Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

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

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

Anti-IL-4R versus Anti-IL-5/5R after Anti-IL-5/5R failure in asthma: an emulated target trial.

BACKGROUND: Switching biologics is now common practice in severe eosinophilic asthma. After insufficient response to anti-interleukin 5 or 5 receptor (anti-IL-5/5R), the optimal switch between an anti-IL-4R monoclonal antibody (mAb) (inter-class) or another anti-IL-5/5R drug (intra-class) remains unknown. OBJECTIVE: We compared the effectiveness of these two strategies on asthma control in patients with severe eosinophilic asthma and insufficient response to an anti-IL-5/5R mAb. METHODS: We emulated a target randomized trial using observational data from the RAMSES Cohort. Eligible patients were switched to an anti-IL-4R mAb or another anti-IL-5/5R drug after insufficient response to an anti-IL-5/5R mAb. The primary outcome was the change in Asthma Control Test (ACT) score at 6 months. RESULTS: Among the 2046 patients in the cohort, 151 were included in the study: 103 switched to an anti-IL-4R mAb and 48 to another anti-IL-5/5R. At 6 months, the difference in ACT score improvement was not statistically significant (mean difference groups, 0.82 [-0.47,2.10], p=0.213). The inter-class group exhibited greater cumulative reduction in oral corticosteroids dose (Pinter-intra -1.05g [-1.76, -0.34], p=0.041). The inter-class group had a better effect, although not significantly, on reducing exacerbations (Δinter-intra -0.37 [-0.77, 0.02], p=0.124) and increasing lung function (FEV1) (126.8 ml [-12.7, 266.4], p=0.124). CONCLUSION: After anti-IL-5/5R mAb insufficient response, switching to dupilumab demonstrated similar improvement in ACT scores compared to intra-class switching. However, it appeared more effective in reducing oral corticosteroid use. Larger studies are warranted to confirm these results.

Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.

BACKGROUND: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. OBJECTIVE: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. METHODS: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). RESULTS: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. CONCLUSION: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. CLINICAL TRIAL REGISTRATION: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).

Eosinophils and tissue remodeling: Relevance to airway disease.

The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways.

Autoantibodies are associated with disease progression in idiopathic pulmonary fibrosis.

Several reports have highlighted a potential role of autoreactive B-cells and autoantibodies that correlates with increased disease severity in patients with idiopathic pulmonary fibrosis (IPF). Here we show that patients with IPF have an altered B-cell phenotype and that those subjects who have autoantibodies against the intermediate filament protein periplakin (PPL) have a significantly worse outcome in terms of progression-free survival. Using a mouse model of lung fibrosis, we demonstrate that introducing antibodies targeting the endogenous protein PPL (mimicking naturally occurring autoantibodies seen in patients) directly in the lung increases lung injury, inflammation, collagen and fibronectin expression through direct activation of follicular dendritic cells, which in turn activates and drives proliferation of fibroblasts. This fibrocyte population was also observed in fibrotic foci of patients with IPF and was increased in peripheral blood of IPF patients compared to aged-matched controls. This study reiterates the complex and heterogeneous nature of IPF, identifying new pathways that may prove suitable for therapeutic intervention.

Benralizumab for eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Benralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) are limited to case reports and small case series. METHODS: We conducted a multicentre, retrospective study including EGPA patients treated with off-label benralizumab. The primary endpoint was the rate of complete response defined as no disease activity (Birmingham Vasculitis Activity Score=0) and a prednisone dose ≤4 mg/day. Partial response was defined as no disease activity and a prednisone dose ≥4 mg/day. RESULTS: Sixty-eight patients were included, including 31 (46%) who had previously received mepolizumab. The use of benralizumab was warranted by uncontrolled asthma in 54 (81%), persistent ear, nose and throat (ENT) manifestations in 27 (40%) and persistent glucocorticoids (GCs) use in 48 (74%) patients. Median (IQR) follow-up after starting benralizumab was 23 (9-34) months. Thirty-three patients (49%) achieved a complete response, 24 (36%) achieved a partial response and 10 (15%) did not respond. Among the 57 patients who initially responded, 10 (18%) eventually required further line treatments. GCs were discontinued in 23 patients (38%). Prior mepolizumab use was associated with a higher rate of primary failure (26.7% vs 5.4%, p=0.034) and less frequent GCs discontinuation (14.8% vs 55.9%, p=0.001). Vasculitis flares occurred in 7 patients (11%) and were associated with histological evidence of vasculitis and/or antineutrophil cytoplasmic antibodies positivity at benralizumab initiation (p=0.004). CONCLUSIONS: Benralizumab appears to be an effective treatment for refractory asthma or ENT manifestations in EGPA and allows GC-sparing. However, its efficacy was lower after prior failure of mepolizumab.

Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Clinico-radiological correlation and prognostic value of baseline chest computed tomography in eosinophilic granulomatosis with polyangiitis.

OBJECTIVES: While chest high-resolution CT (HRCT) is correlated to severity and prognosis in asthma, it has not been studied in eosinophilic granulomatosis with polyangiitis (EGPA). Our objective is to study the prognostic value of baseline HRCT in EGPA patients. METHODS: Retrospective, multicentre observational study in three French hospitals, including EGPA patients with available chest HRCT before any systemic treatment. Two experienced radiologists blinded to clinical data evaluated HRCT images using semi-quantitative scoring. HRCT characteristics were correlated with clinical features and outcome. RESULTS: Among 46 patients, 38 (82.6%) had abnormal parenchymal findings on HRCT, including bronchial wall thickening (69.6%), mosaic perfusion (63.0%), ground-glass opacities (32.6%), bronchiectasis (30.4%), mucous plugging (21.7%) and consolidations (17.4%). Patients were clustered into three groups depending on HRCT features: ground-glass pattern, i.e. with ground-glass opacities with or without bronchial abnormalities (group 1, 28.3%), bronchial pattern (group 2, 41.3%) and extra-pulmonary pattern with no significant abnormality (group 3, 30.4%). Group 2 showed less frequent cardiac involvement (31.6 vs 46.2 and 42.9% in groups 1 and 3), more frequent positive ANCA (52.6 vs 0.0 and 14.3%) and higher eosinophil count (median 7510 vs 4000 and 4250/mm3). Group 1 showed worse prognosis with more frequent steroid-dependency (58.3 vs 11.1 and 28.6%) and requirement for mepolizumab (25.0 vs 11.1 and 7.1%). Conversely, group 2 showed a better outcome with higher rates of remission (88.9 vs 41.6 and 71.4%). CONCLUSION: Chest HRCT at diagnosis of EGPA may have prognostic value and help clinicians better manage these patients.

The long-term effect of dupilumab on dyspnea, sleep, and activity in oral corticosteroid-dependent severe asthma.

BACKGROUND: Severe asthma impacts quality of life (QoL), including dyspnea, sleep, and activity limitation. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4 and -13, which are key and central drivers of type 2 inflammation. Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214) and LIBERTY ASTHMA TRAVERSE open-label extension (NCT02134028) evaluated dupilumab 300 mg vs placebo every 2 weeks for 24 weeks (VENTURE) and dupilumab only for an additional 48 to 96 weeks (TRAVERSE) in patients with oral corticosteroid (OCS)-dependent severe asthma. OBJECTIVE: To assess dupilumab's impact on Asthma QoL Questionnaire (AQLQ) items related to breathing symptoms, sleep, and activity limitation, and on OCS reduction. METHODS: The proportion of patients with AQLQ scores of 6 or 7 for breathing symptoms-, sleeping-, and activity-related items in VENTURE and TRAVERSE, together with OCS dose reductions in VENTURE. RESULTS: In VENTURE, significantly greater proportions of dupilumab- vs placebo-treated patients achieved scores of 6 or 7 by week 24 in breathing symptoms-related (42.7%-60.2% vs 22.4%-39.3%), sleeping-related (45.6%-65.0% vs 27.1%-47.7%), and activity-related (44.7%-51.5% vs 22.4%-34.6%) AQLQ items. Improvements were maintained through TRAVERSE in the dupilumab/dupilumab group and increased to dupilumab treatment levels in the placebo/dupilumab group. Significant OCS dose reductions were observed in VENTURE; up to 90% and 60% of dupilumab-treated vs 65% and 41% of placebo-treated patients with AQLQ scores of 6 or 7 in breathing symptoms-, sleeping-, and activity-related items achieved greater than or equal to 50% dose reduction and eliminated OCS at week 24, respectively. CONCLUSION: In patients with severe OCS-dependent asthma, dupilumab improved QoL related to breathing symptoms, sleep, and activity limitation, and reduced OCS use. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214 and NCT02134028.

Otitis media in severe asthma associated with chronic rhinosinusitis with nasal polyps: a new therapeutic target for biologics.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNPs) is associated with otitis media with effusion (OME) in about 25% of cases. The objective of this study was to assess the clinical efficacy of the 4 biologic agents currently available in France for severe asthma (omalizumab, mepolizumab, benralizumab and dupilumab) in 17 patients followed for both asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and presenting otitis media with effusion (OME) on otoscopy. Methods: It was a multicenter retrospective study performed in 4 academic ENT and respiratory departments in Paris, France, with assessment of the clinical evolution of 17 patients with severe eosinophilic asthma and with chronic refractory OME and CRSwNPs treated by biologic agents. Global evaluation of treatment effectiveness (GETE) on asthma, CRSwNP and OME was classified on a 5-point scale as 1, excellent; 2, good; 3, moderate; 4, poor; or 5, symptoms worsening. Response was defined as an excellent/good score (1 or 2). Results: 17 patients were prescribed a total of 30 biologics. The evolution of OME did not follow that of asthma and CRSwNPs in 15 (88%) and 12 (70%) cases, respectively. Concerning OME, 19/30 (63%) patients were non-responders. Among the 10 patients who successively received ≥ 2 biologic agents, the OME response differed, depending on the considered agent Dupilumab had the highest response rate. Conclusions: Resistant OME, associated with asthma and chronic rhinosinusitis with nasal polyps, can present a disconnected evolution under biologics. CRSwNP-associated OME requires a specific evaluation to define the best treatment.

Digital Action Plan (Web App) for Managing Asthma Exacerbations: Randomized Controlled Trial.

BACKGROUND: A written action plan (WAP) for managing asthma exacerbations is recommended. OBJECTIVE: We aimed to compare the effect on unscheduled medical contacts (UMCs) of a digital action plan (DAP) accessed via a smartphone web app combined with a WAP on paper versus that of the same WAP alone. METHODS: This randomized, unblinded, multicenter (offline recruitment in private offices and public hospitals), and parallel-group trial included children (aged 6-12 years) or adults (aged 18-60 years) with asthma who had experienced at least 1 severe exacerbation in the previous year. They were randomized to a WAP or DAP+WAP group in a 1:1 ratio. The DAP (fully automated) provided treatment advice according to the severity and previous pharmacotherapy of the exacerbation. The DAP was an algorithm that recorded 3 to 9 clinical descriptors. In the app, the participant first assessed the severity of their current symptoms on a 10-point scale and then entered the symptom descriptors. Before the trial, the wordings and ordering of these descriptors were validated by 50 parents of children with asthma and 50 adults with asthma; the app was not modified during the trial. Participants were interviewed at 3, 6, 9, and 12 months to record exacerbations, UMCs, and WAP and DAP use, including the subjective evaluation (availability and usefulness) of the action plans, by a research nurse. RESULTS: Overall, 280 participants were randomized, of whom 33 (11.8%) were excluded because of the absence of follow-up data after randomization, leaving 247 (88.2%) participants (children: n=93, 37.7%; adults: n=154, 62.3%). The WAP group had 49.8% (123/247) of participants (children: n=45, 36.6%; mean age 8.3, SD 2.0 years; adults: n=78, 63.4%; mean age 36.3, SD 12.7 years), and the DAP+WAP group had 50.2% (124/247) of participants (children: n=48, 38.7%; mean age 9.0, SD 1.9 years; adults: n=76, 61.3%; mean age 34.5, SD 11.3 years). Overall, the annual severe exacerbation rate was 0.53 and not different between the 2 groups of participants. The mean number of UMCs per year was 0.31 (SD 0.62) in the WAP group and 0.37 (SD 0.82) in the DAP+WAP group (mean difference 0.06, 95% CI -0.12 to 0.24; P=.82). Use per patient with at least 1 moderate or severe exacerbation was higher for the WAP (33/65, 51% vs 15/63, 24% for the DAP; P=.002). Thus, participants were more likely to use the WAP than the DAP despite the nonsignificant difference between the action plans in the subjective evaluation. Median symptom severity of the self-evaluated exacerbation was 4 out of 10 and not significantly different from the symptom severity assessed by the app. CONCLUSIONS: The DAP was used less often than the WAP and did not decrease the number of UMCs compared with the WAP alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT02869958; https://clinicaltrials.gov/ct2/show/NCT02869958.

Real-life omalizumab exposure and discontinuation in a large nationwide population-based study of paediatric and adult asthma patients.

BACKGROUND: This real-life study aimed to assess omalizumab treatment patterns in adult and paediatric asthma patients, and to describe asthma control and healthcare resource use (HCRU) at omalizumab initiation and discontinuation. METHODS: The French healthcare database system (Système National des Données de Santé (SNDS)) was used to identify asthma patients aged ≥6 years who initiated omalizumab for at least 16 weeks from 2009 to 2019. We examined omalizumab treatment patterns using dispensation records. RESULTS: We identified 16 750 adults and 2453 children initiating omalizumab. Median treatment persistence before discontinuation (TSTOP) was 51.2 (95% CI 49.3-53.4) months in adults and 53.7 (95% CI 50.6-56.4) months in children. At 2 years of omalizumab exposure, rate of hospitalisation for asthma decreased by 75% and use of oral corticosteroids (OCS) by 30%, in adults and children. Among adults who discontinued omalizumab while asthma was controlled, 70%, 39% and 24% remained controlled and did not resume omalizumab at 1, 2 and 3 years after discontinuation, respectively. These proportions were higher in children (76%, 44% and 33%, respectively). Over 2 years of follow-up after discontinuation, HCRU remained stable in adults and children, notably rate of hospitalisations for asthma (none before TSTOP, 1.3% and 0.6% at 2 years) and use of OCS (in adults and children, respectively: 20.0% and 20.2% before TSTOP, 33.3% and 24.6% at 2 years). CONCLUSION: This is the first large-scale study describing omalizumab real-life exposure patterns in adult and paediatric asthma patients in France with >10 years of follow-up. We showed the long-term maintenance of low HCRU in adults and children who discontinued omalizumab while asthma was controlled, notably for OCS use and hospitalisations for asthma.

Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Outcomes and risk factors with COVID-19 or influenza in hospitalized asthma patients.

BACKGROUND: At the time of the SARS-CoV-2 emergence, asthma patients were initially considered vulnerable because respiratory viruses, especially influenza, are associated with asthma exacerbations, increased risk of hospitalization and more severe disease course. We aimed to compare the asthma prevalence in patients hospitalized for COVID-19 or influenza and risk factors associated with poor prognosis with the diseases. METHODS: This retrospective cohort study used the Paris university hospitals clinical data warehouse to identify adults hospitalized for COVID-19 (January to June 2020) or influenza (November 2017 to March 2018 for the 2017-2018 influenza period and November 2018 to March 2019 for the 2018-2019 period). Asthma patients were identified with J45 and J46 ICD-10 codes. Poor outcomes were defined as admission in intensive care or death. RESULTS: Asthma prevalence was significantly higher among influenza than COVID-19 patients (n = 283/3 119, 9.1%, 95% CI [8.1-10.1] in 2017-2018 and n = 309/3 266, 9.5%, 95% CI [8.5-10.5] in 2018-2019 versus n = 402/9 009, 4.5%, 95% CI [4.0-4.9]). For asthma patients, 31% with COVID-19 were admitted to an intensive care unit versus 23% and 21% with influenza. Obesity was a risk factor for the 2017-2018 influenza period, smoking and heart failure for the 2018-2019 period. Among COVID-19 patients with asthma, smoking and obesity were risk factors for the severe form. CONCLUSIONS: In this study, patients with an asthma ICD-10 code were less represented among COVID-19 patients than among influenza-infected ones. However, outcomes were poorer for COVID-19 than influenza patients, both with asthma. These data highlight the importance of protective shields and vaccination against influenza and COVID-19 in this population.

Belief and adherence to COVID 19-lockdown restrictions in patients with asthma versus other chronic diseases: results from a cross-sectional survey nested in the ComPaRe e-cohort, in France.

BACKGROUND: Asthma patients are under-represented among patients with COVID-19. Their behavior during lockdown and associated restrictions is unknown, as well as whether it was influenced by coexistent cardiovascular conditions. METHODS: We conducted a cross-sectional survey in May 2020, in France, nested in ComPaRe, an e-cohort of adults with chronic diseases. A self-administered questionnaire was mailed to 10,859 people; 3701 fully completed questionnaires. The prevalence of self-reported asthma was 7%. Patients were classified in 4 categories: asthma with (n = 106) or without (n = 149) cardiovascular disease and other diseases with (n = 1186) or without (n = 2260) cardiovascular disease. RESULT: Adherence to movement restrictions during the lockdown was very strong: 89% of participants reported a frequency of outings of "less than once per week" and "once or twice per week" for errands and no family-related outings during the lockdown. This proportion and frequency of outings were similar whatever the chronic disease (p = 0.122). Most patients (96%) reported a high feeling of security during the lockdown, but 95% felt anxious or depressed, with no difference by disease. As compared with patients with controlled asthma, those with uncontrolled asthma more frequently reported complaints related to deteriorated medical follow-up, waived care, anxiety or depression. CONCLUSIONS: Behaviors during the lockdown in France among the asthma population did not differ from patients with other chronic diseases in this cohort, which strengthens hypotheses for specific disease-related susceptibility to explain the low representation of asthmatics among COVID-19 cases. Special attention should be paid to the subgroup of patients with uncontrolled asthma during lockdowns.

Is CCL18 a potential biomarker of type-2 asthma endotypes?

Objective: This exploratory cross-sectional study aimed to evaluate the associations between the chemokine ligand 18 (CCL18) blood level and phenotypic characteristics of asthma.Methods: We evaluated in a sample of 173 asthmatic adult patients from the Cohort of Bronchial obstruction and Asthma (63.4% women; median age 50 ± interquartile range 27.5 years; median level of CCL18 was 44.1 ± interquartile range 27.5 ng/mL) the association between CCL18 blood level and allergic features of asthma using a multivariate analysis.Results: We found an association between the log-transformed value of blood CCL18 and age (+0.7% [0.1; 1.3] per 1-year increase, p = 0.033), gender (-25.1% [-42; -3.2] in women, p = 0.029), and nasal polyposis (+38.1% [11.6; 70.9], p = 0.004). No association was observed between CCL18 level and the other main phenotypic characteristics of asthma.Conclusions: Our exploratory study suggests that CCL18 is not an effective biomarker of allergic asthma endotype but may rather be a biomarker of tissue eosinophilia as supported by its association with nasal polyposis.

Clinical and histopathologic predictors of therapeutic response to bronchial thermoplasty in severe refractory asthma.

BACKGROUND: Phenotypes and endotypes predicting optimal response to bronchial thermoplasty (BT) in patients with severe asthma remain elusive. OBJECTIVE: Our aim was to compare the clinical characteristics and hallmarks of airway inflammation and remodeling before and after BT in responder and partial responder patients with severe asthma refractory to oral steroids and to omalizumab. METHODS: In all, 23 patients with severe refractory asthma were divided into BT responders (n = 15) and BT partial responders (n = 8), according to the decrease in asthma exacerbations at 12 months after BT. Clinical parameters were compared at baseline and 12 months after BT, and hallmarks of airway inflammation and remodeling were analyzed by immunohistochemistry in bronchial biopsy specimens before and 3 months after BT. RESULTS: At baseline, the BT responders were around 8 years younger than the BT partial responders (P = .02) and they had a greater incidence of atopy, higher numbers of blood eosinophils (both P = .03) and IgE levels, higher epithelial IFN-α expression, and higher numbers of mucosal eosinophils and IL-33-positive cells (P ≤ .05). A reduction in blood eosinophil count, serum IgE level, type 2 airway inflammation, and numbers of mucosal IL-33-positive cells and mast cells associated with augmented epithelial MUC5AC and IFN-α/ß immunostaining was noted after BT in responders, whereas the numbers of mucosal IL-33-positive cells were augmented in BT partial responders. Most of these changes were correlated with clinical parameters. Subepithelial membrane thickening and airway smooth muscle area were similar in the 2 patient groups at baseline and after BT. CONCLUSION: By reducing allergic type 2 inflammation and increasing epithelial MUC5AC and anti-viral IFN-α/ß expression, BT may enhance host immune responses and thus attenuate exacerbations and symptoms in BT responders. Instead, targeting IL-33 may provide a clinical benefit in BT partial responders.

Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia.

Increased blood fibrocytes are associated with a poor prognosis in fibrotic lung diseases. We aimed to determine whether the percentage of circulating fibrocytes could be predictive of severity and prognosis during coronavirus disease 2019 (COVID-19) pneumonia. Blood fibrocytes were quantified by flow cytometry as CD45+/CD15-/CD34+/collagen-1+ cells in patients hospitalized for COVID-19 pneumonia. In a subgroup of patients admitted in an intensive care unit (ICU), fibrocytes were quantified in blood and bronchoalveolar lavage (BAL). Serum amyloid P (SAP), transforming growth factor-ß1 (TGF-ß1), CXCL12, CCL2, and FGF2 concentrations were measured. We included 57 patients in the hospitalized group (median age = 59 yr [23-87]) and 16 individuals as healthy controls. The median percentage of circulating fibrocytes was higher in the patients compared with the controls (3.6% [0.2-9.2] vs. 2.1% [0.9-5.1], P = 0.04). Blood fibrocyte count was lower in the six patients who died compared with the survivors (1.6% [0.2-4.4] vs. 3.7% [0.6-9.2], P = 0.02). Initial fibrocyte count was higher in patients showing a complete lung computed tomography (CT) resolution at 3 mo. Circulating fibrocyte count was decreased in the ICU group (0.8% [0.1-2.0]), whereas BAL fibrocyte count was 6.7% (2.2-15.4). Serum SAP and TGF-ß1 concentrations were increased in hospitalized patients. SAP was also increased in ICU patients. CXCL12 and CCL2 were increased in ICU patients and negatively correlated with circulating fibrocyte count. We conclude that circulating fibrocytes were increased in patients hospitalized for COVID-19 pneumonia, and a lower fibrocyte count was associated with an increased risk of death and a slower resolution of lung CT opacities.

Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling.

BACKGROUND: Severe asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling. METHODS AND RESULTS: Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice. CONCLUSION: This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma.