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 Pharmacological Rationale for Targeting IL-17 in Asthma

2021 ◽  
Vol 2 ◽  
Author(s):  
Siti Farah Rahmawati ◽  
Maurice te Velde ◽  
Huib A. M. Kerstjens ◽  
Alexander S. S. Dömling ◽  
Matthew Robert Groves ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Current Knowledge ◽  
Experimental Models ◽  
Airflow Limitation ◽  
Interleukin 17 ◽  
Asthma Phenotype ◽  
T Helper 2 ◽  
Bronchial Biopsies

Asthma is a respiratory disease that currently affects around 300 million people worldwide and is defined by coughing, shortness of breath, wheezing, mucus overproduction, chest tightness, and expiratory airflow limitation. Increased levels of interleukin 17 (IL-17) have been observed in sputum, nasal and bronchial biopsies, and serum of patients with asthma compared to healthy controls. Patients with higher levels of IL-17 have a more severe asthma phenotype. Biologics are available for T helper 2 (Th2)-high asthmatics, but the Th17-high subpopulation has a relatively low response to these treatments, rendering it a rather severe asthma phenotype to treat. Several experimental models suggest that targeting the IL-17 pathway may be beneficial in asthma. Moreover, as increased activation of the Th17/IL-17 axis is correlated with reduced inhaled corticosteroids (ICS) sensitivity, targeting the IL-17 pathway might reverse ICS unresponsiveness. In this review, we present and discuss the current knowledge on the role of IL-17 in asthma and its interaction with the Th2 pathway, focusing on the rationale for therapeutic targeting of the IL-17 pathway.

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.

scholarly journals Oral Corticosteroids Dependence and Biologic Drugs in Severe Asthma: Myths or Facts? A Systematic Review of Real-World Evidence

2021 ◽  
Vol 22 (13) ◽  
pp. 7132
Author(s):  
Luigino Calzetta ◽  
Marina Aiello ◽  
Annalisa Frizzelli ◽  
Giuseppina Bertorelli ◽  
Paola Rogliani ◽  
...  
Keyword(s):  
Systematic Review ◽  
Severe Asthma ◽  
Real World ◽  
Symptom Control ◽  
Airflow Limitation ◽  
Biologic Drugs ◽  
Asthmatic Patients ◽  
Severe Asthmatic ◽  
Oral Corticosteroids ◽  
Sparing Effect

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.

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

scholarly journals Dexamethasone-Induced FKBP51 Expression in CD4+ T-Lymphocytes Is Uniquely Associated With Worse Asthma Control in Obese Children With Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Vickram Tejwani ◽  
Amanda McCormack ◽  
Karthik Suresh ◽  
Han Woo ◽  
Ningchun Xu ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Asthma Control ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Inhaled Corticosteroids ◽  
Normal Weight ◽  
Steroid Resistance ◽  
Obese Children ◽  
Ki 67 ◽  
Children With Asthma

IntroductionThere is evidence that obesity, a risk factor for asthma severity and morbidity, has a unique asthma phenotype which is less atopic and less responsive to inhaled corticosteroids (ICS). Peripheral blood mononuclear cells (PBMC) are important to the immunologic pathways of obese asthma and steroid resistance. However, the cellular source associated with steroid resistance has remained elusive. We compared the lymphocyte landscape among obese children with asthma to matched normal weight children with asthma and assessed relationship to asthma control.MethodsHigh-dimensional flow cytometry of PBMC at baseline and after dexamethasone stimulation was performed to characterize lymphocyte subpopulations, T-lymphocyte polarization, proliferation (Ki-67+), and expression of the steroid-responsive protein FK506-binding protein 51 (FKBP51). T-lymphocyte populations were compared between obese and normal-weight participants, and an unbiased, unsupervised clustering analysis was performed. Differentially expressed clusters were compared with asthma control, adjusted for ICS and exhaled nitric oxide.ResultsIn the obese population, there was an increased cluster of CD4+ T-lymphocytes expressing Ki-67 and FKBP51 at baseline and CD4+ T-lymphocytes expressing FKBP51 after dexamethasone stimulation. CD4+ Ki-67 and FKBP51 expression at baseline showed no association with asthma control. Dexamethasone-induced CD4+ FKBP51 expression was associated with worse asthma control in obese participants with asthma. FKBP51 expression in CD8+ T cells and CD19+ B cells did not differ among groups, nor did polarization profiles for Th1, Th2, Th9, or Th17 percentage.DiscussionDexamethasone-induced CD4+ FKBP51 expression is uniquely associated with worse asthma control in obese children with asthma and may underlie the corticosteroid resistance observed in this population.

scholarly journals Effectiveness and Safety of Bronchial Thermoplasty in Severe Asthma in Clinical Practice in Spain

2018 ◽  
Vol 3 (3) ◽  
pp. 1-9 ◽  
Author(s):  
Luis Puente-Maestu ◽  
Milagros Llanos Flores ◽  
Paola Benedetti ◽  
Ingrid Frías Benzant ◽  
Alicia Oliva Ramos ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Asthma Control ◽  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Invasive Procedure ◽  
First Year ◽  
Asthma Control Test ◽  
Bronchial Thermoplasty ◽  
Oral Corticosteroids ◽  
Predominantly Female

Background: Bronchial thermoplasty (BT) is a minimally invasive procedure consisting of application of thermal energy into the airways to produce ablation of the hypertrophic smooth muscle. It was approved for use in moderate-severe asthma in Spain in 2010. Objectives: The aims of the present study are to analyze the effectiveness and the safety of BT in clinical practice in our center. Methods: Participants had a confirmed diagnosis of severe asthma and poor control without therapeutic alternative. Effectiveness was measured by comparing exacerbations, admissions rates, asthma control, and medication 1 year prior and 1 year after BT was completed. All complications appearing during the procedure and in the first year were recorded. Results: Patients had a mean age of 51 (SD 8) years and were predominantly female (17/23). The average number of activations per patient was 147 (16). The number of severe exacerbations was reduced by 75% (p < 0.001). A 38% reduction in admissions per year was also observed (p = 0.03). The Asthma Control Test improved by 7.1 (3.7) points (p = 0.018). Before BT, the dose of inhaled corticosteroids was 1,621 (1,015) µg of budesonide-equivalent and the dose of oral corticosteroids was 15 (13) mg of prednisone-equivalent. There was a reduction in 430 (731) µg of budesonide-equivalent (p = 0.02) and 4 (11) mg of prednisone (p = 0.094). No changes in lung function were observed. Complications were related mostly to exacerbation of asthma in the days following the procedure. Conclusions: BT is effective and safe for severe uncontrolled bronchial asthma in real clinical practice.

scholarly journals Managing problematic severe asthma: beyond the guidelines

2017 ◽  
Vol 103 (4) ◽  
pp. 392-397 ◽  
Author(s):  
Katharine C Pike ◽  
Mark L Levy ◽  
John Moreiras ◽  
Louise Fleming
Keyword(s):  
Young People ◽  
Severe Asthma ◽  
Inhaled Corticosteroids ◽  
Symptom Control ◽  
Asthma Management ◽  
Children And Young People ◽  
Leading Role ◽  
Children With Asthma ◽  
Individualised Care ◽  
New Treatments

This review discusses issues related to managing problematic severe asthma in children and young people. A small minority of children have genuinely severe asthma symptoms which are difficult to control. Children with genuinely severe asthma need investigations and treatments beyond those described within conventional guidelines. However, the majority of children with poor symptom control despite high-intensity treatment achieve improvement in their asthma control once attention has been paid to the basics of asthma management. Basic asthma management requires optimisation of inhaler technique and treatment adherence, avoidance of environmental triggers and self-management education. It is also important that clinicians recognise risk factors that predispose patients to asthma exacerbations and potentially life-threatening attacks. These correctable issues need to be tackled in partnership with children and young people and their families. This requires a coordinated approach between professionals across healthcare settings. Establishing appropriate infrastructure for coordinated asthma care benefits not only those with problematic severe asthma, but also the wider asthma population as similar correctable issues exist for children with asthma of all severities. Investigation and management of genuine severe asthma requires specialist multidisciplinary expertise and a systematic approach to characterising patients’ asthma phenotypes and delivering individualised care. While inhaled corticosteroids continue to play a leading role in asthma therapy, new treatments on the horizon might further support phenotype-specific therapy.

scholarly journals Withdrawal of inhaled corticosteroids versus continuation of triple therapy in patients with COPD in real life: observational comparative effectiveness study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Helgo Magnussen ◽  
◽  
Sarah Lucas ◽  
Therese Lapperre ◽  
Jennifer K. Quint ◽  
...  
Keyword(s):  
Primary Care ◽  
Triple Therapy ◽  
Comparative Effectiveness ◽  
Inhaled Corticosteroids ◽  
Blood Eosinophil ◽  
Research Database ◽  
Effectiveness Study ◽  
Increased Risk ◽  
Comparative Effectiveness Study ◽  
Oral Corticosteroids

Abstract Background Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. Method Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. Results A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94–1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10–1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03–2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL. Conclusions In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).

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