The carbon footprint of as-needed budesonide-formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma (GINA). METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with: as-needed budesonide-formoterol DPI, as-needed salbutamol pMDI, or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e), per person year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide-formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide-formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.

Understanding the impact of adult pertussis and current approaches to vaccination: A narrative review and expert panel recommendations.

Pertussis has several notable consequences, causing economic burden, increased strain on healthcare facilities, and reductions in quality of life. Recent years have seen a trend toward an increase in pertussis cases affecting older children and adults. To boost immunity, and protect vulnerable populations, an enduring approach to vaccination has been proposed, but gaps remain in the evidence surrounding adult vaccination that are needed to inform such a policy. Gaps include: the true incidence of pertussis and its complications in adults; regional variations in disease recognition and reporting; and incidence of severe disease, hospitalizations, and deaths in older adults. Better data on the efficacy/effectiveness of pertussis vaccination in adults, duration of protection, and factors leading to poor vaccine uptake are needed. Addressing the critical evidence gaps will help highlight important areas of unmet need and justify the importance of adult pertussis vaccination to healthcare professionals, policymakers, and payers.

N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses.

INTRODUCTION: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD). METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study. RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients. CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.

The many faces of COPD in real life: a longitudinal analysis of the NOVELTY cohort.

Background: The diagnosis of COPD requires the demonstration of non-fully reversible airflow limitation by spirometry in the appropriate clinical context. Yet, there are patients with symptoms and relevant exposures suggestive of COPD with either normal spirometry (pre-COPD) or preserved ratio but impaired spirometry (PRISm). Their prevalence, clinical characteristics and associated outcomes in a real-life setting are unclear. Methods: To investigate them, we studied 3183 patients diagnosed with COPD by their attending physician included in the NOVELTY study (clinicaltrials.gov identifier NCT02760329), a global, 3-year, observational, real-life cohort that included patients recruited from both primary and specialist care clinics in 18 countries. Results: We found that 1) approximately a quarter of patients diagnosed with (and treated for) COPD in real life did not fulfil the spirometric diagnostic criteria recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), and could be instead categorised as pre-COPD (13%) or PRISm (14%); 2) disease burden (symptoms and exacerbations) was highest in GOLD 3-4 patients (exacerbations per person-year (PPY) 0.82) and lower but similar in those in GOLD 1-2, pre-COPD and PRISm (exacerbations range 0.27-0.43 PPY); 3) lung function decline was highest in pre-COPD and GOLD 1-2, and much less pronounced in PRISm and GOLD 3-4; 4) PRISm and pre-COPD were not stable diagnostic categories and change substantially over time; and 5) all-cause mortality was highest in GOLD 3-4, lowest in pre-COPD, and intermediate and similar in GOLD 1-2 and PRISm. Conclusions: Patients diagnosed COPD in a real-life clinical setting present great diversity in symptom burden, progression and survival, warranting medical attention.

Enhanced prothrombotic and proinflammatory activity of circulating extracellular vesicles in acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with a high rate of cardiovascular events. Thromboinflammation (the interplay between coagulation and inflammation) is probably involved in these events. Extracellular vesicles (EV) increase during AE-COPD, but their role in thromboinflammation in COPD is still unknown. We investigated EV-associated prothrombotic and proinflammatory activity in COPD. METHODS: Patients with AE-COPD, stable COPD (sCOPD) and age- and sex-matched subjects (controls) were enrolled. AE-COPD patients were evaluated at hospital admission and 8 weeks after discharge (recovery; longitudinal arm). In a cross-sectional arm, AE-COPD were compared with sCOPD and controls. EV-mediated prothrombotic activity was tested by measuring the concentration of EV-associated phosphatidylserine, as assessed by a prothrombinase assay, and tissue factor, as assessed by a modified one-stage clotting assay (EV-PS and EV-TF, respectively). Synthesis of interleukin-8 (IL-8) and C-C motif chemokine ligand-2 (CCL-2) by cells of the human bronchial epithelial cell line 16HBE incubated with patients' EV was used to measure EV-mediated proinflammatory activity. RESULTS: Twenty-five AE-COPD (median age [interquartile range] 74.0 [14.0] years), 31 sCOPD (75.0 [9.5] years) and 12 control (67.0 [3.5] years) subjects were enrolled. In the longitudinal arm, EV-PS, EV-TF, IL-8 and CCL-2 levels were all significantly higher at hospital admission than at recovery. Similarly, in the cross-sectional arm, EV-PS, EV-TF and cytokines synthesis were significantly higher in AE-COPD than in sCOPD and controls. CONCLUSIONS: EV exert prothrombotic and proinflammatory activities during AE-COPD and may therefore be effectors of thromboinflammation, thus contributing to the higher cardiovascular risk in AE-COPD.

Dupilumab sustains lung function improvements in patients with moderate-to-severe asthma.

BACKGROUND: TRAVERSE (NCT02134028), a phase 3 open-label extension study, assessed dupilumab safety and efficacy in patients with asthma aged ≥12 years who completed a previous dupilumab asthma study. This analysis evaluated changes in multiple lung function parameters in patients with moderate-to-severe asthma with elevated type 2 biomarkers (baseline eosinophils ≥150 cells·µL-1 or fractional exhaled nitric oxide ≥25 ppb) who completed QUEST (parent study) and 2 years of dupilumab treatment in TRAVERSE. METHODS: Endpoints analyzed included: pre-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), forced expiratory flow (FEF25-75 %), and pre- and post-bronchodilator FEV1/FVC at parent study baseline (PSBL) at Weeks 0, 2, 48, and 96 in TRAVERSE, as well as pre- and post-bronchodilator FEV1 slopes in QUEST and TRAVERSE. Statistical analyses were descriptive. RESULTS: Dupilumab improved pre-bronchodilator FEV1, FVC, and FEF25-75 % in QUEST; these improvements were sustained in TRAVERSE. In QUEST patients who received placebo, dupilumab initiation in TRAVERSE resulted in rapid lung function improvements. Mean (standard deviation) changes from PSBL at TRAVERSE Weeks 48 and 96 in pre-bronchodilator FEV1 were 0.52 (0.59) and 0.45 (0.49) L in the dupilumab/dupilumab group and 0.47 (0.42) and 0.44 L (0.45) in the placebo/dupilumab group, respectively. Similar trends were observed for FVC and FEF25-75 %. Dupilumab also improved FEV1 slopes in QUEST and TRAVERSE. CONCLUSION: Dupilumab demonstrated sustained improvements across multiple spirometric lung function measurements for up to 3 years; patients who received placebo in QUEST experienced rapid lung function improvement upon initiation of dupilumab in TRAVERSE.

Efficacy and safety of respiratory syncytial virus prefusion F protein vaccine (RSVPreF3 OA) in older adults over 2 RSV seasons.

BACKGROUND: The adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD) in ≥60-year-olds over 1 RSV season. We evaluated efficacy and safety of 1 RSVPreF3 OA dose and of 2 RSVPreF3 OA doses given 1 year apart against RSV-LRTD over 2 RSV seasons post-dose 1. METHODS: In this phase 3, blinded trial, ≥60-year-olds were randomized (1:1) to receive RSVPreF3 OA or placebo pre-season 1. RSVPreF3 OA recipients were re-randomized (1:1) to receive a second RSVPreF3 OA dose (RSV_revaccination group) or placebo (RSV_1dose group) pre-season 2; participants who received placebo pre-season 1 received placebo pre-season 2 (placebo group). Efficacy of both vaccine regimens against RSV-LRTD was evaluated over 2 seasons combined (confirmatory secondary objective, success criterion: lower limits of 2-sided confidence intervals [CIs] around efficacy estimates >20%). RESULTS: The efficacy analysis comprised 24,967 participants (RSV_1dose: 6227, RSV_revaccination: 6242, placebo: 12,498). Median efficacy follow-up was 17.8 months. Efficacy over 2 seasons of 1 RSVPreF3 OA dose was 67.2% (97.5% CI: 48.2-80.0) against RSV-LRTD and 78.8% (95% CI: 52.6-92.0) against severe RSV-LRTD. Efficacy over 2 seasons of a first dose followed by revaccination was 67.1% (97.5% CI: 48.1-80.0) against RSV-LRTD and 78.8% (95% CI: 52.5-92.0) against severe RSV-LRTD. Reactogenicity/safety of the revaccination dose were similar to dose 1. CONCLUSION: One RSVPreF3 OA dose was efficacious against RSV-LRTD over 2 RSV seasons in ≥60-year-olds. Revaccination 1 year post-dose 1 was well tolerated but did not seem to provide additional efficacy benefit in the overall study population. ClinicalTrials.gov registration: NCT04886596.

From treatable traits to GETomics in airway disease: moving towards clinical practice.

The treatable traits approach represents a strategy for patient management. It is based on the identification of characteristics susceptible to treatments or predictive of treatment response in each individual patient. With the objective of accelerating progress in research and clinical practice relating to such a treatable traits approach, the Portraits event was convened in Barcelona, Spain, in November 2022. Here, while reporting the key concepts that emerged from the discussions during the meeting, we review the current state of the art related to treatable traits and chronic respiratory diseases management, and we describe the possible actions that clinicians can take in clinical practice to implement the treatable traits framework. Furthermore, we explore the new concept of GETomics and the new models of research in the field of COPD.

Risk of Pneumonia in Patients with COPD Initiating Fixed Dose Inhaled Corticosteroid (ICS) / Long-Acting Bronchodilator (LABD) Formulations Containing Extrafine Beclometasone Dipropionate versus Patients Initiating LABD Without ICS.

Background: Combined ICS and long-acting bronchodilators (LABD) more effectively reduce COPD exacerbations than LABD therapy alone. Corticosteroid-related adverse effects, including pneumonia, limit ICS use. Previous data suggest this risk is lower for extrafine beclometasone (ef-BDP). We compared pneumonia risk among new users of fixed dose ICS/LABD formulations containing ef-BDP, versus patients initiating LABD without any ICS. Methods: A propensity-matched historical cohort study design used data from OPCRD. COPD patients with ≥1 year of continuous data who initiated LABD or ICS/LABD formulations containing ef-BDP were matched. Primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions, with non-inferiority boundary of 15%. Results: 23,898 COPD patients were matched, who were 68±11 years, 54.3% male and 56% current-smokers, while 43% were former-smokers. Initiation of ef-BDP/LABD was not associated with an increased risk of pneumonia versus LABD, for either a sensitive 0.89 (0.78-1.02), P = 0.08 or a specific 0.91 (0.78-1.05), P = 0.18 definition of pneumonia. The probability of remaining pneumonia free 1-year after ef-BDP/LABD was 98.4%, which was comparable to LABD at 97.7%, and was sustained up to 6 years of observation; non-inferiority criterion was met for both definitions. Initiation of ef-BDP/LABD was also associated with a reduced risk of developing LRTIs in the propensity matched cohort. Conclusion: Risk of pneumonia when using ICS for the management of COPD reported in several randomised controlled trials may not be relevant with ef-BDP in a diverse real-world clinical population.

Prevalence, Diagnostic Utility and Associated Characteristics of Bronchodilator Responsiveness.

Rationale: The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear. Objective: To explore this uncertainty in patients aged ⩾12 years with physician-assigned diagnoses of asthma, asthma and chronic obstructive pulmonary disease (COPD), or COPD in NOVELTY, a prospective cohort study in primary and secondary care in 18 countries. Methods: The proportion of patients with a positive BDR test in each diagnostic category was calculated using 2005 (ΔFEV1 or ΔFVC ⩾12% and ⩾200 ml) and 2021 (ΔFEV1 or ΔFVC >10% predicted) European Respiratory Society/American Thoracic Society criteria. Measurements and Main Results: We studied 3,519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma + COPD, and 2,436 with a diagnosis of COPD. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma + COPD), and 24.7% (COPD) using 2005 criteria and 18.1%, 23.3%, and 18.0%, respectively, using 2021 criteria. Using 2021 criteria in patients diagnosed with asthma, BDR was associated with higher fractional exhaled nitric oxide; lower lung function; higher symptom burden; more frequent hospital admissions; and greater use of triple therapy, oral corticosteroids, or biologics. In patients diagnosed with COPD, BDR (2021) was associated with lower lung function and higher symptom burden. Conclusions: BDR prevalence in patients with chronic airway diseases receiving treatment ranges from 18% to 30%, being modestly lower with the 2021 than with the 2005 European Respiratory Society/American Thoracic Society criteria, and it is associated with lower lung function and greater symptom burden. These observations question the validity of BDR as a key diagnostic tool for asthma managed in clinical practice or as a standard inclusion criterion for clinical trials of asthma and instead suggest that BDR be considered a treatable trait for chronic airway disease.

Respiratory Syncytial Virus Prefusion F Protein Vaccine Is Efficacious in Older Adults With Underlying Medical Conditions.

BACKGROUND: Older adults with chronic cardiorespiratory or endocrine/metabolic conditions are at increased risk of respiratory syncytial virus (RSV)-related acute respiratory illness (RSV-ARI) and severe respiratory disease. In an ongoing, randomized, placebo-controlled, multicountry, phase 3 trial in ≥60-year-old participants, an AS01E-adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD), severe RSV-LRTD, and RSV-ARI. We evaluated efficacy and immunogenicity among participants with coexisting cardiorespiratory or endocrine/metabolic conditions that increase the risk of severe RSV disease ("conditions of interest"). METHODS: Medically stable ≥60-year-old participants received 1 dose of RSVPreF3 OA or placebo. Efficacy against first RSV-LRTD and RSV-ARI episodes was assessed in subgroups with/without coexisting cardiorespiratory or endocrine/metabolic conditions of interest. Immunogenicity was analyzed post hoc in these subgroups. RESULTS: In total, 12 467 participants received RSVPreF3 OA and 12 499 received placebo. Of these, 39.6% (RSVPreF3 OA) and 38.9% (placebo) had ≥1 coexisting condition of interest. The median efficacy follow-up was 6.7 months. Efficacy against RSV-LRTD was high in participants with ≥1 condition of interest (94.6%), ≥1 cardiorespiratory (92.1%), ≥1 endocrine/metabolic (100%), and ≥2 conditions of interest (92.0%). Efficacy against RSV-ARI was 81.0% in participants with ≥1 condition of interest (88.1% for cardiorespiratory, 79.4% for endocrine/metabolic conditions) and 88.0% in participants with ≥2 conditions of interest. Postvaccination neutralizing titers were at least as high in participants with ≥1 condition of interest as in those without. CONCLUSIONS: RSVPreF3 OA was efficacious against RSV-LRTD and RSV-ARI in older adults with coexisting medical conditions associated with an increased risk of severe RSV disease. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT04886596.

Into the Dark Serum Proteome: Personalized Features of IgG1 and IgA1 Repertoires in Severe COVID-19 Patients.

Serum proteomics has matured and is now able to monitor hundreds of proteins quantitatively in large cohorts of patients. However, the fine characteristics of some of the most dominant proteins in serum, the immunoglobulins, are in these studies often ignored, due to their vast, and highly personalized, diversity in sequences. Here, we focus exclusively on these personalized features in the serum proteome and distinctively chose to study individual samples from a low diversity population: elderly donors infected by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). By using mass spectrometry-based methods, immunoglobulin IgG1 and IgA1 clonal repertoires were monitored quantitatively and longitudinally in more than 50 individual serum samples obtained from 17 Corona virus disease 2019 patients admitted to intensive care units. These clonal profiles were used to examine how each patient reacted to a severe SARS-CoV-2 infection. All 17 donors revealed unique polyclonal repertoires and substantial changes over time, with several new clones appearing following the infection, in a few cases leading to a few, very high, abundant clones dominating their repertoire. Several of these clones were de novo sequenced through combinations of top-down, middle-down, and bottom-up proteomics approaches. This revealed sequence features in line with sequences deposited in the SARS-CoV-specific antibody database. In other patients, the serological Ig profiles revealed the treatment with tocilizumab, that subsequently dominated their serological IgG1 repertoire. Tocilizumab clearance could be monitored, and a half-life of approximately 6 days was established. Overall, our longitudinal monitoring of IgG1 and IgA1 repertoires of individual donors reveals that antibody responses are highly personalized traits of each patient, affected by the disease and the chosen clinical treatment. The impact of these observations argues for a more personalized and longitudinal approach in patients' diagnostics, both in serum proteomics as well as in monitoring immune responses.

Burden of Uncontrolled Severe Asthma With and Without Elevated Type-2 Inflammatory Biomarkers.

BACKGROUND: Many patients with asthma have type-2 airway inflammation, identified by the presence of biomarkers, including history of allergy, high blood eosinophil (EOS) count, and high fractional exhaled nitric oxide levels. OBJECTIVE: To assess disease burden in relation to type-2 inflammatory biomarker status (history of allergy, blood EOS count, and fractional exhaled nitric oxide level) in patients with uncontrolled and controlled severe asthma in the NOVEL observational longiTudinal studY (NOVELTY) (NCT02760329). METHODS: Asthma diagnosis and severity were physician-reported. Control was defined using Asthma Control Test score (uncontrolled <20, controlled ≥20) and/or 1 or more severe physician-reported exacerbation in the previous year. Biomarker distribution (history of allergy, blood EOS count, and fractional exhaled nitric oxide level), symptom burden (Asthma Control Test score, modified Medical Research Council dyspnea scale), health status (St George's Respiratory Questionnaire score), exacerbations, and health care resource utilization were assessed. RESULTS: Of 647 patients with severe asthma, 446 had uncontrolled and 123 had controlled asthma. Among those with uncontrolled asthma, 196 (44%) had 2 or more positive biomarkers, 187 (42%) had 1 positive biomarker, 325 (73%) had low blood EOS, and 63 (14%) were triple-negative. Disease burden was similarly high across uncontrolled subgroups, irrespective of biomarker status, with poor symptom control (Asthma Control Test score 14.9-16.6), impaired health status (St George's Respiratory Questionnaire total score 46.7-49.4), clinically important breathlessness (modified Medical Research Council grade ≥2 in 47.3%-57.1%), and 1 or more severe exacerbation (70.6%-76.2%). CONCLUSIONS: Type-2 inflammatory biomarkers did not differentiate disease burden in patients with severe asthma. Patients with low type-2 inflammatory biomarker levels have few biologic therapy options; their needs should be addressed.

Can the Rome classification of chronic obstructive pulmonary disease exacerbation severity be applied in the hospital setting?

BACKGROUND: Chronic obstructive pulmonary disease (COPD) exacerbations (ECOPDs) are crucial events in the natural history of the disease. The recent Rome proposal defines exacerbations and their grade of severity using objective parameters derived from published data. AIMS: A) To evaluate the applicability of the Rome proposal in current clinical practice in different hospitals settings, B) to compare the resulting degree of severity with the conventional non-objective classification, C) to evaluate the relationship between ECOPD severity and mortality and D) the outputs in different hospital specialist wards. METHODS: Observational retrospective study in patients admitted to the University Hospital of Ferrara (Italy) with a primary diagnosis of ECOPD in the year 2021. The items of severity of the Rome proposal at admission were acquired from clinical records. A clinical-based score surrogated the missing VAS data on dyspnoea. RESULTS: Data were collected at admission form 320 patients. The data collected allowed the classification of severity based on the Rome proposal in 88.5 % of eligible cases. 18.5 %, 50.5 % and 31 % of ECOPD admissions were categorised as mild, moderate or severe ECOPDs respectively. In-hospital mortality increased with the ECOPD severity and mortality at 12 months was 27 % and 53.2 % in patients who have had a mild vs severe ECOPD, respectively (p = 0.059). Severe ECOPDs were more frequent and mortality rate was lower in patients admitted to Respiratory as compared to Internal Medicine wards. CONCLUSION: The Rome classification is ready to use in hospitalised ECOPD. It could allow for a better identification of the hospital setting most appropriate for ECOPD management.

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.