimizing preanalytical noise. Ultra-deep small RNA sequencing (20 million reads per sample) was performed with the addition of a method to remove highly abundant erythroid RNAs, and thus open bandwidth for the detection of less abundant species originating from the plasma or the immune cellular compartment. We used 100 random data splits to train and evaluate an ensemble of logistic regression classifiers using small RNA expression of 943 individuals, discovered an 18-small RNA feature consensus signature (miLung), and validated this signature in an independent cohort (441 individuals). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin. RESULTS: We generated diagnostic models and report a median receiver-operating characteristic area under the curve of 0.86 (95% confidence interval [CI]: 0.84-0.86) in the discovery cohort and generalized performance of 0.83 in the validation cohort. Diagnostic performance increased in a stage-dependent manner ranging from 0.73 (95% CI: 0.71-0.76) for stage I to 0.90 (95% CI: 0.89-0.90) for stage IV in the discovery cohort and from 0.76 to 0.86 in the validation cohort. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased after surgery with curative intent. In additional experiments, results of dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted through home sampling. CONCLUSIONS: These data suggest the potential of a small RNA-based blood test as a viable alternative to low-dose computed tomography screening for early detection of smoking-associated lung cancer.

Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts.

BACKGROUND: In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV1) and in the scores on the St. George's Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS-COPD; range, 0 to 40, with lower scores indicating less severe symptoms). RESULTS: A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of -9.7 (95% CI, -11.3 to -8.1) with dupilumab and -6.4 (95% CI, -8.0 to -4.8) with placebo (LS mean difference, -3.4; 95% CI, -5.5 to -1.3; P = 0.002). The E-RS-COPD score at week 52 had improved by an LS mean of -2.7 (95% CI, -3.2 to -2.2) with dupilumab and -1.6 (95% CI, -2.1 to -1.1) with placebo (LS mean difference, -1.1; 95% CI, -1.8 to -0.4; P = 0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups. CONCLUSIONS: Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; BOREAS ClinicalTrials.gov number, NCT03930732.).

The microbial composition of larval airways from Drosophila melanogaster differ between specimens from laboratory and natural habitats.

BACKGROUND: The fruit fly Drosophila melanogaster lives in natural habitats and has also long been used as a model organism in biological research. In this study, we used a molecular barcoding approach to analyse the airways microbiome of larvae of D. melanogaster, which were obtained from eggs of flies of the laboratory strain w1118 and from immune deficient flies (NF-kB-K), and from wild-caught flies. To assess intergenerational transmission of microbes, all eggs were incubated under the same semi-sterile conditions. RESULTS: The airway microbiome of larvae from both lab-strains was dominated by the two families Acetobacteraceae and Lactobacillaceae, while larvae from wild-caught flies were dominated by Lactobacillaceae, Anaplasmataceae and Leuconostocaceae. Barcodes linked to Anaplasmataceae could be further assigned to Wolbachia sp., which is a widespread intracellular pathogen in arthropods. For Leuconostoceae, the most abundant reads were assigned to Weissella sp. Both Wolbachia and Weissella affect the development of the insects. Finally, a relative high abundance of Serratia sp. was found in larvae from immune deficient relish-/- compared to w1118 and wild-caught fly airways. CONCLUSIONS: Our results show for the first time that larvae from D. melanogaster harbor an airway microbiome, which is of low complexity and strongly influenced by the environmental conditions and to a lesser extent by the immune status. Furthermore, our data indicate an intergenerational transmission of the microbiome as shaped by the environment.

Targeting Type 2 Inflammation and Epithelial Alarmins in Chronic Obstructive Pulmonary Disease: A Biologics Outlook.

Chronic obstructive pulmonary disease (COPD) is a complex, heterogeneous, progressive inflammatory airway disease associated with a significant impact on patients' lives, including morbidity and mortality, and significant healthcare costs. Current pharmacologic strategies, including first- and second-line therapies such as long-acting ß2-agonists, long-acting muscarinic antagonists, inhaled corticosteroids, phosphodiesterase-4 inhibitors, and macrolides, provide relief to patients with COPD. However, many patients remain symptomatic, with persistent symptoms and/or acute exacerbations and progressive lung function loss. Although neutrophilic inflammation is the most common type of inflammation in COPD, 20-40% of patients with COPD exhibit type 2 inflammation, with roles for CD4+ (cluster of differentiation 4) T-helper cell type 1 cells, type 2 innate lymphoid cells, eosinophils, and alternatively activated macrophages. On the basis of the current limitations of available therapies, a significant unmet need exists in COPD management, including the need for targeted therapies to address the underlying pathophysiology leading to disease progression, such as type 2 inflammation, as well as biomarkers to help select the patients who would most benefit from the new therapies. Significant progress is being made, with evolving understanding of the pathobiology of COPD leading to novel therapeutic targets including epithelial alarmins. In this review, we describe the current therapeutic landscape in COPD, discuss unmet treatment needs, review the current knowledge of type 2 inflammation and epithelial alarmins in COPD, explore potential biomarkers of type 2 inflammation in COPD, and finally provide a rationale for incorporating therapies targeting type 2 inflammation and epithelial alarmins in COPD. Video Abstract available online at www.atsjournals.org.

Dupilumab improves long-term outcomes in patients with uncontrolled, moderate-to-severe GINA-based type 2 asthma, irrespective of allergic status.

BACKGROUND: Previous research has shown greater efficacy of dupilumab in patients with uncontrolled asthma and type 2 inflammation. We analyzed dupilumab's efficacy in patients from the TRAVERSE study with or without evidence of allergic asthma and type 2 inflammation per current GINA guidelines (≥150 eosinophils/µL or FeNO ≥20 ppb). METHODS: All patients aged ≥12 years who rolled over from the placebo-controlled QUEST study (NCT02414854) to TRAVERSE (NCT02134028) received add-on dupilumab 300 mg every 2 weeks for up to 96 weeks. We assessed annualized severe asthma exacerbation rates (AERs) and changes from parent-study baseline (PSBL) in pre-bronchodilator FEV1 and 5-item asthma control questionnaire (ACQ-5) score in patients with moderate-to-severe type 2 asthma with and without evidence of allergic asthma at PSBL. RESULTS: In TRAVERSE, dupilumab consistently reduced AER across all subgroups. By Week 96, dupilumab increased pre-bronchodilator FEV1 from PSBL by 0.35-0.41 L in patients receiving placebo during QUEST (placebo/dupilumab) and 0.34-0.44 L in those receiving dupilumab during QUEST (dupilumab/dupilumab) with an allergic phenotype at baseline. In patients without evidence of allergic asthma, pre-bronchodilator FEV1 improved by 0.38-0.41 L and 0.33-0.37 L, respectively. By Week 48, ACQ-5 scores decreased from PSBL by 1.63-1.69 (placebo/dupilumab) and 1.74-1.81 (dupilumab/dupilumab) points across subgroups with allergic asthma, and 1.75-1.83 (placebo/dupilumab) and 1.78-1.86 (dupilumab/dupilumab) in those without. CONCLUSIONS: Long-term treatment with dupilumab reduced exacerbation rates and improved lung function and asthma control in patients with asthma with type 2 inflammation as per current GINA guidance and irrespective of evidence of allergic asthma.

Long-term effect of dupilumab on prevention of lung function decline in patients with uncontrolled moderate-to-severe asthma: ATLAS trial design.

Background: Many patients with asthma experience loss of lung function over time, and in certain patients this can lead to progressive obstructive patterns similar to COPD. Patients with severe asthma may experience accelerated lung function decline (LFD). However, characteristics and risk factors for LFD in asthma have not been well described. Dupilumab may prevent or slow the rate of LFD in patients with uncontrolled, moderate-to-severe asthma. ATLAS trial is designed to evaluate the role of dupilumab in preventing/slowing LFD over a period of 3 years versus standard-of-care therapy. Methods: ATLAS (clinicaltrials.gov identifier NCT05097287) is a randomised, double-blind, placebo-controlled, multicentre study that will include adult patients with uncontrolled moderate-to-severe asthma. ∼1828 patients will be randomised (2:1) to dupilumab 300 mg or placebo in combination with maintenance therapy every 2 weeks for 3 years. The primary objective is to assess the effect of dupilumab on preventing or slowing LFD by year 1 in the exhaled nitric oxide fraction (F eNO) population (patients with F eNO ≥35 ppb). The effect of dupilumab in slowing the rate of LFD by year 2 and year 3 in both F eNO and total populations, exacerbations, asthma control, quality of life, biomarker changes and utility of F eNO as a biomarker of LFD will also be evaluated. Discussion: ATLAS is the first trial assessing the effect of a biologic on LFD, designed to establish the role of dupilumab in prevention of long-term loss of lung function and its potential effect on disease modification, which may provide unique insights into asthma pathophysiology, including predictive and prognostic factors of LFD.

Dupilumab Efficacy in Patients with Uncontrolled Moderate-to-Severe Type 2 Asthma Regardless of Perennial Aeroallergen Sensitization.

Purpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 (T2) inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), dupilumab vs placebo significantly reduced asthma exacerbation rates (AER) and improved pre-bronchodilator forced expiratory volume in 1 second (FEV1) in patients with uncontrolled, moderate-to-severe asthma, with greater effects in patients with elevated T2 biomarkers (≥150 eosinophils/µL or fractional exhaled nitric oxide [FeNO] ≥25 parts per billion). Overall safety was consistent with the known dupilumab safety profile. This post hoc analysis assessed dupilumab efficacy in QUEST patients with T2 asthma with evidence of an allergic phenotype (baseline serum IgE ≥30 IU/mL and aeroallergen-specific IgE ≥0.35 IU/mL) by number of aeroallergen sensitizations: 1, 2, 3, or ≥4. Non-sensitized patients (serum total IgE <30 IU/mL without evidence of allergic phenotype) were also assessed. Patients and Methods: Endpoints were annualized AER, change from baseline in pre-bronchodilator FEV1 and asthma control (5-item Asthma Control Questionnaire [ACQ-5]), and FeNO and serum total IgE levels over the 52-week treatment period. Results: In all subgroups by number of allergens sensitized, dupilumab vs placebo reduced AER by 35-67% and improved both pre-bronchodilator FEV1 at Week 12 (least squares mean differences: 0.10-0.26 L across subgroups) and ACQ-5 score at Week 52 (-0.26 to -0.43). Dupilumab significantly reduced FeNO and total IgE levels at Week 52 compared with placebo. Similar results were observed in non-sensitized patients. Conclusion: Dupilumab improved clinical outcomes and reduced biomarker levels in patients with uncontrolled, moderate-to-severe T2 asthma irrespective of allergen sensitization status or number. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02414854.

High inhaler resistance does not limit successful inspiratory maneuver among patients with asthma or COPD.

INTRODUCTION: There has been an active discussion on the sustainability of inhaler therapy in respiratory diseases, and it has cast a shadow on pMDIs which rely on propellant with high global warming potential (GWP). DPIs offer a lower GWP and effective alternative, but there has been concern whether all patients can generate sufficient inspiratory effort to disperse the drug. This review focuses on airflow resistance of DPIs and its clinical relevance. AREAS COVERED: For this narrative review, we searched the literature for studies comparing flow patterns with different devices. We also included a section on clinical trials comparing reliever administration with DPI, pMDI with spacer, and nebulizer during exacerbation. EXPERT OPINION: The evidence supports the efficacy of DPIs irrespective of respiratory condition or age of the patient even during acute exacerbations. Air flow resistance does not limit the use of DPIs and the patients were able to generate sufficient inspiratory flow rate with almost any device studied. None of 16 identified clinical trials comparing reliever administration via DPIs to other types of devices during exacerbation or bronchial challenge showed statistically significant difference between the device types in FEV1 recovery. DPIs performed as well as other types of inhaler devices even during asthma or COPD exacerbation.

Minimal clinically important difference for impulse oscillometry in adults with asthma.

BACKGROUND: Impulse oscillometry (IOS) allows an effort-independent evaluation of small airway function in asthma. Unfortunately, well-determined minimal clinically important differences (MCIDs) for IOS measures are lacking. Here, we provide MCIDs for frequently used IOS measures, namely frequency dependence of resistance (FDR) and area of reactance (AX), in patients with asthma. METHODS: We performed IOS at baseline and 1 year later in adult patients with mild-to-severe asthma (n=235). In a two-step approach, we first applied a distribution-based method to statistically determine the MCID. Next, we validated the proposed MCID according to patient-reported outcome measures (PROMs): Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire-7 (ACQ-7) and Asthma Control Test (ACT). We used multivariable analyses to investigate the proposed MCIDs as predictors for improvements in PROMs compared with the established MCID of forced expiratory volume in 1 s (FEV1). RESULTS: The proposed MCID was a decline of ≥0.06 kPa·L-1·s-1 and ≥0.65 kPa·L-1 for FDR and AX, respectively. Patients who had changes beyond the MCIDs for both FDR and AX showed greater improvements in all PROMs than those who had not. The mean improvements in PROMs were beyond the established MCIDs for ACQ-7 and AQLQ, and approximated the MCID for ACT. Multivariable analyses demonstrated the MCIDs for both FDR and AX as independent predictors for the MCIDs of all PROMs. The MCID for FDR was a stronger predictor of all PROMs than the MCID for FEV1. CONCLUSIONS: This study provides MCIDs for IOS-derived measures in adult patients with asthma and emphasises that small airway function is a distinguished end-point beyond the conventional measure of FEV1.

Validation of the Asthma Severity Scoring System (ASSESS) in the ALLIANCE Cohort.

BACKGROUND: The Asthma Severity Scoring System (ASSESS) quantifies asthma severity in adolescents and adults. Scale performance in children younger than 12 years is unknown. OBJECTIVE: To validate the ASSESS score in the All Age Asthma Cohort and explore its use in children younger than 12 years. METHODS: Scale properties, responsiveness, and known-group validity were assessed in 247 children (median age, 11 years; interquartile range, 8-13 years) and 206 adults (median age, 52 years; interquartile range, 43-63 years). RESULTS: Overall, measures of internal test consistency and test-retest reliability were similar to the original data of the Severe Asthma Research Program. Cronbach α was 0.59 in children aged 12 to 18 years and 0.73 in adults, reflecting the inclusion of multiple and not-always congruent dimensions to the ASSESS score, especially in children. Analysis of known-group validity confirmed the discriminatory power, because the ASSESS score was significantly worse in patients with poor asthma control, exacerbations, and increased salbutamol use. In children aged 6 to 11 years, test-retest reliability was inferior compared with that in adults and adolescents (Cronbach α, 0.27) mostly because of a less lung function impairment in children with asthma of this age group. Known-group validity, however, confirmed good discriminative power regarding severity-associated variables similar to adolescents and adults. CONCLUSIONS: Test-retest reliability and validity of the ASSESS score was confirmed in the All Age Asthma Cohort. In children aged 6 to 11 years, internal consistency was inferior compared with that in older patients with asthma; however, test validity was good and thus encourages age-spanning usage of the ASSESS score in all patients 6 years or older.