Anti-IgE and Biologic Approaches for the Treatment of Asthma.

Current asthma treatments are effective for the majority of patients with mild-to-moderate disease. However, in those with more severe refractory asthma, agents other than inhaled corticosteroids and beta-agonists are needed both to better manage this group of patients and to avoid the side effects of high-dose corticosteroids and the social and personal hardship endured. Several biological pathways have been targeted over the last 20 years, and this research has resulted in pharmacological approaches to attempt to better treat patients with severe refractory asthma. The flagship of the biologics, the anti-IgE monoclonal antibody, omalizumab, has proven efficacious in selected subgroups of asthma patients. Tailoring asthma treatments to suit specific subtypes of asthma patients is in keeping with ideals of personalized medicine. Research in the complex interplay of allergens, epithelial host defenses, cytokines, and innate and adaptive immunity interactions has allowed better understanding of the mechanics of allergy and inflammation in asthma. As a result, new biologic treatments have been developed that target several different phenotypes and endotypes in asthma. As knowledge of the efficacy of these biological agents in asthma emerges, as well as the type of patients in whom they are most beneficial, the movement toward personalized asthma treatment will follow.

The prevalence of severe refractory asthma.

BACKGROUND: Severe asthma is characterized by difficulty to achieve disease control despite high-intensity treatment. However, prevalence figures of severe asthma are lacking, whereas longstanding estimates vary between 5% and 10% of all asthmatic patients. Knowing the exact prevalence of severe refractory asthma as opposed to difficult-to-control asthma is important for clinical decision making, drug development, and reimbursement policies by health authorities. OBJECTIVE: We sought to estimate the prevalence of severe refractory asthma as defined by the Innovative Medicine Initiative consensus. METHODS: Adult patients with a prescription for high-intensity treatment (high-dose inhaled corticosteroids and long-acting ß2-agonists or medium- to high-dose inhaled corticosteroids combined with oral corticosteroids and long-acting ß2-agonists) were extracted from 65 Dutch pharmacy databases, representing 3% of the population (500,500 inhabitants). Questionnaires were sent to 5,002 patients, of which 2,312 were analyzed. The diagnosis of asthma and degree of asthma control were derived from questionnaires to identify patients with difficult-to-control asthma. Inhalation technique was assessed in a random sample of 60 adherent patients (prescription filling, ≥80%). Patients with difficult-to-control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. Results were mirrored to the Dutch population. RESULTS: Of asthmatic adults, 3.6% (95% CI, 3.0% to 4.1%) qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants. CONCLUSION: The prevalence of severe refractory asthma might be lower than estimated by expert opinion. This implies that currently recognized severe asthma subphenotypes could meet the criteria of rare diseases.

Unremitting Asthma as a Presentation of Pulmonary Nocardiosis: A Case Report.

Severe, refractory asthma requires a combination of multiple maintenance inhalers and medications including high-dose inhaled corticosteroids and immunomodulators to achieve control of symptoms. The use of inhaled corticosteroids, however, increases the susceptibility of opportunistic bacterial infections, such as Nocardia, resulting in pulmonary nocardiosis. This case describes a 46-year-old patient with a history of severe, refractory asthma who presented with progressively worsening asthma exacerbation symptoms. She was treated with immunomodulators, high-dose inhaled corticosteroids and oral steroids, and several courses of antibiotics. CT imaging revealed bibasilar peri-bronchial thickening and tree-in-bud nodularity in the right lower lobe. Pulmonary cultures collected from bronchoscopy grew Nocardia nova complex. This was a rare case of persistent asthma exacerbation by N. nova complex bronchopulmonary infection. Broad differentials should be considered in patients with severe, refractory asthma who were previously controlled and were found to fail treatment therapies. Immunocompromised patients with chronic lung disease are at higher risk of severe infection with disseminated nocardiosis. These patients have a higher mortality and morbidity risk if early diagnosis of pulmonary nocardiosis does not occur.

Dupilumab and tezepelumab in severe refractory asthma: new opportunities.

Bronchial asthma is a chronic inflammatory condition with increasing prevalence worldwide that may present as heterogeneous phenotypes defined by the T2-mediated pattern of airway inflammation T2-high and T2-low asthma. Severe refractory asthma includes a subset of asthmatic patients who fail to control their disease despite maximal therapy and represent a group of patients needing marked resource utilization and hence may be eligible to add-on biological therapies. Among the new biologics, we focused our attention on two monoclonal antibodies: dupilumab, exerting a dual blockade of cytokine (interleukin (IL)-4 and IL-13) signaling; and tezepelumab, acting at a higher level preventing the binding of thymic stromal lymphopoietin (TSLP) to its receptor, thus blocking TSLP, IL-25, and IL-33 signaling, hence modulating airway T2 immune responses. With their different mechanisms of action, these two biologics represent important options to provide an enhanced personalized treatment regimen. Several clinical trials have been conducted testing the efficacy and safety of dupilumab in severe refractory asthmatic patients showing improvements in lung function, asthma control, and reducing exacerbations. Similar results were reported with tezepelumab that, differently from dupilumab, acts irrespectively on eosinophilic or non-eosinophilic phenotype. In this review, we provide an overview of the most important highlights regarding dupilumab and tezepelumab characteristics and mechanism of action with a critical review of the principal results of clinical (Phase II and III) studies concluded and those still in progress.

The role of systemic corticosteroids in severe asthma and new evidence in their management and tapering.

INTRODUCTION: Based on the latest literature evidence, between 30% and 60% of adults with severe refractory asthma (SRA) are systemic corticosteroid (SCS) dependent. There are numerous therapeutic options in asthma, which are often not effective in severe forms. In these cases, SCS should be considered, but it is increasingly recognized that their regular use is often associated with significant and potentially serious adverse events. AREAS COVERED: The aim of this article is to provide an update about the recent and significant literature on SCS and to establish their role in the management of SRA. We summarized the most important and recent evidence and we provided useful indications for clinicians. EXPERT OPINION: There is now strong evidence supporting the increased risk of comorbidities and complications with long-term SCS therapies, regardless of the dose. New evidence on SCS tapering and withdrawal will allow to define protocols to address SCS management with greater safety and effectiveness, after starting efficient steroid-sparing strategies. In the next 5years, it will be necessary to implement corrective actions to address these unmet needs, to reduce the inappropriate use of SCS by maximizing the application of more innovative and effective therapies.

Real world effectiveness of benralizumab on respiratory function and asthma control.

BACKGROUND: Biological drugs have been recognized as a breakthrough in the treatment of severe refractory asthma. This retrospective real-life observational study aims to evaluate the effect of add-on benralizumab on lung function, exacerbation rate, oral corticosteroids (OCS) reduction and asthma control questionnaire (ACQ) score after 52-weeks. METHODS: In this observational study, a cohort of 18 patients with severe eosinophilic asthma (SEA) according to the ERS / ATS and GINA 2020 classifications, with reference to the Pulmonology Unit of the Azienda USL - IRCCS, Reggio Emilia, Italy, were enrolled from 1 September 2019 to 31 August 2020. For each patient, the following data were collected: demographic data (age, sex, age of onset of asthma, history of smoking and atopy); comorbidity; clinical data (lung function, exacerbations, emergency room visits and hospitalizations); asthma control questionnaire (ACQ); biomarkers (blood eosinophil count and total serum IgE); asthma control drugs as high-dose inhaled corticosteroids / long-acting beta-adrenoceptor agonists (ICS / LABA), long-acting muscarinic antagonists (LAMA), leukotriene receptor antagonists (LTRA), theophylline, OCS. The benralizumab 30 mg treatment schedule was based on the currently recommended dosing regimen. RESULTS: After end-of-treatment (EOT), a complete weaning of all patients from OCS was confirmed. After 26 weeks, the number of exacerbations decreased from 2.90 to 0.05 (p<0.0001), hospitalizations and ACQ score decreased from 3.37 to 0.97 (p<0.0001). At EOT, the number of exacerbations was unchanged, while no hospitalizations had occurred. Overall, lung function markedly improved over the study period. After 52 weeks, the increase in FEV1 from baseline was 26,8% (p=0.0002). The subset of patients with nasal polyposis (NP) had an increase of nearly 50% (1008 ml) and patients with blood eosinophils count (BEC) greater than 500 cells / µl showed an increase of 68% (1081 ml) in FEV1 at EOT. CONCLUSIONS: The notable improvement in respiratory function is a significant result in this study and it is much higher than what has emerged to date. This result, together with the OCS sparing effect and the excellent clinical control of asthma, makes benralizumab a reliable and safe therapeutic option for SEA.

Anti-IL5 Therapies for Severe Eosinophilic Asthma: Literature Review and Practical Insights.

Severe refractory asthma (SRA) still has a high economic and social impact, including a reduction in quality of life (QoL), productivity, a greater risk of exacerbations and emergency department (ED) visits. Another major issue is the need of oral corticosteroids (OCS), often due to a poor response to standard therapies or the lack of indication for currently available biological drugs. A thorough understanding of the immunological pathways and eosinophilopoietic processes allows a correct application of the new pharmacological strategies and leads to better clinical responses. For these unmet needs, several monoclonal antibody (mAb) drugs have been introduced over the past few years. These are mainly available for allergic and especially eosinophilic uncontrolled refractory asthma. As the number of therapeutic options increases, the choice of biological drugs can be made only after careful considerations of the particular asthma endotype, patients' comorbidities and clinical data. The selection of the correct therapeutic option can therefore be guided after a careful evaluation of the particular endotype and phenotype, from the combined evaluation of inflammatory biomarkers, clinical picture and comorbidities. The careful evaluation of all these parameters can therefore help the physician in the optimal management of these complex patients, for whom it is often possible to achieve exceptional results by managing the available options in the best possible way. The aim of this review is to define the positioning of the biological drugs currently available for type 2 asthma, with a special focus on options for eosinophilic asthma in the context of the most recent knowledge of immunological pathways.

Case Report: Acute effect of benralizumab on asthma exacerbation without concomitant corticosteroid use.

Background: Monoclonal antibodies are a relatively new therapeutic option for patients with severe refractory asthma, which can be used as an add-on to maintenance therapy, reducing the need for systemic corticosteroid usage, improving asthma symptom control and reducing exacerbations. We report a case of a patient with severe refractory eosinophilic asthma, reluctant to take systemic steroids, who was successfully treated with benralizumab alone during an acute asthma attack. Case presentation: A 59-year-old Caucasian woman with a history of allergic asthma since childhood showed a progressive decline in lung function with difficult to control symptoms and an increased number of hospitalizations despite maximal maintenance treatment, and was diagnosed with severe refractory asthma. She was reluctant to take systemic corticosteroids during exacerbations due to severe urinary retention; therefore, she started omalizumab with a partial reduction of symptoms and exacerbations over time. During a follow-up visit, she showed signs of acute exacerbation and she was switched to benralizumab during her acute phase with a rapid, dramatic amelioration of respiratory symptoms and pulmonary function, without concomitant systemic corticosteroid administration. During the treatment and at follow-up after one month, good tolerance and no side effects were observed. Conclusions: The use of benralizumab seems to be feasible, rapid, and safe in treating acute exacerbation of severe eosinophilic asthma without the use of systemic corticosteroids.

Bronchial thermoplasty: implementing best practice in the era of cost containment.

Increasing dependence on advanced technologies in the 21st century has created a dilemma between the practice and business of medicine. From information technology to robotic surgery, new technologies have expanded treatment possibilities and have potentially improved patient outcomes and safety. Simultaneously, their escalating costs limit access for certain patients and health care facilities. Nevertheless, medical decisions should not simply be based on cost. Input from physicians and other health care specialists as well as adherence to best practice position statements, are vital to implementing truly cost-effective strategies in medicine. Bronchial thermoplasty (BT), a US Food and Drug Administration approved bronchoscopy procedure in difficult-to-control persistent asthma, is a prime example of a new technology facing cost and implementation challenges. We discuss the specific indications and contraindications for BT and review recent real-world experiences that can provide the foundation for building a comprehensive asthma program that provides BT for difficult-to-control asthma patients who fail national guideline treatment recommendations after an adequate clinical trial of one. We also offer insight into the barriers to implementing a successful BT program and strategies for overcoming them.

Low interleukin (IL)-18 levels in sputum supernatants of patients with severe refractory asthma.

BACKGROUND: Severe refractory asthma (SRA) is characterized by persistent asthma symptoms, amplified airway inflammation despite treatment with high dose inhaled steroids and increased airway bacterial colonization. Interleukin (IL)-18 is a pleiotropic pro-inflammatory cytokine that modulates airway inflammation. Furthermore, as a product of the inflammasome, IL-18 is involved in host defence against viral and bacterial stimuli by modulating the immune response. OBJECTIVE: To determine IL-18 levels in sputum supernatants of patients with asthma and to investigate whether underlying severity affects its levels. Furthermore, possible associations with atopy and mediators and cells involved in the inflammatory process of the airways were examined. METHODS: Forty-five patients with mild intermittent asthma (21 smokers) and 18 patients with SRA in stable state were studied. All subjects underwent lung function tests, skin prick tests, and sputum induction for cell count identification. IL-18 and ECP levels were measured in sputum supernatants. Furthermore, sputum samples were examined for the commonest respiratory pathogens and viruses by real time polymerase chain reaction (RT-PCR). RESULTS: Patients with SRA had significantly lower IL-18 levels in sputum supernatants compared to mild asthmatics (p < 0.001). Twelve out of eighteen patients with SRA were colonized by viruses and/or bacterial pathogens. IL-18 levels correlated with the percentage of macrophages (r = 0.635, p = 0.026) and inversely correlated with the percentage of neutrophils in sputum (r = -0.715, p = 0.009). No correlations were found between IL-18, ECP and the percentage of eosinophils in the sputum of SRA. CONCLUSIONS: In SRA IL-18 is possibly involved in chronic airway inflammation through an eosinophil independent pathway. The decreased levels of IL-18 in SRA support the hypothesis of deregulated inflammasome activation, justifying the susceptibility of these patients for bacterial colonization or infection.

Monoclonal Anti-TNF-α Antibodies for Severe Steroid-Dependent Asthma: A Case Series.

BACKGROUND: Refractory asthma represents an important condition, with considerable morbidity and mortality. Tumor necrosis factor α (TNF-α) is a potential target for treatment of severe asthma. However, controlled studies have shown controversial results and the risk-benefit profile of TNF-blocking agents is still debated. OBJECTIVES: To describe the effect of infliximab on asthma control in patients with severe, uncontrolled, steroid-dependent asthma. METHODS: From 2007 to 2010, 7 patients received infliximab in our center. All had severe refractory asthma, with frequent severe exacerbations and hospitalizations in the intensive care unit despite maximal inhaled treatment, daily oral steroids and omalizumab treatment. RESULTS: Asthma control improved in the 6 patients who received infliximab for at least 3 months. Oral steroids could be stopped in 4 and the frequency of exacerbations and hospitalizations was greatly reduced, especially for the 3 patients with brittle asthma. Two patients showed severe adverse effects (bacterial pneumonia and extension of spreading melanoma). Three patients have received infliximab for more than 2 years, with good tolerance. CONCLUSION: This case series suggests that anti-TNF-α drugs may improve the condition of a subgroup of patients with severe steroid-refractory asthma, with a favourable risk-benefit profile for most, considering asthma severity, occurrence of life-threatening exacerbations and complications of long-term oral steroids. Specific controlled trials of this subgroup are warranted.