Severe Therapy-resistant Asthma In Children Research Articles

Reducing the burden of asthma: time to set research and clinical priorities

There is a substantial global burden of asthma in terms of prevalence, morbidity, mortality, and cost. It has been estimated that there are over 300 million people with asthma worldwide, most of whom do not have well controlled symptoms. Long-term trends in country-specific asthma mortality have been dominated by the effects of treatments, with β-adrenoceptor agonist-related increases in mortality in the 1960s and 1980s, and a progressive reduction in mortality from the 1990s into the 21st century attributed to the widespread use of inhaled corticosteroids (ICS). 1 Pavord ID Beasley R Agusti A et al. After asthma: redefining airways diseases. Lancet. 2018; 391: 350-400 Summary Full Text Full Text PDF PubMed Scopus (589) Google Scholar Although the asthma mortality rate has continued to fall in some countries and regions, the estimated global mortality rate has not changed appreciably since 2006. 2 Ebmeier S Thayabaran D Braithwaite I Bénamara C Weatherall M Beasley R Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993–2012). Lancet. 2017; 390: 935-945 Summary Full Text Full Text PDF PubMed Scopus (169) Google Scholar This absence of change suggests that the progress made in the previous 2 decades might have stalled, and that better implementation of proven current management strategies, together with novel approaches, are required to achieve further reductions in mortality and, more generally, the burden of asthma. The genetics of asthma and the promise of genomics-guided drug target discoveryAsthma is an inflammatory airway disease that is estimated to affect 339 million people globally. The symptoms of about 5–10% of patients with asthma are not adequately controlled with current therapy, and little success has been achieved in developing drugs that target the underlying mechanisms of asthma rather than suppressing symptoms. Over the past 3 years, well powered genetic studies of asthma have increased the number of independent asthma-associated genetic loci to 128. In this Series paper, we describe the immense progress in asthma genetics over the past 13 years and link asthma genetic variants to possible drug targets. Full-Text PDF Advances in understanding and reducing the burden of severe asthma in childrenSevere asthma in children is rare, accounting for only a small proportion of childhood asthma. After addressing modifiable factors such as adherence to treatment, comorbidities, and adverse exposures, children whose disease is not well controlled on high doses of medication form a heterogeneous group of severe asthma phenotypes. Over the past decade, considerable advances have been made in understanding the pathophysiology of severe therapy-resistant asthma in children. However, asthma attacks and hospital admissions are frequent and mortality is still unacceptably high. Full-Text PDF Primary prevention of asthma: from risk and protective factors to targeted strategies for preventionAsthma is a complex disease that often starts in childhood. Genomic and environmental factors as well as aberrant immune maturation early in life can contribute to the onset of disease, with great disparity over time and geographical regions. Epidemiological studies have scrutinised environmental exposures and attempted to translate these exposures into prevention strategies. Some approaches for patients with asthma have been successful (eg, smoking ban, the Finnish Asthma Programme), and primary prevention of wheeze in pre-school children (age 0–5 years) by the supplementation of vitamin D or fish oil, or both, to pregnant women seems promising. Full-Text PDF

Does allergy explain why some children have severe asthma?

Asthma is a common disease in childhood with a minority of affected children having severe therapy-resistant asthma (STRA). Children with STRA can be differentiated from those with mild-moderate disease by greater allergic sensitization, increased eosinophilic airway inflammation, increased airway remodelling and reduced corticosteroid responsiveness. The aetiology of STRA in children is multifactorial but allergy seems to play a key role. Many children with asthma have coexisting allergic disease, and severe rhinitis seems to be an important driver of STRA in children. Allergies to foods, moulds, pollen and pets have also been associated with severe asthma exacerbations. Identifying allergens that are driving asthma symptoms in children with STRA may provide additional strategies for improving their disease control. Avoidance strategies may be possible. Additional monoclonal antibody therapy with Omalizumab or Mepolizumab may be helpful in children with clinically important polysensitization.

Can inflammatory markers in induced sputum be used to detect phenotypes and endotypes of pediatric severe therapy-resistant asthma?

The phenotypes and endotypes of severe therapy-resistant asthma (STRA) have not been fully elucidated in children. The aim of the present study was to investigate inflammatory markers in the induced sputum of children with STRA and to compare them with those present in a group of children who achieved control. A prospective cohort of children (6-18 years of age) diagnosed with severe asthma (GINA criteria) who had undergone treatment for at least 6 months was comprehensively followed for 3 months. Inhalation technique, adherence to treatment, ACT score, and main comorbidities were assessed. Induced sputum samples were collected for cytology analysis and quantitative assessment of cytokines; the participants also underwent spirometry, plethysmography, and fractional exhaled nitric oxide (FeNO) measurement. Forty patients were included (average age 12.8 years; 62.5% male); of these, 13 (32.5%) were classified as STRA at the end of follow-up. There were no significant differences between the STRA and control groups in demographic data, functional test results, or FeNO levels. The eosinophilic inflammatory pattern predominated in both groups; however, the STRA group showed a proportionally higher percentage of sputum neutrophils (P < 0.05). The median sputum levels of the cytokines IL-10, GM-CSF, IFN-γ, and TNF-α were significantly higher in the STRA group (P < 0.05). GM-CSF and TNF-α levels showed inverse correlations with ACT scores. The presence of neutrophils, the cytokines IL-10, and IFN-γ and, more particularly, TNF-α, and GM-CSF in the sputum may play an important role in the pathophysiological mechanism of STRA in children and adolescents. Specific antagonists for these cytokines may represent a future therapeutic strategy.

INKT cells are increased in children with severe therapy-resistant asthma

BackgroundInvariant natural killer T (iNKT) cells play complex functions in the immune system, releasing both Th1 and Th2 cytokines. The role of iNKT cells in human asthma is still controversial and never described in severe therapy-resistant asthma in children. The objective of this work was to analyse iNKT frequency in peripheral blood of children with severe therapy-resistant asthma (STRA), compared to children with milder asthma and healthy controls. MethodsChildren with asthma (n=136) (non-severe and STRA) from a referral centre and healthy controls (n=40) were recruited. Peripheral blood mononuclear cells were isolated, stained with anti-CD3 and anti-iNKT (Vα24Jα18), and analysed through flow cytometry. Atopic status was defined by measuring specific IgE in serum. Airway inflammation was assessed by induced sputum. ResultsChildren with asthma presented an increased frequency of CD3+iNKT+ cells (median 0.38% IQR 0.18–1.9), compared to healthy controls (median 0.26% IQR 0.10–0.43) (p=0.025). Children with STRA also showed an increased frequency of iNKT cells (1.5% IQR 1.05–2.73) compared to healthy controls and non-severe asthmatic children (0.35% IQR 0.15–1.6; p=0.002). The frequency of iNKT cells was not different between atopic and non-atopic children. In addition, iNKT cells were not associated with any inflammatory pattern of induced sputum studied. ConclusionOur data suggests that iNKT cells play a role in paediatric asthma, which is also associated with the severity of disease, but independent of the atopic status.

Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies.

Although a rare disease, severe therapy-resistant asthma in children is a cause of significant morbidity and results in utilization of approximately 50% of health-care resources for asthma. Improving control for children with severe asthma is, therefore, an urgent unmet clinical need. As a group, children with severe asthma have severe and multiple allergies, steroid resistant airway eosinophilia, and significant structural changes of the airway wall (airway remodeling). Omalizumab is currently the only add-on therapy that is licensed for use in children with severe asthma. However, limitations of its use include ineligibility for approximately one-third of patients because of serum IgE levels outside the recommended range and lack of clinical efficacy in a further one-third. Pediatric severe asthma is thus markedly heterogeneous, but our current understanding of the different mechanisms underpinning various phenotypes is very limited. We know that there are distinctions between the factors that drive pediatric and adult disease since pediatric disease develops in the context of a maturing immune system and during lung growth and development. This review summarizes the current data that give insight into the pathophysiology of pediatric severe asthma and will highlight potential targets for novel therapies. It is apparent that in order to identify novel treatments for pediatric severe asthma, the challenge of undertaking mechanistic studies using age appropriate experimental models and airway samples from children needs to be accepted to allow a targeted approach of personalized medicine to be achieved.

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

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.

Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines

The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood. We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the T(H)2 cytokines IL-4, IL-5, and IL-13. Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen T(H)2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation. Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5(+) and IL-13(+) cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid T(H)2 cytokines had significantly lower lung function than those with undetectable BAL fluid T(H)2 cytokines. STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the T(H)2 mediators that are thought to drive allergic asthma were mostly absent.