Rationale: Non-adherence to medication is common in COPD and leads to poor outcomes. Digital interventions have improved inhaler adherence in small short-term studies, but there is minimal evidence of their impact on clinical outcomes. Methods: Our 12-month pragmatic cluster randomised trial (MAGNIFY) evaluated the impact of providing primary care with access to a complex intervention for COPD patients designed to enhance adherence (10.2147/POR.S302809). The intervention included identification of high-risk COPD patients (≥2 moderate/severe exacerbations in last 2 years) using Optimum Patient Care electronic medical record (EMR) driven quality improvement algorithms, a remote COPD review and a digital adherence support package (comprising Ultibro® Breezhaler®, Propeller Health electronic inhaler monitoring device and smartphone app). To minimise contamination, primary care centres were randomised to offer the intervention or continue usual care (control). In practices randomized to the intervention arm, high-risk patients aged ≥40 years and deemed clinically suitable and poorly adherent to inhaled therapy at the review, were offered the digital adherence support package and those that accepted were included in the study. In control practices, we identified high-risk COPD patients aged ≥40 years on the basis of LABA/LAMA prescription date. Primary outcome was time to treatment failure (moderate/severe exacerbation, prescription of ICS or other additional COPD therapy, or death) and secondary outcomes were moderate/severe exacerbation rate and time to exacerbation in 12-month follow-up. Analyses were adjusted for three pre-specified confounders: age, baseline exacerbation rate & baseline adherence. Results: 164 primary care centres (87 intervention, 77 control) were included in the trial. 835 patients were offered the digital adherence support package and 656 (78.6%) accepted. There was a 23% reduced risk of treatment failure over the 12-month trial period (adjusted HR 0.77; 95% CI 0.64, 0.94; p=0.009) in patients provided with the digital intervention compared to controls. The median time to treatment failure was 263 days in the intervention and 361 days in the control arm. Exacerbation rates were 11% lower in the intervention arm (adjusted IRR 0.89; 95% CI 0.79, 0.99; p=0.047). In pre-specified subgroups, the intervention was more effective in patients with FEV1<80% predicted, no previous exacerbations, or a Cambridge Multimorbidity Score ≥3 (Table 1). Conclusions: Offering a digital intervention to optimise adherence reduced risk of treatment failure by almost 25% and reduced exacerbation rate by over 10% in high-risk patients with COPD. This is the first large, year-long trial demonstrating improved clinical outcomes in a real-world primary care setting.

Omalizumab is recommended as an add-on therapy in patients aged ≥6 years with inadequately controlled, moderate-to-severe persistent allergic asthma. The efficacy and safety of omalizumab treatment in allergic asthma clinical trials and its effectiveness in the real world have been reported in numerous studies. In this review, we examine clinical evidence in pediatric and adult patients with allergic asthma who received omalizumab treatment for at least 2 years, to assess its effectiveness, durability, and trajectory of response over time as well as safety. We performed a literature search from inception until March 2022 in PubMed using the keywords "omalizumab" and "allergic asthma" to retrieve articles examining the effects of omalizumab in patients with allergic asthma, aged ≥6 years. Only articles that evaluated the effectiveness of omalizumab for at least 2 years were included. Data from case reports were excluded. Our review confirmed the long-term effectiveness and safety of omalizumab, demonstrating reduced rate of exacerbations, improved lung function, asthma control, and quality of life, decreased health care resource utilization, and use of corticosteroids (oral/inhaled) with a favorable safety and tolerability profile for up to 9 years in adult patients with moderate-to-severe allergic asthma. Similar results were also observed in the pediatric population with up to 7.5 years of omalizumab treatment. This review highlights and confirms the sustained clinical benefits of omalizumab over long periods of treatment in pediatric and adult populations with allergic asthma.

Background Poor treatment adherence in COPD patients is associated with poor clinical outcomes and increased healthcare burden. Personalized approaches for adherence management, supported with technology-based interventions, may offer benefits to patients and providers but are currently unproven in terms of clinical outcomes as opposed to adherence outcomes. Methods Maximizing Adherence and Gaining New Information For Your COPD (MAGNIFY COPD study), a pragmatic cluster randomized trial, aims to evaluate the impact of an adherence technology package (interventional package), comprising an adherence review, ongoing provision of a dual bronchodilator but with an add-on inhaler sensor device and a connected mobile application. This will compare time to treatment failure and other clinical outcomes in patients identified at high risk of exacerbations with historic poor treatment adherence as measured by prescription collection to mono/dual therapy over one year (1312 patients) versus usual care. Treatment failure is defined as the first occurrence of one of the following: (1) moderate/severe COPD exacerbation, (2) prescription of triple therapy (inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]), (3) prescription of additional chronic therapy for COPD, or (4) respiratory-related death. Adherence, moderate/severe exacerbations, respiratory-related healthcare resource utilization and costs, and intervention package acceptance rate will also be assessed. Eligible primary care practices (N=176) participating in the Optimum Patient Care Quality Improvement Program will be randomized (1:1) to either adherence support cluster arm (suitable patients already receiving or initiated Ultibro® Breezhaler® [indacaterol/glycopyrronium] will be offered interventional package) or the control cluster arm (suitable patients continue to receive usual clinical care). Patients will be identified and outcomes collected from anonymized electronic medical records within the Optimum Patient Care Research Database. On study completion, electronic medical record data will be re-extracted to analyze outcomes in both study groups. Registration Number ISRCTN10567920. Conclusion MAGNIFY will explore patient benefits of technology-based interventions for electronic adherence monitoring.

BACKGROUND:Assessment of clinical outcomes in the real-world corroborates findings from randomized controlled trials (RCTs). OBJECTIVE:This meta-analysis evaluated real-world data of omalizumab on treatment response, lung function, exacerbations, oral corticosteroid (OCS) use, patient-reported outcomes (PROs), health care resource utilization (HCRU), and school/work absenteeism at 4, 6, and 12 months after treatment. METHODS:Observational studies in patients with severe allergic asthma (≥6 years) treated with omalizumab for ≥16 weeks, published from January 2005 to October 2018, were retrieved from PubMed, Embase, and Cochrane. A random-effects model was used to assess heterogeneity. RESULTS:In total, 86 publications were included. Global evaluation of treatment effectiveness (GETE) was good/excellent in 77% patients at 16 weeks (risk difference: 0.77; 95% confidence interval [CI]: 0.70-0.84; I2 = 96%) and in 82% patients at 12 months (0.82, 0.73-0.91; 97%). The mean improvement in forced expiratory volume in 1 second was 160, 220, and 250 mL at 16 weeks, 6 months, and 12 months, respectively. There was a decrease in Asthma Control Questionnaire score at 16 weeks (-1.14), 6 months (-1.56), and 12 months (-1.13) after omalizumab therapy. Omalizumab significantly reduced annualized rate of severe exacerbations (risk ratio [RR]: 0.41, 95% CI: 0.30-0.56; I2 = 96%), proportion of patients receiving OCS (RR: 0.59, 95% CI: 0.47-0.75; I2 = 96%), and number of unscheduled physician visits (mean difference: -2.34, 95% CI: -3.54 to -1.13; I2 = 98%) at 12 months versus baseline. CONCLUSION:The consistent improvements in GETE, lung function, and PROs, and reductions in asthma exacerbations, OCS use, and HCRU with add-on omalizumab in real-life confirm and complement the efficacy data of RCTs.

Allergic sensitisation and viral respiratory tract infections represent the main risk factors for asthma development and severity. IgE plays a key role in the pathophysiology of allergic asthma and allergic multimorbidities [1, 2]. Omalizumab, a recombinant humanised monoclonal antibody against IgE, has been used to treat allergic asthma in children and adults for many years [3–5]. Omalizumab restores the capacity of human plasmacytoid dendritic cells (pDCs) to produce interferon (IFN)-α, increasing their antiviral activity and reducing viral-induced asthma exacerbations [6, 7]. pDCs prime T-helper cell (Th)1 or Th2 responses depending on the encountered antigens. IgE-FcεR1 cross-linking on human pDCs impairs their capacity to generate regulatory T-cells and in vitro omalizumab restores this ability. These findings may pave the way for novel biomarkers to assess omalizumab clinical efficacy and responder patients. https://bit.ly/2ZQbJ9t

Artificial intelligence (AI) and machine learning, a subset of AI, are increasingly used in medicine. AI excels at performing welldefined tasks, such as image recognition; for example, classifying skin biopsy lesions, determining diabetic retinopathy severity, and detecting brain tumors. This article provides an overview of the use of AI in medicine and particularly in respiratory medicine, where it is used to evaluate lung cancer images, diagnose fibrotic lung disease, and more recently is being developed to aid the interpretation of pulmonary function tests and the diagnosis of a range of obstructive and restrictive lung diseases. The development and validation of AI algorithms requires large volumes of well-structured data, and the algorithms must work with variable levels of data quality. It is important that clinicians understand how AI can function in the context of heterogeneous conditions such as asthma and chronic obstructive pulmonary disease where diagnostic criteria overlap, how AI use fits into everyday clinical practice, and how issues of patient safety should be addressed. AI has a clear role in providing support for doctors in the clinical workplace, but its relatively recent introduction means that confidence in its use still has to be fully established. Overall, AI is expected to play a key role in aiding clinicians in the diagnosis and management of respiratory diseases in the future, and it will be exciting to see the benefits that arise for patients and doctors from its use in everyday clinical practice. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Background COPD is a heterogeneous disease and patients may respond differently to therapies depending on baseline symptom burden. Methods This post-hoc analysis from the 52-week FLAME study investigated the impact of baseline symptom burden in terms of health status, dyspnoea, bronchitis status, eosinophil levels and smoking status on the subsequent risk of moderate or severe exacerbations. Health status was measured by St. George’s Respiratory Questionnaire (SGRQ) score (higher ≥46.6 and lower < 46.6) and COPD Assessment Test (CAT) score (higher ≥17 and lower < 17); dyspnoea and bronchitis were assessed via an electronic diary (eDiary). Differential response to once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 μg versus twice-daily salmeterol/fluticasone (SFC) 50/500 μg was assessed. Results Data from 3354 patients was analysed. The risk of exacerbations was lower in patients who had less severe health impairment (rate ratio [RR] [95% CI]): SGRQ-C, (0.88 [0.78, 0.99]); CAT, 0.85 [0.75, 0.96]) and lower dyspnoea (0.79 [0.69, 0.90]) at baseline versus those with more severe health impairment and higher dyspnoea, respectively. Compared with SFC, IND/GLY led to better prevention of moderate-to-severe exacerbations in the majority of groups studied. Conclusion Patients with more severe health status impairment and greater symptom burden at baseline subsequently experienced more exacerbations in the FLAME study. IND/GLY was overall more effective in preventing exacerbations versus SFC, regardless of baseline symptom burden. Our results suggest that future studies on novel exacerbation therapies should consider targeting patients with higher symptom burden at baseline. Clinical trial identifier NCT01782326 .

Background:Chronic obstructive pulmonary disease (COPD) exacerbations are difficult outcomes to measure in clinical trials. It would be valuable to be able to predict which patients are likely to benefit in terms of exacerbation prevention based on their early response in lung function and symptoms. Methods:This was a post-hoc analysis from the 52-week, randomized, double-blind, double-dummy, non-inferiority FLAME trial. Early clinically important improvement (ECII) was defined as achievement of minimal clinically important difference in trough forced expiratory volume in 1 second (FEV1; ≥100 mL increase) and one patient-reported outcome (PRO): either St. George's Respiratory Questionnaire for COPD (≥4-unit reduction; D1), or COPD assessment test (≥2-point reduction; D2) at Week 4 or 12. Results:Approximately 18-20% of patients achieved ECII at Week 4 or 12 post-randomization according to any of the two definitions. The rate of subsequent exacerbations was lower in patients who achieved ECII at Week 4 (D1: ratio of rates [95% CI], 0.85 [0.74 to 0.98]; D2, 0.88 [0.77 to 1.00]) or at Week 12 (D1, 0.85 [0.74 to 0.98]; D2, 0.86 [0.75 to 1.00]) versus patients not achieving ECII. Patients who achieved ECII experienced longer time-to-first exacerbation between Week 4 or 12 to end of study. More patients achieved ECII with indacaterol/glycopyrronium versus salmeterol/fluticasone according to both definitions at Week 4 (D1, odds ratio [95% CI], 1.69 [1.40 to 2.04]; D2, 1.61 [1.34 to 1.93]), and 12 (D1, 2.01 [1.66 to 2.44]; D2, 1.80 [1.48 to 2.18]). Conclusion:ECII is a novel composite endpoint, based on clinically relevant improvement in lung function and PROs in the early phase of treatment intervention that may predict subsequent exacerbation risk and may be used in clinical trials.

BACKGROUND:The efficacy and safety of once-daily (o.d.) fixed-dose combination of indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF) via Breezhaler® versus concurrent administration of salmeterol/fluticasone (SAL/FLU) twice-daily (b.i.d.) via Accuhaler®+Tiotropium (TIO) o.d. via Respimat® was evaluated in patients with uncontrolled asthma. METHODS:Patients (aged ≥18 years), symptomatic (Asthma Control Questionnaire [ACQ]-7 ≥1.5) despite treatment with long-acting β2-agonist/inhaled corticosteroid medium- or high-dose, received IND/GLY/MF high- (150/50/160 μg) or medium-dose (150/50/80 μg) o.d. or SAL/FLU high-dose (50/500 μg) b.i.d.+Tio 5 μg o.d. for 24 weeks. The primary objective was to confirm the non-inferiority of either dose of IND/GLY/MF to SAL/FLU high dose + TIO in terms of Asthma Quality of Life Questionnaire (AQLQ). Additional endpoints: ACQ-7, lung function, health status (St George's Respiratory Questionnaire [SGRQ]), exacerbations, and safety after 24 weeks. RESULTS:IND/GLY/MF high- and medium-dose met the primary endpoint, confirming non-inferiority to SAL/FLU high dose + TIO for AQLQ (least square mean treatment difference [Δ]: 0.073 and -0.038, respectively; both p < 0.001). IND/GLY/MF high-dose improved ACQ-7 (Δ: -0.124; p = 0.004), trough FEV1 (Δ: 96 mL; p < 0.001), peak expiratory flow (morning [Δ: 9.56 L/min; p = 0.005], evening [Δ: 9.15 L/min; p = 0.006]) and SGRQ (Δ: -2.00; p = 0.04) versus SAL/FLU high dose + TIO. Improvements in these endpoints were comparable for IND/GLY/MF medium-dose and SAL/FLU high dose + TIO. Adverse events were generally comparable across treatments. CONCLUSIONS:IND/GLY/MF high- and medium-dose o.d. via a single inhaler were non-inferior to SAL/FLU high-dose b.i.d. + TIO o.d. via two inhalers for AQLQ. IND/GLY/MF high-dose o.d. improved lung function, asthma control and health status versus SAL/FLU high dose + TIO, while IND/GLY/MF medium-dose had comparable efficacy but at a corresponding lower steroid dose.

Introduction: Human plasmacytoid dendritic cells (pDCs) play key roles in anti-viral responses and induce regulatory T cells (Treg), which are essential for healthy immune responses to allergens and prevent airway remodelling. IgE-FcεR1 (IgE) cross-linking on pDCs impairs anti-viral responses but the effects in Treg generation remain elusive. Methods: Blood pDCs were purified and incubated with Omalizumab or untreated. pDCs were then activated with CpG ODN 2006 (TLR9-L) in the presence of IgE crosslinker. Flow cytometry, ELISA, quantitative PCR and co-cultures were performed to assess the effects of IgE cross-linking in the capacity of TLR9-L-activated pDCs to generate Treg. Results: IgE cross-linking on TLR9-L-activated pDCs significantly reduced the expression of tolerogenic markers PD‐L1, IDO and ICOSL, inhibited IFN-α production whereas increased proinflammatory TNF-α. The capacity of TLR9-L-activated pDCs to induce functional CD4+CD25highFOXP3+Treg was significantly impaired upon IgE cross-linking, which was reverted by the pretreatment of pDCs with Omalizumab. Corticosteroids abolished the capacity of TLR9-L-activated pDCs to generate Treg. Mechanistically, IgE cross-linking on TLR9-L-activated pDCs promotes a misbalance in tolerogenic molecules and cytokine signature that impairs their capacity to generate Treg. Conclusion: IgE cross-linking breaks the capacity of pDCs to generate Treg in vitro, which can be restored by Omalizumab. We shed light into potential novel immunomodulatory mechanisms by which Omalizumab might exert beneficial clinical effects compared to the general suppression promoted by corticosteroids.

Allergic asthma often coexists with different pathological conditions, called multimorbidities, that are mostly of allergic nature and share a common underlying inflammatory pathophysiological mechanism. Multimorbidities of allergic asthma may influence asthma control, its severity, and patients' response to treatment, and contribute to the overall socioeconomic burden of the disease. Immunoglobulin E (IgE) is known to play a central role in the pathogenesis of various allergic diseases, including asthma. Thus, IgE-mediated immunologic pathways present an attractive target for intervention in asthma and multimorbidities. In this review, we discuss the most frequently reported IgE-mediated multimorbidities in allergic asthma, including allergic rhinitis, rhinoconjunctivitis, atopic dermatitis, vernal keratoconjunctivitis, chronic rhinosinusitis with nasal polyps, food allergies, and allergic bronchopulmonary aspergillosis. Omalizumab is a recombinant humanized monoclonal antibody against IgE and has been in use to treat allergic asthma for more than a decade. We comprehensively review the clinical evidence for omalizumab in the treatment of the aforementioned multimorbidities in allergic asthma. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Systemic/oral corticosteroids (OCS) have been used for decades in the management of acute asthma exacerbations and chronically in patients with uncontrolled severe asthma. However, while OCS are effective at treating acute exacerbations, there is only empirical evidence regarding the efficacy of OCS at reducing the rate of exacerbations. Evidence, although scarce, is suggestive of high exacerbation rates in severe asthma patients even when receiving maintenance treatment with OCS. In addition, use of OCS is associated with undesirable effects. Despite all this, physicians have continued to use OCS for managing severe asthma and acute exacerbation due to the lack of availability of effective alternatives. Fortunately, in the last decade several biologics have been proven safe and effective for patients with uncontrolled severe asthma. This has led to the Global Initiative for Asthma (GINA) recommending the use of biologics, instead of maintenance OCS, in patients with severe asthma (GINA Step 5). These include one biologic targeting immunoglobulin E (IgE) (omalizumab), and different biologics targeting interleukin-5 (IL-5), the IL-5 receptor (IL-5R) or IL-4 receptor α-unit (IL-4R α), including mepolizumab (subcutaneous), reslizumab (intravenous), benralizumab (subcutaneous) and dupilumab (subcutaneous).

Systemic/oral corticosteroids (OCS) have been used for decades in the management of acute asthma exacerbations and chronically in patients with uncontrolled severe asthma. However, while OCS are effective at treating acute exacerbations, there is only empirical evidence regarding the efficacy of OCS at reducing the rate of exacerbations. Evidence, although scarce, is suggestive of high exacerbation rates in severe asthma patients even when receiving maintenance treatment with OCS. In addition, use of OCS is associated with undesirable effects. Despite all this, physicians have continued to use OCS for managing severe asthma and acute exacerbation due to the lack of availability of effective alternatives. Fortunately, in the last decade several biologics have been proven safe and effective for patients with uncontrolled severe asthma. This has led to the Global Initiative for Asthma (GINA) recommending the use of biologics, instead of maintenance OCS, in patients with severe asthma (GINA Step 5). These include one biologic targeting immunoglobulin E (IgE) (omalizumab), and different biologics targeting interleukin-5 (IL-5), the IL-5 receptor (IL-5R) or IL-4 receptor alpha-unit (IL-4R alpha), including mepolizumab (subcutaneous), reslizumab (intravenous), benralizumab (subcutaneous) and dupilumab (subcutaneous). Omalizumab for the treatment of severe allergic asthma reduces exacerbations, irrespective of blood eosinophil levels. Anti-IL-5/IL-5R biologics are indicated in patients with severe eosinophilic asthma and repetitive exacerbations, irrespective of the presence or absence of allergy. Recently, an anti-IL4R alpha biologic has been approved by the FDA for eosinophilic phenotype or oral corticosteroid-dependent asthma. Finally, physicians should consider using biologics as an alternative to chronic OCS therapy.

Background: For the past 15-years, omalizumab has demonstrated clinical effectiveness in real-world and controlled studies in patients with severe allergic asthma. The objective of this systematic literature review was to assess the effectiveness of omalizumab on exacerbations and oral corticosteroid (OCS) use in real-life settings in the published literature. Methods: A systematic review was performed using PubMed, EMBASE and Cochrane databases between 2005 and 2018 for relevant published real-world studies that examined the clinical effectiveness of omalizumab in patients aged ≥6 years with severe persistent allergic asthma. Results: In total, 85 studies were included in this systematic review, of which 40 studies assessed asthma exacerbations and 43 studies examined OCS use. Omalizumab treatment resulted in a reduction in the rate of severe exacerbations at 16 weeks, 12 months and at the end of the study compared to the previous year. Omalizumab treatment also reduced the mean daily OCS dose and decreased the proportion of patients receiving OCS at all time points compared with baseline (Table). Conclusions: This review of real-world data underpins the consistent positive impact of omalizumab on the reduction of exacerbations and OCS use among patients with severe allergic asthma.

Rationale: COPD is a heterogenous disease and patients may respond differently to therapies depending on symptom burden. An evaluation of which patients respond best to dual bronchodilator therapy would facilitate personalised treatment. Methods: The 52-week FLAME study randomised COPD patients with ≥1 exacerbation in past year to indacaterol/glycopyrronium (IND/GLY 110/50µg od) or salmeterol/fluticasone (SFC 50/500µg bid) (Wedzicha et al. NEJM 2016). In this post-hoc analysis, patients were divided in low or high baseline symptom burden using total e-diary scores, COPD Assessment Test (CAT), and St. George’s Respiratory Questionnaire (SGRQ) scores, with split at median, based on levels obtained during trial run-in. Moderate/severe exacerbations were analysed. Results: Patients with low baseline symptom burden had lower exacerbation rates than patients with high baseline symptom burden, as measured by CAT (low vs. high; ratio of rates 0.83, 95%CI 0.74, 0.94) and SGRQ (low vs. high; 0.86, 95%CI 0.76, 0.98), but not e-diary total score (low vs. high; 0.97, 95%CI 0.81, 1.16) regardless of treatment received. Patients treated with IND/GLY experienced fewer exacerbations regardless of baseline symptom group than those who received SFC (Table). Conclusions: Patients with greater symptom burden experience more exacerbations. IND/GLY was more effective in exacerbation prevention than SFC in both high and low baseline symptom groups, measured by SGRQ.