scholarly journals The dark side of the moon: severe therapy-resistant asthma in children

2015 ◽  
Vol 77 (2) ◽  
Author(s):  
F.M. De Benedictis ◽  
I. Carloni ◽  
A. Bush
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Therapeutic Option ◽  
Treatment Plan ◽  
Dark Side ◽  
High Dose ◽  
Adherence To Treatment ◽  
Pediatric Diseases ◽  
International Collaborations ◽  
Evidence Based Treatments

Problematic severe asthma is the term used to describe children whose asthma is not responsive to standard therapy with high-dose inhaled corticosteroids and additional controllers. These children need to be assessed by a step-wise systematic protocol in order to confirm the diagnosis, evaluate co-morbidities, assess the adherence to treatment, and finally evaluate the basic management. More than half of these children have “difficult-to-treat asthma”, which improves if the basic management is correct. Children whose asthma remains uncontrolled despite resolution of any reversible factors are termed “severe therapy-resistant” asthmatics; for them, an individualised treatment plan is developed after a detailed and invasive protocol of investigation. Therapeutic options for these patients can be divided into medications used in lower doses for children with less severe asthma, and those used in other pediatric diseases but not for asthma. Most treatments are unlicensed and there is a lack of high-quality evidence. Children with recurrent severe exacerbations, in particular in the context of good baseline asthma control, are particularly difficult to treat, and there is no evidence on which therapeutic option to recommend. International collaborations, using standard protocols of investigation, are needed to better understand mechanisms of severe therapy-resistant asthma and to deliver evidence-based treatments in the future.

Diagnosis and Management of Severe Asthma

2018 ◽  
Vol 39 (01) ◽  
pp. 091-099 ◽  
Author(s):  
Kian Fan Chung
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Immunoglobulin E ◽  
High Dose ◽  
Blood Eosinophil ◽  
Exhaled Breath ◽  
Eosinophilic Asthma ◽  
Severe Eosinophilic Asthma ◽  
Asthma Patients ◽  
Long Acting

AbstractSevere therapy-resistant asthma has been defined as “asthma which requires treatment with high dose inhaled corticosteroids (ICSs) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy”. Patients who usually present with ‘difficult-to-treat asthma’ should first be assessed to determine whether he/she has asthma with the exclusion of other diagnoses and if so, whether the asthma can be classified as severe therapy-resistant. This necessitates an assessment of adherence to medications, confounding factors, and comorbidities. Increasingly, management of severe therapy-resistant asthma will be helped by the determination of phenotypes to optimize responses to existing and new therapies. Severe asthma patients are usually on a combination of high dose ICS and long-acting β-agonist (LABA) and, in addition, are often on a maintenance dose of oral corticosteroids. Phenotyping can be informed by measuring blood eosinophil counts and the level of nitric oxide in exhaled breath, and the use of sputum granulocytic counts. Severe allergic asthma and severe eosinophilic asthma are two defined phenotypes for which there are efficacious targeted biologic therapies currently available, namely anti-immunoglobulin E (IgE) and anti-interleukin (IL)-5 antibodies, respectively. Further progress will be realized with the definition of noneosinophilic or non-T2 phenotypes. It will be important for patients with severe asthma to be ultimately investigated and managed in specialized severe asthma centers.

scholarly journals Stereotactic Radiosurgery Associated Neurotoxicity

2003 ◽  
Vol 2 (2) ◽  
pp. 147-151 ◽  
Author(s):  
William H. St. Clair ◽  
Curtis A. Given
Keyword(s):  
Stereotactic Radiosurgery ◽  
Therapeutic Option ◽  
Treatment Plan ◽  
Three Dimensional ◽  
Reference Points ◽  
Therapeutic Modality ◽  
High Dose ◽  
Lesion Volume ◽  
Three Dimensional Mapping ◽  
Effective Therapeutic Option

Stereotactic radiosurgery (SRS) is an evolving therapeutic modality for well demarcated intracranial lesions. Since the inception of stereotactic radiosurgery the types of parenchymal CNS lesions addressed by this mode of treatment has increased. All modern stereotactic radiosurgical procedures employ several common features. Patients are fitted with a stereotactic head frame or fiducial markers followed by radiographic imaging which allows for external reference points and three-dimensional mapping of the intracranial lesion. Armed with this information a highly conformal treatment plan is developed to deliver a high dose of radiation to a sharply defined target, with rapid dose fall-off outside the lesion volume. While an extremely effective therapeutic option, SRS is not without risk of neurotoxicity, with radiation necrosis being the most commonly recognized complication. The neurotoxic effects of SRS are reviewed and discussed.

scholarly journals Eosinophils Target Therapy for Severe Asthma: Critical Points

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
L. Brussino ◽  
E. Heffler ◽  
C. Bucca ◽  
S. Nicola ◽  
G. Rolla
Keyword(s):  
Severe Asthma ◽  
Eosinophil Count ◽  
Inhaled Corticosteroids ◽  
Response To Treatment ◽  
High Dose ◽  
Blood Eosinophil ◽  
Moderate Increase ◽  
Eosinophilic Asthma ◽  
Peripheral Blood Eosinophil ◽  
Blood Eosinophil Count

Asthma is a chronic and heterogeneous disease, which is defined as severe disease whenever it requires treatment with a high dose of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming ‘‘uncontrolled’’ or if it remains ‘‘uncontrolled’’ despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma, which is characterized by sputum eosinophilia, associated with mild to moderate increase in blood eosinophil count, frequently adult-onset, and associated with chronic rhinosinusitis with nasal polyps in half of the cases. Eosinophilic asthma is driven by T2 inflammation, characterized, among the others, by interleukin-5 production. IL-5 plays a key role in the differentiation, survival, migration, and activation of eosinophils, and it has become an appealing therapeutic target for eosinophilic asthma. In recent years two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5 and one monoclonal antibody directed against the alpha-subunit of the IL-5 receptor (benralizumab) have been developed. All these IL-5 target drugs have been shown to reduce the number of exacerbation in patients with severe asthma selected on the basis of peripheral blood eosinophil count. There are still a number of unresolved issues related to the anti-IL5 strategy in eosinophilic asthma, which are here reviewed. These issues include the effects of such therapy on airway obstruction and asthmatic symptoms, the level of baseline eosinophils that predicts a response to treatment, the relationship between blood and airway eosinophilia, and, perhaps most importantly, how to elucidate the pathogenetic role played by eosinophils in the individual patient with severe eosinophilic asthma.

scholarly journals Identification of Druggable Genes for Asthma by Integrated Genomic Network Analysis

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 113
Author(s):  
Wirawan Adikusuma ◽  
Wan-Hsuan Chou ◽  
Min-Rou Lin ◽  
Jafit Ting ◽  
Lalu Muhammad Irham ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Target Genes ◽  
Inhaled Corticosteroids ◽  
Association Studies ◽  
Therapeutic Option ◽  
Drug Repurposing ◽  
Genome Wide Association Studies ◽  
Biological Drugs ◽  
Risk Genes ◽  
Asthma Risk

Asthma is a common and heterogeneous disease characterized by chronic airway inflammation. Currently, the two main types of asthma medicines are inhaled corticosteroids and long-acting β2-adrenoceptor agonists (LABAs). In addition, biological drugs provide another therapeutic option, especially for patients with severe asthma. However, these drugs were less effective in preventing severe asthma exacerbation, and other drug options are still limited. Herein, we extracted asthma-associated single nucleotide polymorphisms (SNPs) from the genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) catalog and prioritized candidate genes through five functional annotations. Genes enriched in more than two categories were defined as “biological asthma risk genes.” Then, DrugBank was used to match target genes with FDA-approved medications and identify candidate drugs for asthma. We discovered 139 biological asthma risk genes and identified 64 drugs targeting 22 of these genes. Seven of them were approved for asthma, including reslizumab, mepolizumab, theophylline, dyphylline, aminophylline, oxtriphylline, and enprofylline. We also found 17 drugs with clinical or preclinical evidence in treating asthma. In addition, eleven of the 40 candidate drugs were further identified as promising asthma therapy. Noteworthy, IL6R is considered a target for asthma drug repurposing based on its high target scores. Through in silico drug repurposing approach, we identified sarilumab and satralizumab as the most promising drug for asthma treatment.

scholarly journals Problematic, severe asthma in children: a new concept and how to manage it

2010 ◽  
Vol 17 (1-2) ◽  
pp. 51-64
Author(s):  
Andrew BUSH
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Treatment Plan ◽  
Airflow Limitation ◽  
Steroid Resistance ◽  
Single Intramuscular Injection ◽  
Children With Asthma ◽  
Oral Corticosteroids ◽  
The Stability ◽  
Future Work

Most children with asthma respond to low doses of inhaled corticosteroids, but a few remain symptomatic despite being prescribed the routine usual asthma medications. The first steps are to ensure that the diagnosis is correct and that the inhaled medications are being given regularly with an appropriately used device. If the children continue to be symptomatic, with any or all of chronic symptoms, acute exacerbations, the need for regular oral corticosteroids, or persistent airflow limitation, then they are considered to have problematic, severe asthma. The next step is to perform a detailed evaluation, including a nurse-lead home visit, to determine whether the child has difficult to treat asthma which improves if the basics are got right, or severe, therapy-resistant asthma; the latter group would be candidates for cytokine-specific therapies. If severe, therapy-resistant asthma is the likely issue, then a detailed invasive investigation is performed, including bronchoscopy, bronchoalveolar lavage and endobronchial biopsy, and trial of adherence with a single intramuscular injection of depot triamcinolone. After detailed phenotyping, an individualised treatment plan is determined. Future work will determine the roles of proximal and distal inflammation, as well as the relative importance of intramural (mucosal) and intraluminal infection. The stability of paediatric asthma phenotypes over time is more variable than those of adults, and the implications of a change of phenotype are yet to be determined. Keywords: steroid resistance, allergen exposure, passive smoking, omalizumab, prednisolone, steroid-sparing agent, phenotype, nitric oxide, induced sputum, endobronchial biopsy

scholarly journals The Role of Omalizumab in the Treatment of Severe Allergic Asthma

2006 ◽  
Vol 13 (suppl b) ◽  
pp. 1B-9B ◽  
Author(s):  
Kenneth R Chapman ◽  
Andre Cartier ◽  
Jacques Hébert ◽  
R Andrew McIvor ◽  
R Robert Schellenberg
Keyword(s):  
Severe Asthma ◽  
Adjunctive Therapy ◽  
Conventional Therapy ◽  
Inhaled Corticosteroids ◽  
Immunoglobulin E ◽  
Severe Disease ◽  
Phase Iii ◽  
High Dose ◽  
Two Phase ◽  
Long Acting

BACKGROUND: A novel anti-immunoglobulin E (anti-IgE) therapy for asthma, omalizumab, has been approved for use in Canada.OBJECTIVE: To review the basic and clinical data for omalizumab, and to examine its possible role for asthma management in Canada.METHODS: A literature search from 1960 to 2006 was conducted in MEDLINE to identify studies of omalizumab. In addition, abstracts from recent respiratory and allergy scientific meetings were sought, and any unpublished data were requested from the manufacturer. A consensus panel of respiratory and allergy specialists reviewed and summarized the data, and derived a set of recommendations for omalizumab use.RESULTS: Omalizumab is a humanized monoclonal antibody designed to bind to the C epsilon 3 domain of the IgE molecule, forming soluble immune complexes that are cleared by the reticuloendothelial system. Subcutaneous injections, given at two- or fourweek intervals at the recommended dose, result in a rapid decrease in free circulating IgE levels. In two phase III clinical trials of 1405 adult and adolescent patients with moderate to severe asthma maintained on moderate doses of inhaled corticosteroids (ICS), omalizumab reduced exacerbation rates compared with placebo, and was associated with improved symptoms and a greater corticosteroid-sparing effect. In a trial of 419 patients with severe disease that was uncontrolled despite the use of high-dose ICS and concurrent long-acting beta2-agonists, severe exacerbations were 50% less frequent in omalizumabtreated patients than in control subjects. Retrospective analyses have identified the characteristics of patients most likely to respond to omalizumab treatment.RECOMMENDATIONS: Omalizumab may be considered as a potential adjunctive therapy in atopic patients with severe asthma uncontrolled by conventional therapy with optimal doses of ICS and appropriate adjunctive therapy (eg, long-acting beta2-agonists). Typically, patients are identified by the need for frequent short course or continuous oral corticosteroids. Therapy should be initiated only after review by a specialist to confirm the diagnosis and that conventional therapy is optimal.

scholarly journals Bronchial Thermoplasty in the Treatment of Severe Asthma

2020 ◽  
pp. 1-9
Author(s):  
Nightingale Syabbalo ◽  
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Airway Disease ◽  
Airflow Limitation ◽  
Response To Treatment ◽  
High Dose ◽  
Eosinophilic Asthma ◽  
Bronchial Thermoplasty ◽  
Long Acting ◽  
Refractory Asthma

Asthma is a chronic inflammatory airway disease with several distinct phenotypes, characterized by different immunopathological pathways, clinical presentation, severity of the disease, and response to treatment. The phenotypes of asthma include eosinophilic, neutrophilic, mixed granulocytic, and paucigranulocytic asthma. Approximately 3.6-10% of patients with asthma have severe refractory disease, which is unresponsive to high dose inhaled corticosteroids (ICS), and long-acting β2-agonists (LABA). Most patients with eosinophilic asthma are responsive to corticosteroids, and interleukintargeted biologics, whereas, patients from other phenotypes, such as neutrophillic and paucigranullocytic asthma are resistant to treatment with ICS and biotherapeutics. The hallmark of severe refractory asthma is airway hyperresponsiveness, and remodeling. Histopathologically, patients with severe asthma have airway smooth muscle (ASM) hyperplasia and hypertrophy; subepithelial basement membrane thickening and fibrosis; all which contribute to fixed airflow limitation. Severe refractory asthma is very difficult to treat pharmacologically. It requires innovative therapies, such as bronchial thermoplasty which reduces the hypertrophied ASM mass and relieves the AHR, and broncoconstriction. Bronchial thermoplasty has been shown to improve asthma control, reduce severe exacerbations, hospitalizations, emergency room visits, and improve the quality of life, which persist up to 5 years following the procedure

SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis

2020 ◽  
Vol 56 (3) ◽  
pp. 2000625 ◽  
Author(s):  
Paola Rogliani ◽  
Beatrice Ludovica Ritondo ◽  
Josuel Ora ◽  
Mario Cazzola ◽  
Luigino Calzetta
Keyword(s):  
Severe Asthma ◽  
Treatment Option ◽  
Low Dose ◽  
Therapeutic Option ◽  
Meta Analysis ◽  
Specific Treatment ◽  
High Dose ◽  
Asthmatic Patients ◽  
The Impact ◽  
Medium Dose

To date, there are no network meta-analyses comparing the impact of as-needed treatments in asthma, including the single maintenance and reliever therapy (known as “SMART” or “MART”; for simplicity, SMART will be used hereafter) and the use of inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) combination exclusively on an as-needed basis. Therefore, we performed a systematic review and network meta-analysis concerning the efficacy and safety of SMART and as-needed therapies in asthma. Data from 32 096 asthmatic patients were extracted from 21 studies, lasting from 6 to 12 months. In adult mild-to-moderate asthmatic patients low-dose SMART and as-needed low-dose ICS/LABA combination were significantly (relative effect <0.78; p<0.05) more effective than the other as-needed therapies in reducing the risk of exacerbation, and both were ranked as the first treatment option reaching the first quartile of the surface under the cumulative ranking curve analysis (SUCRA). In adult moderate-to-severe asthmatic patients, low-dose to medium-dose SMART and high-dose ICS/LABA+as-needed short-acting β2-agonist were equally effective in reducing the risk of severe asthma exacerbation (p>0.05), although only low- to medium-dose SMART was ranked as the first treatment option (first SUCRA quartile). Overall, these treatments were well tolerated, and effective also on lung function and disease control. This study supports SMART and as-needed therapies as a suitable therapeutic option for asthma, by providing the most effective positioning of each specific treatment according to the disease severity.

Dual biologic therapy in a patient with severe asthma and other allergic disorders

2021 ◽  
Vol 14 (5) ◽  
pp. e242211
Author(s):  
Joshua Ray Caskey ◽  
David Kaufman
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Chronic Idiopathic Urticaria ◽  
High Dose ◽  
Dramatic Improvement ◽  
Eosinophilic Asthma ◽  
Severe Eosinophilic Asthma ◽  
Systemic Corticosteroids ◽  
Acute Exacerbations ◽  
H1 Antihistamines

Severe asthma is very difficult to manage in many individuals, and systemic corticosteroids are often used to prevent or manage acute exacerbations. Furthermore, comorbid allergic conditions may render standard therapies inadequate. A 51-year-old man presented with severe eosinophilic asthma requiring nearly constant oral corticosteroid usage despite using high-dose inhaled corticosteroids and secondary asthma controllers. His condition was complicated by aspirin-exacerbated respiratory disease, including severe nasal polyposis, chronic rhinosinusitis, as well as chronic idiopathic urticaria. Mepolizumab was initiated and led to dramatic improvement of asthma over 6 months. However, he continued to experience exacerbations of chronic idiopathic urticaria not responsive to H1-antihistamines. Omalizumab was added, and the patient’s urticaria attained marked improvement with only an occasional breakthrough rash. Dual biologic therapies can be a unique and useful steroid-sparing treatment option for patients with uncontrolled severe asthma and chronic idiopathic urticaria.

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