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The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (28 September 2021) | Viewed by 32035

Special Issue Editors

Prof. Dr. Nicola Scichilone

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Guest Editor
Department of Pulmonology, AOUP Policlinico Paolo Giaccone, University of Palermo, Palermo, Italy
Interests: asthma; chronic obstructive pulmonary disease
Special Issues, Collections and Topics in MDPI journals
Dr. Alida Benfante

E-Mail
Guest Editor
Department of Promoting Health, Maternal-Infant, Excellence and Internal and Specialized Medicine (Promise) G. D’Alessandro, University of Palermo, 90133 Palermo, Italy
Interests: severe asthma; phenotypes; biologic therapies; pathophysiological mechanisms; interstitial lung disease; pulmonary fibrosis

Special Issue Information

Dear Colleagues,

Severe asthma is an emerging topic in respiratory diseases, due to its high impact on morbidity and mortality as well as on healthcare resources. Many challenges still exist in the management of the most difficult-to-treat forms of the disease. The introduction of biologic drugs has led to a new era in the management of severe asthma. This Special Issue on “Factors Predicting the Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma” represents an opportunity to gather experts in the field with the goal to summarize current understanding about precision medicine in severe asthma, and to identify gaps in knowledge and research opportunities in the area of biologic drugs. This Special Issue will accept original as well as review articles on the functional, biological or clinical factors contributing to predict the response to treatment in severe asthma and to explore the mechanisms of resistance to biological drugs, contributing to identify factors limiting the response to pharmacological agents.

Dr. Nicola Scichilone
Dr. Alida Benfante
Guest Editors

Manuscript Submission Information

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Keywords

  • severe asthma
  • precision medicine
  • biologic drug
  • mechanism of action
  • asthma treatment
  • asthma control

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Published Papers (6 papers)

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Research

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9 pages, 1017 KiB  
Article
Changes in Serum MicroRNAs after Anti-IL-5 Biological Treatment of Severe Asthma
by Manuel J. Rial, José A. Cañas, José M. Rodrigo-Muñoz, Marcela Valverde-Monge, Beatriz Sastre, Joaquín Sastre and Victoria del Pozo
Int. J. Mol. Sci. 2021, 22(7), 3558; https://doi.org/10.3390/ijms22073558 - 30 Mar 2021
Cited by 18 | Viewed by 3079
Abstract
There is currently enough evidence to think that miRNAs play a role in several key points in asthma, including diagnosis, severity of the disease, and response to treatment. Cells release different types of lipid double-membrane vesicles into the extracellular microenvironment, including exosomes, which [...] Read more.
There is currently enough evidence to think that miRNAs play a role in several key points in asthma, including diagnosis, severity of the disease, and response to treatment. Cells release different types of lipid double-membrane vesicles into the extracellular microenvironment, including exosomes, which function as very important elements in intercellular communication. They are capable of distributing genetic material, mRNA, mitochondrial DNA, and microRNAs (miRNAs). Serum miRNA screening was performed in order to analyze possible changes in serum miRNAs in 10 patients treated with reslizumab and 6 patients with mepolizumab after 8 weeks of treatment. The expression of miR-338-3p was altered after treatment (p < 0.05), although no significant differences between reslizumab and mepolizumab were found. Bioinformatic analysis showed that miR-338-3p regulates important pathways in asthma, such as the MAPK and TGF-β signaling pathways and the biosynthesis/degradation of glucans (p < 0.05). However, it did not correlate with an improvement in lung function. MiRNA-338-3p could be used as a biomarker of early response to reslizumab and mepolizumab in severe eosinophilic asthmatic patients. In fact, this miRNA could be involved in airway remodeling, targeting genes related to MAPK and TGF-β signaling pathways. Full article
(This article belongs to the Special Issue The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma)
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Review

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23 pages, 6418 KiB  
Review
Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence
by Luigino Calzetta, Marina Aiello, Annalisa Frizzelli, Giuseppina Bertorelli, Paola Rogliani and Alfredo Chetta
Int. J. Mol. Sci. 2021, 22(13), 7132; https://doi.org/10.3390/ijms22137132 - 1 Jul 2021
Cited by 13 | Viewed by 4634
Abstract
Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the [...] Read more.
Airway inflammation represents an important characteristic in asthma, modulating airflow limitation and symptom control, and triggering the risk of asthma exacerbation. Thus, although corticosteroids represent the cornerstone for the treatment of asthma, severe patients may be dependent on oral corticosteroids (OCSs). Fortunately, the current humanised monoclonal antibodies (mAbs) benralizumab, dupilumab, mepolizumab, omalizumab, and reslizumab have been proven to induce an OCS-sparing effect in randomized controlled trials (RCTs), thus overcoming the problem of OCS dependence in severe asthma. Nevertheless, a large discrepancy has been recognized between selected patients enrolled in RCTs and non-selected asthmatic populations in real-world settings. It is not possible to exclude that the OCS-sparing effect of mAbs resulting from the RCTs could be different than the real effect resulting in clinical practice. Therefore, we performed a systematic review and correlation analysis to assess whether mAbs are effective in eliciting an OCS-sparing effect and overcoming the OCS dependence in severe asthmatic patients in real-world settings. Overall, real-world studies support the evidence that OCS dependence is a real condition that, however, can be found only in a small number of really severe asthmatic patients. In most patients, the dependence on OCS can be related to modifying factors that, when adequately modulated, may lead to a significant reduction or suspension of OCS maintenance. Conversely, in severe asthmatics in whom OCS resistance is proved by a high daily dose intake, mAbs allow reversion of the OCS dependence, leading to the suspension of OCS therapy in most patients or >50% reduction in the daily OCS dose. Full article
(This article belongs to the Special Issue The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma)
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13 pages, 2178 KiB  
Review
Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma
by Corrado Pelaia, Giulia Pelaia, Claudia Crimi, Angelantonio Maglio, Luca Gallelli, Rosa Terracciano and Alessandro Vatrella
Int. J. Mol. Sci. 2021, 22(9), 4369; https://doi.org/10.3390/ijms22094369 - 22 Apr 2021
Cited by 48 | Viewed by 12133
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma)
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10 pages, 593 KiB  
Review
Genetic Determinants of Poor Response to Treatment in Severe Asthma
by Ricardo G. Figueiredo, Ryan S. Costa, Camila A. Figueiredo and Alvaro A. Cruz
Int. J. Mol. Sci. 2021, 22(8), 4251; https://doi.org/10.3390/ijms22084251 - 20 Apr 2021
Cited by 10 | Viewed by 3348
Abstract
Severe asthma is a multifactorial disorder with marked phenotypic heterogeneity and complex interactions between genetics and environmental risk factors, which could, at least in part, explain why during standard pharmacologic treatment, many patients remain poorly controlled and at an increased risk of airway [...] Read more.
Severe asthma is a multifactorial disorder with marked phenotypic heterogeneity and complex interactions between genetics and environmental risk factors, which could, at least in part, explain why during standard pharmacologic treatment, many patients remain poorly controlled and at an increased risk of airway remodeling and disease progression. The concept of “precision medicine” to better suit individual unique needs is an emerging trend in the management of chronic respiratory diseases. Over the past few years, Genome-Wide Association Studies (GWAS) have revealed novel pharmacogenetic variants related to responses to inhaled corticosteroids and the clinical efficacy of bronchodilators. Optimal clinical response to treatment may vary between racial/ethnic groups or individuals due to genetic differences. It is also plausible to assume that epigenetic factors play a key role in the modulation of gene expression patterns and inflammatory cytokines. Remarkably, specific genetic variants related to treatment effectiveness may indicate promising pathways for novel therapies in severe asthma. In this review, we provide a concise update of genetic determinants of poor response to treatment in severe asthma and future directions in the field. Full article
(This article belongs to the Special Issue The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma)
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12 pages, 267 KiB  
Review
Treatment Challenges in Severe Eosinophilic Asthma: Differential Response to Anti-IL-5 and Anti-IL-5R Therapy
by Agamemnon Bakakos, Nikoleta Rovina and Petros Bakakos
Int. J. Mol. Sci. 2021, 22(8), 3969; https://doi.org/10.3390/ijms22083969 - 12 Apr 2021
Cited by 20 | Viewed by 3957
Abstract
Severe asthma greatly affects patients’ quality of life. Major advances have occurred in the management of severe eosinophilic asthma the past few years due to the new targeted biological therapies. There are three anti-IL-5 mAbs, mepolizumab, reslizumab and benralizumab. Despite the different mechanism [...] Read more.
Severe asthma greatly affects patients’ quality of life. Major advances have occurred in the management of severe eosinophilic asthma the past few years due to the new targeted biological therapies. There are three anti-IL-5 mAbs, mepolizumab, reslizumab and benralizumab. Despite the different mechanism of blocking IL-5 the clinical effects are quite similar as randomized controlled trials and real-life studies have shown. Moreover, there are reports of responding to one after failing to respond to another anti-IL-5 therapy. Accordingly, it is challenging to explore the possible differences in the response to anti-IL-5 treatments. This might help us not only understand possible mechanisms that contribute to the resistance to treatment in this particular asthma endotype, but also to phenotype within severe eosinophilic asthma in order to treat our patients more efficiently. Full article
(This article belongs to the Special Issue The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma)

Other

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11 pages, 2963 KiB  
Case Report
IL13 May Play an Important Role in Developing Eosinophilic Chronic Rhinosinusitis and Eosinophilic Otitis Media with Severe Asthma
by Hideyasu Shimizu, Masamichi Hayashi, Hisayuki Kato, Mitsuru Nakagawa, Kazuyoshi Imaizumi and Mitsushi Okazawa
Int. J. Mol. Sci. 2021, 22(20), 11209; https://doi.org/10.3390/ijms222011209 - 18 Oct 2021
Cited by 9 | Viewed by 4037
Abstract
A woman in her 50s was a super responder to benralizumab administered for the treatment of severe bronchial asthma (BA) with eosinophilic chronic rhinosinusitis with nasal polyp (ECRS) and eosinophilic otitis media (EOM). She exhibited the gradual exacerbation of ECRS/EOM despite good control [...] Read more.
A woman in her 50s was a super responder to benralizumab administered for the treatment of severe bronchial asthma (BA) with eosinophilic chronic rhinosinusitis with nasal polyp (ECRS) and eosinophilic otitis media (EOM). She exhibited the gradual exacerbation of ECRS/EOM despite good control of BA approximately 1 year after benralizumab initiation. Therefore, the treatment was switched to dupilumab, and the condition of the paranasal sinuses and middle ear greatly improved with the best control of her asthma. The patient reported that her physical condition was the best of her life. However, she developed a pulmonary opacity on chest computed tomography after 6 months. Histological examination of the lung parenchyma and cell differentiation of the bronchoalveolar lavage fluid indicated atypical chronic eosinophilic pneumonia, and treatment was switched to mepolizumab. Similarly to the period of benralizumab treatment, exacerbation of ECRS/EOM reduced her quality of life approximately 10 months after the administration of mepolizumab. Dupilumab was again introduced as a replacement for mepolizumab. The clinical course and consideration of the interaction between inflammatory cells led us to speculate that interleukin-13 could play a key role in the development of ECRS/EOM with severe BA. Full article
(This article belongs to the Special Issue The Response to Drugs and Mechanisms of Resistance to Treatment in Severe Asthma)
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