Biologics in severe asthma: A pragmatic approach for choosing the right treatment for the right patient

Correction Critical Care Medicine

Real World Effectiveness of Benralizumab in Severe Eosinophilic Asthma (vol 159, pg 496, 2022)

[Anonymous]

CHEST (2023)

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Article Allergy

Biologics in the treatment of asthma in children and adolescents

Leonard B. Bacharier et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2023)

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Article Cardiac & Cardiovascular Systems

Efficacy and safety of dupilumab as add-on therapy for patients with severe asthma: A real-world Dutch cohort study

John C. Thelen et al.

Summary: The study demonstrates that adding dupilumab as a treatment for severe uncontrolled asthma leads to significant improvements in asthma control, quality of life, and reduction in exacerbation rate and dependency on oral corticosteroids.

RESPIRATORY MEDICINE (2023)

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Review Allergy

Biologics for severe asthma: The real-world evidence, effectiveness of switching, and prediction factors for the efficacy

Hiroyuki Nagase et al.

Summary: Biologics, such as anti-IgE, anti-IL-5, anti-IL-4/IL-13, and anti-TSLP, have been effective in the treatment of severe asthma. However, real-world research is needed to include patients who may have been excluded from clinical trials. The identification of biomarkers for predicting response to different biologics is crucial, and there is a need to evaluate the effectiveness and safety of switching biologics and discontinuation.

ALLERGOLOGY INTERNATIONAL (2023)

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Article Critical Care Medicine

Long-term safety and efficacy of tezepelumab in people with severe, uncontrolled asthma (DESTINATION): a randomised, placebo-controlled extension study

Andrew Menzies-Gow et al.

Summary: This study evaluated the long-term safety and efficacy of tezepelumab, a monoclonal antibody, in individuals with severe, uncontrolled asthma. The results showed that tezepelumab reduced asthma exacerbations and demonstrated sustained efficacy and good tolerability over a period of two years.

LANCET RESPIRATORY MEDICINE (2023)

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Review Respiratory System

Definitions of non-response and response to biological therapy for severe asthma: a systematic review

Ekaterina Khaleva et al.

Summary: This study systematically reviewed the definitions of response to biologics for severe asthma and found that although high-quality definitions are available, most are based on minimal clinically important difference (MCID) or minimal important difference (MID), which may not be sufficient to justify the cost-effectiveness of continuing biologics.

ERJ OPEN RESEARCH (2023)

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Article Allergy

Efficacy of dupilumab in patients with moderate-to-severe asthma and persistent airflow obstruction

Nicola A. Hanania et al.

Summary: The study showed that Dupilumab is effective in improving clinical outcomes in patients with persistent airflow obstruction.

ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY (2023)

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Review Immunology

Eosinophilic granulomatosis with polyangiitis: A review

J. P. E. White et al.

Summary: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease characterized by late-onset asthma, eosinophilia, and vasculitis. It is different from other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and has a unique pathophysiology. There is currently no standard therapy for EGPA, and further research is needed to understand its complex pathogenesis and develop more effective treatment options.

AUTOIMMUNITY REVIEWS (2023)

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Review Medicine, Research & Experimental

New insights into the pathophysiology and therapeutic targets of asthma and comorbid chronic rhinosinusitis with or without nasal polyposis

Ilja Striz et al.

Summary: Asthma and chronic rhinosinusitis with nasal polyps often co-exist and are driven by type 2 inflammation. Targeted biologics have shown clinical efficacy in patients with refractory T2 airway inflammation, but no consistent efficacy has been observed in non-type-2 endotypes. Multiple therapeutic targets are being explored to expand current treatment options for severe asthma with and without comorbid CRSwNP.

CLINICAL SCIENCE (2023)

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Article Cardiac & Cardiovascular Systems

Imaging-derived biomarkers in Asthma: Current status and future perspectives

Esther Pompe et al.

Summary: Asthma is a common disorder with a global impact, affecting approximately 315 million individuals. The heterogeneity of asthma has gained significance in the personalized treatment and assessment of response. Radiological imaging modalities such as X-ray, CT, and MRI are used for diagnosis and research purposes in asthma. Quantitative imaging analysis, along with artificial intelligence (AI), shows potential in identifying different phenotypes with distinct disease progression and therapeutic response. However, further research is needed to fully understand the role of AI in clinical practice.

RESPIRATORY MEDICINE (2023)

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Article Cardiac & Cardiovascular Systems

Severe asthma clinical remission after biologic treatment with anti-IL4/ IL13: A real-life experience

Andrea Portacci et al.

Summary: This study found that treatment with Dupilumab can induce clinical remission in patients with severe asthma, with 38.9% of patients achieving remission at the end of the treatment. The treatment also significantly reduced asthma exacerbations and oral corticosteroid use, and improved asthma control in patients.

RESPIRATORY MEDICINE (2023)

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Article Allergy

Severe Asthma Network Italy Definition of Clinical Remission in Severe Asthma: A Delphi Consensus

Giorgio Walter Canonica et al.

Journal of Allergy and Clinical Immunology-In Practice (2023)

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Article Allergy

Baseline type 2 biomarker levels and response to tezepelumab in severe asthma

Jonathan Corren et al.

Summary: Tezepelumab significantly reduces T2 inflammatory biomarker levels and asthma exacerbation rates in patients with severe asthma. After 52 weeks of treatment, tezepelumab effectively reduces all measured biomarker levels and decreases asthma exacerbations.

ALLERGY (2022)

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Review Allergy

A rational approach to compare and select biologic therapeutics in asthma

Eileen Wang et al.

Summary: This article reviews key literature on asthma biologic therapeutics, including currently available and under investigation biologic therapies. Precision medicine guidance and shared decision-making are important factors in selecting biologic therapeutics. Consideration of biomarkers and key clinical characteristics can help guide the selection of biologics.

ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY (2022)

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Article Critical Care Medicine

Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study

Michael E. Wechsler et al.

Summary: The study assessed the long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma over 96 weeks of treatment. The findings demonstrated good safety and efficacy during the study period, supporting the long-term use of dupilumab in this patient population.

LANCET RESPIRATORY MEDICINE (2022)

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Article Allergy

Real World Biologic Use and Switch Patterns in Severe Asthma: Data from the International Severe Asthma Registry and the US CHRONICLE Study

Andrew N. Menzies-Gow et al.

Summary: This study described real-life patterns of biologic use for severe asthma in multiple countries, showing that most patients continued their initial biologic treatment, while some stopped or switched to a different biologic. Patients who stopped or switched were more likely to have higher baseline blood eosinophil count, higher exacerbation rate, lower lung function, and greater healthcare resource utilization.

JOURNAL OF ASTHMA AND ALLERGY (2022)

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Letter Allergy

Safety of combining biologics in severe asthma: Asthma-related and unrelated combinations

Marek Lommatzsch et al.

ALLERGY (2022)

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Article Allergy

Real-world effectiveness of benralizumab: Results from the ZEPHYR 1 Study

Yen Chung et al.

Summary: Patients with severe eosinophilic asthma treated with benralizumab experienced clinical and economic benefits in the real world, as demonstrated by a reduction in exacerbations and healthcare resource utilization.

ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY (2022)

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Article Pediatrics

Severe asthma in children: Description of a large multidisciplinary clinical cohort

Maria Forero Molina et al.

Summary: This study reviewed the electronic health records of a severe asthma clinic in a children's hospital, finding that children with severe asthma had high morbidity and healthcare utilization. The study also showed that patients with a history of hospital admissions for asthma were more likely to be nonwhite and highly atopic and have lower lung function. Following enrollment in a multidisciplinary clinic, the frequency of severe exacerbations decreased.

PEDIATRIC PULMONOLOGY (2022)

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Editorial Material Respiratory System

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework

Simon Couillard et al.

RESPIROLOGY (2022)

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Review Biotechnology & Applied Microbiology

Understanding the Cellular Sources of the Fractional Exhaled Nitric Oxide (FeNO) and Its Role as a Biomarker of Type 2 Inflammation in Asthma

Jose M. Escamilla-Gil et al.

Summary: FeNO is a biomarker of type 2 inflammation in asthma, useful for monitoring inflammation, evaluating corticosteroid treatment, and identifying patients suitable for personalized therapy.

BIOMED RESEARCH INTERNATIONAL (2022)

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Article Critical Care Medicine

Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study

Michael E. Wechsler et al.

Summary: This study evaluated the efficacy of tezepelumab in reducing oral corticosteroid dose in patients with oral corticosteroid-dependent asthma. The results showed no significant improvement in the overall population, but improvement was observed in patients with higher baseline blood eosinophil counts.

LANCET RESPIRATORY MEDICINE (2022)

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Article Allergy

Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis

Michael E. Wechsler et al.

Summary: Transient increases in eosinophil counts have been observed in dupilumab clinical trials, but they do not affect efficacy and are rarely associated with clinical consequences.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2022)

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Review Pediatrics

How to Choose the Correct Drug in Severe Pediatric Asthma

Andrew Bush

Summary: When a child with severe asthma does not respond to treatment, it is important to consider alternative or additional diagnoses. Detailed assessments can help determine the nature of the problem and personalize the treatment. For preschool asthma, simple measurements can guide the use of inhaled corticosteroids.

FRONTIERS IN PEDIATRICS (2022)

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Heterogeneous Condition of Asthmatic Children Patients: A Narrative Review

Cristiano Caruso et al.

Summary: Asthma is the most common chronic disorder in children, with diverse phenotypes and various factors influencing its presentation. Improving outcomes in pediatric asthma remains a hot topic, despite advancements in disease management. The global challenges of climate change and the COVID-19 pandemic have a significant impact on childhood and adolescent asthma, warranting preventive strategies and targeted treatment approaches.

CHILDREN-BASEL (2022)

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Review Allergy

Biologics and airway remodeling in severe asthma

Gilda Varricchi et al.

Summary: Asthma is a chronic inflammatory airway disease that can result in irreversible airflow obstruction. Biologics have been shown to improve airflow obstruction and possibly reverse fixed remodeling. Therefore, analyzing the therapeutic effects of biologics in severe asthma, both early and late, is crucial.

ALLERGY (2022)

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Article Allergy

Comparative efficacy of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma: A Bayesian network meta-analysis

Ayobami Akenroye et al.

Summary: There are minimal differences in the efficacy and safety of mepolizumab, benralizumab, and dupilumab in individuals with severe eosinophilic asthma.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2022)

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Severe pediatric asthma therapy: Dupilumab

Giuliana Ferrante et al.

Summary: Dupilumab, a biological agent used for treating severe pediatric asthma, has shown efficacy in inhibiting the inflammatory cascade of IL-4 and IL-13, leading to improved asthma symptoms. Although approved for treating uncontrolled severe asthma, further research is needed to evaluate its long-term effectiveness and potential impact on the natural history of atopy.

FRONTIERS IN PEDIATRICS (2022)

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REALITI-A Study: Real-World Oral Corticosteroid-Sparing Effect of Mepolizumab in Severe Asthma

Charles Pilette et al.

Summary: This 1-year analysis demonstrates that real-world mepolizumab treatment is clinically effective in patients with severe asthma, providing disease control while reducing the need for mOCS and SCS bursts.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2022)

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Do not forget asthma comorbidities in pediatric severe asthma!

Lucia Ronco et al.

Summary: This article describes the characteristics of comorbidities in pediatric severe asthma, providing clinicians with tools to recognize and manage these conditions properly.

FRONTIERS IN PEDIATRICS (2022)

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Severe Pediatric Asthma Therapy: Mepolizumab

Nicola Ullmann et al.

Summary: There is a growing need for advanced treatment in children with persistent and severe asthma symptoms. Mepolizumab, a humanized monoclonal antibody targeting interleukin-5 (IL-5), has been proven effective in controlling eosinophil proliferation in children and adolescents. The recommended dose for children aged 6 to 11 years is 40 mg every 4 weeks, and for patients aged 12 years and above is 100 mg every 4 weeks. Mepolizumab has demonstrated similar therapeutic effects and safety profile to that observed in adults.

FRONTIERS IN PEDIATRICS (2022)

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Biological Therapy of Severe Asthma and Nasal Polyps

Agamemnon Bakakos et al.

Summary: This review focuses on the correlation between asthma and nasal polyps, and evaluates the treatment efficacy of various monoclonal antibodies in patients with severe asthma and nasal polyps, as well as in patients with nasal polyps without asthma or with mild-to-moderate asthma. The selection of the right biologic agent becomes an important target, but is challenging due to the lack of comparative head-to-head studies.

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Biologic Therapies in Pediatric Asthma

Evanthia P. Perikleous et al.

Summary: Childhood asthma is a common and complex chronic condition in children, and the management of severe asthma remains challenging. The use of biologic agents has shown promise in treating severe childhood asthma, but long-term effects are still unclear. Further research is needed to determine the most effective biologic agents and predictors of treatment response for pediatric patients.

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Integrated systems modeling of severe asthma: Exploration of IL-33/ST2 antagonism

Kapil Gadkar et al.

Summary: Asthma is a complex disease with a high unmet medical need. In this study, a computational model of asthma biology was developed to integrate preclinical and clinical data, and a virtual population was created to capture clinical heterogeneity. The model's simulated responses to different therapies aligned with clinical endpoints and biomarkers. The model was used to explore the potential benefits of targeting the IL-33 pathway and to interpret trial results. Sensitivity analyses revealed the mechanisms behind the predicted biomarker changes. This model provides mechanistic insights and supports clinical program design for novel therapies.

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY (2022)

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Airway autoimmunity, asthma exacerbations, and response to biologics

Carmen Venegas Garrido et al.

Summary: Biologic therapies are an effective treatment for severe asthma by targeting specific inflammatory modulators. However, some patients may have inadequate responses to these therapies, leading to exacerbations. Exacerbations can occur due to several reasons, such as inaccurate identification of dominant effector pathways, additional inflammatory pathways not targeted by the biologics, and errors in treatment guidance. This review discusses how airway autoimmune responses can drive exacerbations in patients on biologics and suggests strategies for evaluation and switching of therapies.

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Scientific journey to the first FDA-approved drug for eosinophilic esophagitis

Marc E. Rothenberg

Summary: Eosinophilic esophagitis (EoE) is a separate disease entity driven by allergic inflammation, with IL-13 playing a crucial role in its development. Inhibiting IL-13 signaling has shown potential as a treatment for EoE. Dupilumab, the first drug approved for EoE by the FDA, improves clinical symptoms and disease features in patients.

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Nicola A. Hanania et al.

Summary: This review examined the clinical evidence of omalizumab treatment in patients with allergic asthma for at least 2 years. The findings confirmed the long-term effectiveness and safety of omalizumab, with reduced exacerbations, improved lung function and quality of life, decreased healthcare utilization, and favorable safety and tolerability profiles. Similar results were observed in both pediatric and adult populations.

WORLD ALLERGY ORGANIZATION JOURNAL (2022)

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Anne-Noelle Frix et al.

Summary: Our study revealed significant heterogeneity in the use of asthma biologics across Europe. Further investigation is needed to assess the impact of this heterogeneity on clinical outcomes relevant to patients and healthcare services.

ERJ OPEN RESEARCH (2022)

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Birgit Pfaller et al.

Summary: Biologicals have revolutionized the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. While the number of approved biologicals for treating atopic diseases continues to rise, there is a lack of research and information regarding the safety of these treatments during pregnancy, emphasizing the need for multidisciplinary approaches and long-term follow-up studies.

ALLERGY (2021)

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EAACI Biologicals Guidelines-Recommendations for severe asthma

Ioana Agache et al.

Summary: Severe asthma poses significant challenges in management, but targeted treatments with biologicals offer new hope for patients. However, further research is needed on issues such as selection of biologicals, response definition, treatment duration, and cost-effectiveness.

ALLERGY (2021)

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Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial

Liam G. Heaney et al.

Summary: The study compared a biomarker-based treatment adjustment strategy with a symptom-risk-based algorithm in severe asthma patients, finding that the biomarker strategy resulted in a higher proportion of patients reducing corticosteroid dose. Understanding patient non-compliance with treatment advice is an important area for future research. The prevalence of T2 biomarker-low severe asthma was found to be low.

LANCET RESPIRATORY MEDICINE (2021)

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Jean Bousquet et al.

Summary: This meta-analysis evaluated real-world data of omalizumab in the treatment of patients with severe allergic asthma, finding significant improvements in treatment effectiveness, lung function, patient-reported outcomes, and exacerbation rates, as well as reductions in oral corticosteroid use and healthcare resource utilization.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2021)

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Andrew P. Hearn et al.

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Michael E. Wechsler et al.

Summary: The study found that the monoclonal antibody itepekimab targeting interleukin-33 was more effective than placebo in improving lung function and reducing the incidence of loss of asthma control events in patients with moderate-to-severe asthma.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Asthma Patients Who Stop Asthma Biologics Have a Similar Risk of Asthma Exacerbations as Those Who Continue Asthma Biologics

Molly M. Jeffery et al.

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JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2021)

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Complications of switching from anti-IL-5 or anti-IL-5R to dupilumab in corticosteroid-dependent severe asthma

Katrien Eger et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2021)

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Luis Perez de Llano et al.

Summary: A valid score was developed to quantify the response to monoclonal antibodies in severe uncontrolled asthma patients, with four core items selected and weighted accordingly. This scoring system allows clinicians to measure the level of response in patients being treated with mAbs, providing valuable guidance in clinical practice.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2021)

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Feasibility of Discontinuing Biologics in Severe Asthma: An Algorithmic Approach

Kazuki Hamada et al.

Summary: Biologics targeting key mediators of T2 inflammation have significantly improved management of severe asthma. Discontinuation of biologics may be feasible in subset of patients meeting specific criteria, such as absence of symptoms, controlled T2 inflammation, and other factors. Our proposed algorithm aims to guide physicians in decision-making for discontinuation of biologics.

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Article Medicine, General & Internal

Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma

Andrew Menzies-Gow et al.

Summary: Tezepelumab, a monoclonal antibody targeting thymic stromal lymphopoietin, effectively reduces asthma exacerbations in patients with severe, uncontrolled asthma, leading to improved lung function, asthma control, and quality of life.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Joseph K. Han et al.

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LANCET RESPIRATORY MEDICINE (2021)

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Asthma biologics Real-world effectiveness, impact of switching biologics, and predictors of response

Farrukh Abbas et al.

Summary: The study demonstrates that in the real-world setting, the use of asthma biologics can effectively improve exacerbations, asthma control, and lung function in asthma patients. Patients who have suboptimal response to one biologic may still benefit from treatment with a different biologic.

ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY (2021)

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Severe asthma exacerbations in the United States: Incidence, characteristics, predictors, and effects of biologic treatments

Jennifer Trevor et al.

Summary: The real-world incidence, characteristics, and predictors of exacerbations among patients with severe asthma in the United States have not been well described. The study found that patients receiving biologics had a lower exacerbation burden.

ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY (2021)

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Letter Allergy

Hypereosinophilia with systemic manifestations under dupilumab and possibility of dual benralizumab and dupilumab therapy in patients with asthma and CRSwNP

Ignaz Briegel et al.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2021)

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John W. Upham et al.

Summary: Using a modified Delphi process, severe asthma experts developed an international consensus-based definition of a severe asthma super-responder, with major and minor criteria established. This definition is crucial for better understanding the prevalence, predictive factors, and mechanisms involved in super-responders, emphasizing the need for further research in these areas.

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE (2021)

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Article Critical Care Medicine

Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma

Joanne E. Kavanagh et al.

Summary: In patients with severe eosinophilic asthma treated with benralizumab, a significant reduction in asthma exacerbation rates was observed, with a subset of patients achieving super response. Blood eosinophil count increase was associated with treatment nonresponse.

CHEST (2021)

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Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort

Jennifer A. Namazy et al.

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Systematic Literature Review of Systemic Corticosteroid Use for Asthma Management

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2020)

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Trends and Disparities in Asthma Biologic Use in the United States

Jonathan W. Inselman et al.

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Characteristics and treatment regimens across ERS SHARP severe asthma registries

Job J. M. H. van Bragt et al.

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An expert consensus framework for asthma remission as a treatment goal

Andrew Menzies-Gow et al.

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Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort

Clairelyne Dupin et al.

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Tim Harrison et al.

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Biological Therapies of Severe Asthma and Their Possible Effects on Airway Remodeling

Grzegorz Kardas et al.

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Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials

Philippe Gevaert et al.

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Predictors of response toanti-IL-5biologics

Parameswaran Nair

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Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial

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Omalizumab Effectiveness by Biomarker Status in Patients with Asthma: Evidence From PROSPERO, A Prospective Real-World Study

Thomas B. Casale et al.

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Anti-IL-5 treatments in patients with severe asthma by blood eosinophil thresholds: Indirect treatment comparison

William Busse et al.

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CT and Functional MRI to Evaluate Airway Mucus in Severe Asthma

Sarah Svenningsen et al.

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Short- and long-term real-world effectiveness of omalizumab in severe allergic asthma: systematic review of 42 studies published 2008-2018

Karen M. MacDonald et al.

EXPERT REVIEW OF CLINICAL IMMUNOLOGY (2019)

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The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma

Kenneth R. Chapman et al.

ALLERGY (2019)

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Prognostic and Predictive Value of Blood Eosinophil Count, Fractional Exhaled Nitric Oxide, and Their Combination in Severe Asthma: A Post Hoc Analysis

Rahul Shrimanker et al.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE (2019)

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Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study

Sandhya Khurana et al.

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Assessment of the long-term safety of mepolizumab and durability of clinical response in patients with severe eosinophilic asthma

Sumita Khatri et al.

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