Left Atrial Strain in Cardiomyopathies and Congenital Heart Disease: A Call for Its Integration into Clinical Practice.

Despite the long-standing neglect, there is now a mounting interest in the left atrium (LA) physiology.

Pathobiology of Type 2 Inflammation in Asthma and Nasal Polyposis.

Asthma and nasal polyposis often coexist and are frequently intertwined by tight pathogenic links, mainly consisting of the cellular and molecular pathways underpinning type 2 airway inflammation. The latter is characterized by a structural and functional impairment of the epithelial barrier, associated with the eosinophilic infiltration of both the lower and upper airways, which can be driven by either allergic or non-allergic mechanisms. Type 2 inflammatory changes are predominantly due to the biological actions exerted by interleukins 4 (IL-4), 13 (IL-13), and 5 (IL-5), produced by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). In addition to the above cytokines, other proinflammatory mediators involved in the pathobiology of asthma and nasal polyposis include prostaglandin D2 and cysteinyl leukotrienes. Within this context of 'united airway diseases', nasal polyposis encompasses several nosological entities such as chronic rhinosinusitis with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD). Because of the common pathogenic origins of asthma and nasal polyposis, it is not surprising that the more severe forms of both these disorders can be successfully treated by the same biologic drugs, targeting many molecular components (IgE, IL-5 and its receptor, IL-4/IL-13 receptors) of the type 2 inflammatory trait.

Severe Asthma Remissions Induced by Biologics Targeting IL5/IL5r: Results from a Multicenter Real-Life Study.

Add-on biological therapy has proven to be effective in many patients with severe eosinophilic asthma. In this observational multicenter retrospective study, we report the results obtained with mepolizumab and benralizumab in severe asthmatics treated for 12 months in a real-life setting. In these patients, peripheral eosinophil levels, pulmonary function trends, exacerbation rates, systemic corticosteroid use, and symptom control were evaluated during the observation period, to understand which patients met all the criteria in order to be considered in disease remission. The percentage of remittent patients was 30.12% in the mepolizumab-treated subgroup, while in the benralizumab-treated subgroup, patients in complete disease remission were 40%, after 12 months. The results of this study confirm the efficacy of anti-IL-5 biologic drugs in the treatment of severe eosinophilic asthma in a real-life setting.

Effectiveness of Benralizumab in OCS-Dependent Severe Asthma: The Impact of 2 Years of Therapy in a Real-Life Setting.

Patients with severe OCS-dependent asthma can be considered a subgroup of asthma patients with severe disease and great risk of complications, related to chronic OCS use. The introduction of biological drugs has represented a turning point in the therapeutic strategy for severe asthma, offering a valid alternative to OCS. Benralizumab, like other anti-IL-5 agents, has been shown to reduce exacerbations and OCS intake/dosage and improve symptom control and lung function. While these findings have also been confirmed in real-life studies, data on long-term efficacy are still limited. METHODS: In this retrospective study, we evaluated the effects of 2 years of treatment with benralizumab on 44 patients with OCS-dependent severe asthma by analyzing clinical, biological and functional data. RESULTS: After 2 years of benralizumab, 59.4% discontinued OCS and patients who continued to use OCS had their mean dose reduced by approximately 85% from baseline. Meanwhile, 85% of patients had their asthma well-controlled (ACT score > 20) and had no exacerbations, and 41.6% had normal lung function. CONCLUSIONS: Our findings support the long-term effectiveness of benralizumab in severe OCS-dependent asthma in a real-life setting, suggesting potential reductive effects on costs and complications such as adverse pharmacological events.

What Is the Role of Sex-Related Differences in the Effectiveness and Safety of Biological Drugs Used in Patients With Severe Asthma?

Biological drugs are used to treat severe asthma with an improvement of clinical symptoms. Data on sex difference of these drugs in patients with severe asthma are sparse. This study aimed to assess the effects of sex-related differences on biological drugs in patients with severe asthma. In this observational, open-label, prospective, noncontrolled, single-center cohort pilot study, we enrolled adult patients aged >18 years diagnosed with severe asthma and not previously treated with biological drugs. The first clinical end point was the statistical difference (P < .05) in the efficacy of biological drugs evaluated using the asthma control test and spirometry between sexes. The first safety end point was the statistical difference (P < .05) in developing adverse drug reactions between sexes. We enrolled 74 patients with severe asthma (48 women and 26 men) with a mean age of 59.4 (standard deviation, 11.8) years. The mean forced expiratory volume in 1 second was 6.9 (standard deviation, 13.9) for women and 9.4 (standard deviation, 10.7) for men and improved significantly after the treatment (P < .01), with no significant differences in sex (P = .8). Similarly, the asthma control test improved 12 months after the beginning of the treatment without significant differences between men and women (P = .5). The most common drug used was omalizumab (45.9% of the patients; P < .01) without significant differences between sex (P > .05). We did not observe the development of adverse drug reactions during the study. In conclusion, in asthmatic patients, sex does not have a role in either the effectiveness or safety of biological drugs.

Eosinophilic inflammation: An Appealing Target for Pharmacologic Treatments in Severe Asthma.

Severe asthma is characterized by different endotypes driven by complex pathologic mechanisms. In most patients with both allergic and non-allergic asthma, predominant eosinophilic airway inflammation is present. Given the central role of eosinophilic inflammation in the pathophysiology of most cases of severe asthma and considering that severe eosinophilic asthmatic patients respond partially or poorly to corticosteroids, in recent years, research has focused on the development of targeted anti-eosinophil biological therapies; this review will focus on the unique and particular biology of the eosinophil, as well as on the current knowledge about the pathobiology of eosinophilic inflammation in asthmatic airways. Finally, current and prospective anti-eosinophil therapeutic strategies will be discussed, examining the reason why eosinophilic inflammation represents an appealing target for the pharmacological treatment of patients with severe asthma.

Biological Therapy of Severe Asthma with Dupilumab, a Dual Receptor Antagonist of Interleukins 4 and 13.

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are key cytokines involved in the pathophysiology of both immune-inflammatory and structural changes underlying type 2 asthma. IL-4 plays a pivotal role in Th2 cell polarization, immunoglobulin E (IgE) synthesis and eosinophil recruitment into the airways. IL-13 synergizes with IL-4 in inducing IgE production and also promotes nitric oxide (NO) synthesis, eosinophil chemotaxis, bronchial hyperresponsiveness and mucus secretion, as well as the proliferation of airway resident cells such as fibroblasts and smooth muscle cells. The biological effects of IL-4 and IL-13 are mediated by complex signaling mechanisms activated by receptor dimerization triggered by cytokine binding to the α-subunit of the IL-4 receptor (IL-4Rα). The fully human IgG4 monoclonal antibody dupilumab binds to IL-4Rα, thereby preventing its interactions with both IL-4 and IL-13. This mechanism of action makes it possible for dupilumab to effectively inhibit type 2 inflammation, thus significantly reducing the exacerbation of severe asthma, the consumption of oral corticosteroids (OCS) and the levels of fractional exhaled NO (FeNO). Dupilumab has been approved not only for the add-on therapy of severe asthma, but also for the biological treatment of atopic dermatitis and nasal polyposis.

Novel Biological Therapies for Severe Asthma Endotypes.

Severe asthma comprises several heterogeneous phenotypes, underpinned by complex pathomechanisms known as endotypes. The latter are driven by intercellular networks mediated by molecular components which can be targeted by specific monoclonal antibodies. With regard to the biological treatments of either allergic or non-allergic eosinophilic type 2 asthma, currently available antibodies are directed against immunoglobulins E (IgE), interleukin-5 (IL-5) and its receptor, the receptors of interleukins-4 (IL-4) and 13 (IL-13), as well as thymic stromal lymphopoietin (TSLP) and other alarmins. Among these therapeutic strategies, the best choice should be made according to the phenotypic/endotypic features of each patient with severe asthma, who can thus respond with significant clinical and functional improvements. Conversely, very poor options so far characterize the experimental pipelines referring to the perspective biological management of non-type 2 severe asthma, which thereby needs to be the focus of future thorough research.

Biologics in severe asthma.

Asthma is a chronic airway disease consisting of usually variable airflow limitation and bronchial hyperresponsiveness. Many different phenotypes characterize the clinical expression of asthma, determined by heterogeneous inflammatory patterns driven by distinct cellular and molecular mechanisms known as endotypes. Inside the complex framework of asthma pathobiology, several molecules such as immunoglobulins E (IgE), pro-inflammatory cytokines and their receptors can be targeted by present and future biological treatments of severe asthma. Within this context, already registered monoclonal antibodies including omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab may interfere at various levels with the pathogenic pathways responsible for type-2 airway inflammation. In particular, these drugs target IgE (omalizumab), IL-5 (mepolizumab and reslizumab), IL-5 receptor (benralizumab) and IL-4/IL-13 receptors (dupilumab), respectively. Moreover, other biological therapies are under evaluation in premarketing trials, mainly aimed to assess the efficacy and safety of monoclonal antibodies directed against innate cytokines such as IL-33 and thymic stromal lymphopoietin (TSLP). Among current and perspective therapeutic approaches, clinicians can choose phenotype/endotype-driven tailored treatments, able to pursue an effective control of difficult to treat type-2 asthma.

Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological Therapies of Severe Asthma.

Alarmins are innate cytokines, including thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25), which are mainly produced by airway epithelium and exert a prominent role in asthma pathobiology. In particular, several environmental factors such as allergens, cigarette smoking, airborne pollutants, and infectious agents trigger the release of alarmins, which in turn act as upstream activators of pro-inflammatory pathways underlying type 2 (T2-high) asthma. Indeed, alarmins directly activate group 2 innate lymphoid cells (ILC2), eosinophils, basophils, and mast cells and also stimulate dendritic cells to drive the commitment of naïve T helper (Th) cells towards the Th2 immunophenotype. Therefore, TSLP, IL-33, and IL-25 represent suitable targets for add-on therapies of severe asthma. Within this context, the fully human anti-TSLP monoclonal antibody tezepelumab has been evaluated in very promising randomized clinical trials. Tezepelumab and other anti-alarmins are thus likely to become, in the near future, valuable therapeutic options for the biological treatment of uncontrolled severe asthma.

Predictors of Renal Function Worsening in Patients with Chronic Obstructive Pulmonary Disease (COPD): A Multicenter Observational Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients have multiple comorbidities which may affect renal function. Chronic kidney disease (CKD) is a risk factor for adverse outcomes in COPD patients. The predictors of CKD in COPD are not well investigated. METHODS: A multicenter observational cohort study including patients affected by COPD (GOLD stages 1 and 2) was carried out. Principal endpoints were the incidence of CKD, as defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, and the rapid decline of eGFR >5 mL/min/1.73 m2/year. RESULTS: We enrolled 707 outpatients. Overall, 157 (22.2%) patients had CKD at baseline. Patients with CKD were older, with higher serum uric acid (UA) levels, and lower FEV1. During a mean follow-up of 52.3 ± 30.2 months, 100 patients developed CKD, and 200 patients showed a rapid reduction of eGFR. Multivariable Cox regression analysis displayed that UA (hazard ratio (HR) 1.148, p < 0.0001) and diabetes (HR 1.050, p < 0.0001) were predictors of incident CKD. The independent predictors of rapidly declining renal function were represented by an increase of 1 mg/dL in UA (odds ratio (OR) 2.158, p < 0.0001)), an increase of 10 mL/min/1.73 m2 in baseline eGFR (OR 1.054, p < 0.0001) and the presence of diabetes (OR 1.100, p < 0.009). CONCLUSIONS: This study shows that COPD patients have a significant worsening of renal function over time and that UA and diabetes were the two strongest predictors. Optimal management of these risk factors may reduce the incidence of CKD in this population thus probably improving clinical outcome.

Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma.

Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and efficacy profile in patients with severe, uncontrolled asthma.