Severe Therapy-resistant Asthma Research Articles

Bioinformatics analysis of ferroptosis-related gene AKR1C3 as a potential biomarker of asthma and its identification in BEAS-2B cells

Ferroptosis is a newly discovered type of cell death and has recently been shown to be associated with asthma. However, the relationship between them at the genetic level has not been elucidated via informatics analysis. In this study, bioinformatics analyses are conducted using asthma and ferroptosis datasets to identify candidate ferroptosis-related genes using the R software. Weighted gene co-expression network analysis is performed to identify co-expressed genes. Protein–protein interaction networks, the Kyoto encyclopedia of genes and genomes, and gene ontology enrichment analysis are used to identify the potential functions of the candidate genes. We experimentally validate the results of our analysis using small interfering RNAs and plasmids to silence and upregulate the expression of the candidate gene in human bronchial epithelial cells (BEAS-2B). The ferroptosis signature levels are examined. Bioinformatics analysis of the asthma dataset GDS4896 shows that the level of the aldo-keto reductase family 1 member C3 (AKR1C3) gene in the peripheral blood of patients with severe therapy-resistant asthma and controlled persistent mild asthma (MA) is significantly upregulated. The AUC values for asthma diagnosis and MA are 0.823 and 0.915, respectively. The diagnostic value of AKR1C3 is verified using the GSE64913 dataset. The gene module of AKR1C3 is evident in MA and functions through redox reactions and metabolic processes. Ferroptosis indicators are downregulated by the overexpression of AKR1C3 and upregulated by silencing AKR1C3. The ferroptosis-related gene AKR1C3 can be used as a diagnostic biomarker for asthma, particularly for MA, and regulates ferroptosis in BEAS-2B cells.

Current Needs Assessment for Using Lung Clearance Index for Asthma in Clinical Practice.

Asthma pathophysiology has shown that remodeling of the bronchial airways mainly affects the small rather than large airways. The severity of asthma is conventionally measured by forced expiratory volume 1 (FEV1) but this maneuver is insensitive to changes in distal airways with smaller diameter. The aim of this review is to evaluate the current evidence supporting LCI as a clinical tool for assessing small airways disease in asthma patients, as well as whether it is useful as a treatment response parameter in severe therapy-resistant asthma (STRA) patients. There is an increasing need for novel tests that can assess distal airway disease in asthma. Lung Clearance Index (LCI) may be a useful test for assessing more severe airway obstruction and the persistence of small airway disease. LCI measurement has been shown to be more sensitive than spirometry in cystic fibrosis (CF), but its clinical utility in asthma has not been thoroughly investigated. LCI abnormalities may be a sensitive marker for the persistence of small distal airway disease and may be associated with a more severe asthma endotype unresponsive to inhaled glucocorticoids. There is a need to identify other lung function tests for asthma that can identify early airway remodeling while simultaneously measuring the rate of lung function impairment. When compared to other conventional methods, multiple-breath washout (MBW) measures the lung clearance index (LCI), a more sensitive predictor of early airway disease that is feasible to perform in children. The goal of this review is to evaluate the current evidence of LCI as a clinical tool in asthma patients.

Childhood asthma: pathogenesis and phenotypes.

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.

Pediatric problematic severe asthma: Recent advances in management.

Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of "difficult-to-treat" asthma (DA) and "severe therapy-resistant asthma" (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once-daily maintenance therapy, single-device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12years.

Continuous positive airway pressure acutely increases exercise duration in children with severe therapy-resistant asthma: a randomized crossover trial.

Lower exercise tolerance is an important component of asthma and the possible effects of non-invasive ventilation on exercise capacity in individuals with severe therapy-resistant asthma (STRA) are unknown. This study aimed to evaluate the immediate effect of continuous positive airway pressure (CPAP) on exercise tolerance in children with STRA. We performed a controlled, randomized, crossover clinical trial including subjects aged 6 to 18years old diagnosed with STRA. Clinical, anthropometric and lung function data were collected. The participants in the intervention group (IG) used CPAP (PEEP 10cmH2O and FiO2 0.21) for a period of 40min. Subjects in the control group (CG) used CPAP with minimum PEEP at 1 cmH20 also for 40min. Afterwards, subjects from both groups underwent cardiopulmonary exercise testing (CPET). After a 15-day washout period, on a subsequent visit, subjects participated in the opposite group to the initial one. Thirteen subjects with a mean age of 12.30 ± 1.7years were included. The variables of peak expiratory flow (PEF) and forced expiratory volume in the first second (FEV1) before using CPAP and after performing CPET did not show significant differences. Regarding CPET results, there was no significant difference (P = 0.59) between groups at peak exercise for oxygen consumption-VO2 (CG: 33.4 ± 6.3 and IG: 34.5 ± 5.9, mLkg-1min-1). However, the IG (12.4 ± 2.1) presented a total test time (min) significantly (P = 0.01) longer than the CG (11.5 ± 1.3). The results suggest that the use of CPAP before physical exercise increases exercise duration in children and adolescents with STRA.

When adherence and inhalation technique matter: Difficult-to-control pediatric asthma in low- to middle-income countries.

Despite relatively recent advances in our understanding of the physiopathology of asthma and the availability of highly effective controller medications, such as inhaled corticosteroids (ICS), currently many pediatric patients fail to control their asthma, especially in low- and middle-income countries (LMICs). Although some of these difficult-to-control asthmatic children have severe therapy-resistant asthma, most of them experience poor asthma control due to various modifiable factors, among which poor adherence to inhaled controller therapy and inadequate inhaler technique are the most common. Although electronic monitoring devices have been considered to be essential tools in identifying patients with severe therapy-resistant asthma, their high cost and low availability have currently limited their use in clinical practice. For these reasons, clinicians might consider using validated self-reported questionnaires and the weight of inhaler canisters and as alternative and valid options for assessing adherence to inhaled controller therapy. Furthermore, clinicians might consider adopting validated instruments as an objective measurement of the adequacy of inhaler technique. Although recognizing poor adherence does not automatically lead to improved adherence, it is usually an essential first step in effectively targeting adherence behavior, especially if the reasons for low or erratic compliance are explored by means of non-judgmental doctor-patient communication. These recommendations could assist in overcoming our inability to have pediatric asthmatic patients use ICS and in avoiding escalating their controller therapy toward more expensive medications, eventually reaching the use biologics. Promoting the rational and cost-effective use of asthma controller therapy could help to optimize the limited health resources in many LMICs.

Shorter telomeres in children with severe asthma, an indicative of accelerated aging.

Severe therapy-resistant asthma (STRA) is closely associated with distinct clinical and inflammatory pheno-endotypes, which may contribute to the development of age-related comorbidities. Evidence has demonstrated a contribution of accelerated telomere shortening on the poor prognosis of respiratory diseases in adults. Eotaxin-1 (CCL11) is an important chemokine for eosinophilic recruitment and the progression of asthma. In the last years has also been proposed as an age-promoting factor. This study aimed to investigate the association of relative telomere length (rTL) and eotaxin-1 in asthmatic children. Children aged 8-14 years (n=267) were classified as healthy control (HC, n=126), mild asthma (MA, n=124) or severe therapy-resistant asthma (STRA, n=17). rTL was performed by qPCR from peripheral blood. Eotaxin-1 was quantified by ELISA from fresh-frozen plasma. STRA had shorter telomeres compared to HC (p=0.02) and MA (p=0.006). Eotaxin-1 levels were up-regulated in STRA [median; IQR25-75)] [(1,190 pg/mL; 108–2,510)] compared to MA [(638 pg/mL; 134–1,460)] (p=0.03) or HC [(627 pg/mL; 108–1,750)] (p<0.01). Additionally, shorter telomeres were inversely correlated with eotaxin-1 levels in STRA (r=-0.6, p=0.013). Our results suggest that short telomeres and up-regulated eotaxin-1, features of accelerated aging, could prematurely contribute to a senescent phenotype increasing the risk for early development of age-related diseases in asthma.

Diagnostic performance of the physical activity-related question of the GINA questionnaire to detect exercise-induced bronchoconstriction in asthma

IntroductionThe aim of the study was to evaluate the diagnostic performance of the item concerning physical activity of the Global Initiative for Asthma (GINA) asthma control questionnaire for detection of exercise-induced bronchoconstriction (EIB) in children and adolescents. Material and methodsWe divided participants (aged 6–18 years) with a diagnosis of asthma into two groups according to the GINA severity classification: mild/moderate asthma (MMA) and severe therapy-resistant asthma (STRA). We collected anthropometric, clinical and functional data (spirometry) and performed an EIB test. We used item 4 of the GINA questionnaire regarding exercise-induced symptoms to assess the diagnostic power of this instrument. ResultsWe included 40 patients (17 with MMA and 23 with STRA) with a mean age of 11.3 years and a mean FEV1z-score of –0.33, of who 13 (32.5%) were classified as having uncontrolled asthma. Of the patients with uncontrolled asthma, 7 (53.8%) exhibited a decrease in the FEV1 after the EIB test. We found a higher frequency of EIB in participants with FEV1 z-score values of less than –1.0 compared to those with a z-score of –1.0 or greater (P = .05). There were no significant differences in the frequency of EIB based on disease severity and control. We also found no association of item 4 (GINA) with EIB. The area under the ROC curve demonstrated that the discriminative power of the GINA questionnaire for the detection of EIB is inadequate (P = .41), with sensitivity of 42.1% and specificity of 57.1%. ConclusionsThe item concerning physical activity in the GINA questionnaire has insufficient diagnostic power to detect EIB in children and adolescents with asthma.

Difficult and Severe Asthma in Children.

Asthma is the most frequent chronic inflammatory disease of the lower airways affecting children, and it can still be considered a challenge for pediatricians. Although most asthmatic patients are symptom-free with standard treatments, a small percentage of them suffer from uncontrolled persistent asthma. In these children, a multidisciplinary systematic assessment, including comorbidities, treatment-related issues, environmental exposures, and psychosocial factors is needed. The identification of modifiable factors is important to differentiate children with difficult asthma from those with true severe therapy-resistant asthma. Early intervention on modifiable factors for children with difficult asthma allows for better control of asthma without the need for invasive investigation and further escalation of treatment. Otherwise, addressing a correct diagnosis of true severe therapy-resistant asthma avoids diagnostic and therapeutic delays, allowing patients to benefit from using new and advanced biological therapies.

Diagnosis and Management of Problematic Severe Asthma.

This review will outline an evidence-based approach for diagnosing and managing children with problematic severe asthma (PSA). Children with PSA have uncontrolled asthma symptoms, despite maximal prescribed asthma treatment. These children have high morbidity and mortality and should be referred for specialist respiratory assessment and management. The first step in the assessment of a child with PSA is confirming the diagnosis of asthma using objective evidence. Following this, an assessment of inhaled corticosteroid adherence and a multi-disciplinary team approach is essential for separating difficult asthma (DA) from severe therapy resistant asthma (STRA). The majority of children have DA which entails uncontrolled asthma symptoms due to underlying modifiable factors including poor treatment adherence, poor inhaler technique, exposure to environmental allergens, co-morbid conditions and psycho-social factors. Approximately 20% of children with PSA have STRA, and have persistent asthma symptoms despite good treatment adherence and correction of modifiable factors. Children with STRA typically have multiple and severe aeroallergen sensitization, eosinophilic airway inflammation and high fraction exhaled nitric oxide (FeNO). Further investigation of children with STRA includes an assessment of systemic steroid responsiveness, this is important for confirming the diagnosis of STRA and guiding the choice of additional treatment. Biologics are an add on (immune targeted) therapy for STRA. The current biologics used in children target the T2 helper (Th2) pathway mediating eosinophilic, allergic asthma. CONCLUSION: Future clinical trials of biologics in children will be essential to help identify childhood specific biomarkers and to decide which biologic is best for which individual child.

This Child's Asthma Appears to Be Severe: But Where Actually Is the Severe Problem?

The aim of this manuscript is to outline an approach to severe asthma, which is among the most challenging problems faced by paediatric pulmonologists. A logical, protocolised approach is essential. The first step is to rule out alternative diagnoses. The next step is a multidisciplinary assessment. Severe, therapy resistant asthma (STRA) is rare, and most of those referred will improve if basic management is corrected, especially adherence to treatment. However some are unable or unwilling to make necessary changes (refractory asthma plus or refractory difficult asthma). Some, especially asthma in the obese, and those thought to have STRA, progress to bronchoscopic airway phenotyping and a parenteral steroid trial to determine an individualised treatment plan. Those with persistent eosinophilc airway inflammation should be considered for omalizumab, and mepolizumab. Pauci-inflammatory asthma remains a therapeutic challenge, with a paucity of evidence; increasing steroid therapy seems neither logical nor efficacious, but options include tiotropium and azithromycin. However the most important message to the paediatrician looking after a child with apprently severe asthma is that the answer is not uncritically escalating treatment, but finding the answer to the question, what is it about this child, and his/her environment, which means there is no response to what should be easily treated airway pathology? The answer usually requires input from a skilled and experienced multi-disciplinary team, without which management is unlikely to be succesful. CONCLUSION: When managing a child with severe asthma, a detailed multi-disciplinary is essential to get the basic management right, before prescribing biologicals.

Determinants of exercise capacity in children and adolescents with severe therapy-resistant asthma

Objective To evaluate the exercise capacity of children and adolescents with severe therapy resistant asthma (STRA) aiming to identify its main determinants. Methods Cross-sectional study including individuals aged 6–18 years with a diagnosis of STRA. Clinical (age and gender), anthropometric (weight, height and body mass index) and disease control data were collected. Lung function (spirometry), cardiopulmonary exercise testing (CPET) and exercise-induced bronchoconstriction (EIB) test were performed. Results Twenty-four patients aged 11.5 ± 2.6 years were included. The mean forced expiratory volume in one second (FEV1) was 91.3 ± 9.2%. EIB occurred in 54.2% of patients. In CPET, the peak oxygen uptake (VO2peak) was 34.1 ± 7.8 mL kg−1 min−1. A significant correlation between ventilatory reserve and FEV1 (r = 0.57; p = 0.003) was found. Similarly, there was a significant correlation between CPET and percent of FEV1 fall in the EIB test for both V E/VO2 (r = 0.47; p = 0.02) and V E/VCO2 (r = 0.46; p = 0.02). Patients with FEV1<80% had lower ventilatory reserve (p = 0.009). In addition, resting heart rate correlated with VO2peak (r=-0.40; p = 0.04), V E/VO2 (r = 0.46; p = 0.02) and V E/VCO2 (r = 0.48; p = 0.01). Conclusions Exercise capacity is impaired in approximately 30% of children and adolescents with STRA. The results indicate that different aspects of aerobic fitness are influenced by distinct determinants, including lung function and EIB.

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

Impaired airway epithelial cell wound-healing capacity is associated with airway remodelling following RSV infection in severe preschool wheeze.

Respiratory syncytial virus (RSV) causes exacerbations of asthma and preschool wheeze (PSW). However, the anti-viral and repair responses of the bronchial epithelium in children with severe therapy-resistant asthma (STRA) and PSW are poorly understood. Children with STRA (age 12 [6-16] years), PSW (age 2 [1-5] years) and non-asthmatic controls (age 7 [2-14] years) underwent bronchoscopy with endobronchial brushings and biopsies. Anti-viral, wound injury responses were quantified in biopsies and primary bronchial epithelial cells (PBECs) in response to RSV, poly(I:C), house dust mite (HDM) or IL-33 using RT-qPCR, Luminex and live cell imaging. Collagen deposition and tissue expression of epithelial growth factor receptor (EGFR), IL-33 and receptor ST2 were investigated in bronchial biopsies. PBECs from STRA and PSW had increased TLR3 gene expression and increased secretion of anti-viral and pro-inflammatory cytokines (IFN-γ, IL-6 and IL-13) in response to RSV compared to controls. Exposure of PBECs to concomitant TLR3 agonist poly(I:C) and HDM resulted in a significant reduction in epithelial cell proliferation in PSW compared to controls. Wound-healing was also impaired in PSW compared to controls at baseline and following IL-33 stimulation. In addition, tissue EGFR expression was significantly reduced in PSW and correlated with collagen deposition in endobronchial biopsies. Despite increased anti-viral responses, preschool children with severe wheeze had impaired airway epithelial proliferative responses following damage. This might be connected to the low expression of EGFR in PSW which may affect epithelial function and contribute to asthma pathogenesis.

Bronchoalveolar lavage cytokine patterns in children with severe neutrophilic and paucigranulocytic asthma

Asthma is a complex heterogeneous disease occurring in adults and children that is characterized by distinct inflammatory patterns. While numerous studies have been performed in adults, little is known regarding the heterogeneity of severe asthma in children, particularly inflammatory signatures involving the air spaces. We sought to determine the relationship of bronchoalveolar lavage (BAL) cytokine/chemokine expression patterns in children with severe therapy-resistant asthma stratified according to neutrophilic versus nonneutrophilic BAL inflammatory cell patterns. Children with severe asthma with inadequate symptom control despite therapy underwent diagnostic bronchoscopy and BAL. Inflammatory cytokine/chemokine concentrations were determined using a multiplex protein bead assay. Analysis of BAL constituents with an unbiased clustering approach revealed distinct cytokine/chemokine patterns, and these aligned with pathways associated with type 2 innate lymphoid cells, monocytes, neutrophil trafficking, and T effector cells. All cytokines examined (n= 27) with 1 exception (vascular endothelial growth factor) were overexpressed with BAL neutrophilia compared with nonneutrophilic asthma, and this was confirmed in a cross-validation analysis. Cytokines specifically responsible for Th17 (IL-17, IL-6, G-CSF) and Th1 differentiation and expression (IL-12, TNF-α, IFN-γ) were enhanced in the neutrophilic cohorts. Neutrophilic groups were also characterized by higher prevalence of bacterial and viral pathogens; however, cytokine expression patterns manifested independently of pathogen expression. The results demonstrate that children with refractory asthma and neutrophilic inflammation had a BAL cytokine pattern consistent with a mixed Th17/Th1/Th2 response. In contrast, nonneutrophilic asthma presented independently of cytokine overexpression.

Which Child with Asthma is a Candidate for Biological Therapies?

In asthmatic adults, monoclonals directed against Type 2 airway inflammation have led to major improvements in quality of life, reductions in asthma attacks and less need for oral corticosteroids. The paediatric evidence base has lagged behind. All monoclonals currently available for children are anti-eosinophilic, directed against the T helper (TH2) pathway. However, in children and in low and middle income settings, eosinophils may have important beneficial immunological actions. Furthermore, there is evidence that paediatric severe asthma may not be TH2 driven, phenotypes may be less stable than in adults, and adult biomarkers may be less useful. Children being evaluated for biologicals should undergo a protocolised assessment, because most paediatric asthma can be controlled with low dose inhaled corticosteroid if taken properly and regularly. For those with severe therapy resistant asthma, and refractory asthma which cannot be addressed, the two options if they have TH2 inflammation are omalizumab and mepolizumab. There is good evidence of efficacy for omalizumab, particularly in those with multiple asthma attacks, but only paediatric safety, not efficacy, data for mepolizumab. There is an urgent need for efficacy data in children, as well as data on biomarkers to guide therapy, if the right children are to be treated with these powerful new therapies.

Severe uncontrolled asthma in children: practical approach on diagnosis and management.

Severe uncontrolled asthma in children is a complex and heterogeneous disease and is considered a challenge for the pediatricians. Although nearly 5% of children with asthma present with a severe uncontrolled disease, these patients and their caregivers face a significant burden, including troublesome persistent symptoms, life-threatening acute attacks, medication side effects, impaired school performance, neuropsychological problems, and lower quality of life (QoL). Moreover, these patients also account for substantially higher healthcare resource use and costs than average patients with asthma. Thus, it is essential to accurately define and diagnose severe asthma in children as they potentially need close monitoring and additional treatment with advanced therapies. This review aims to update knowledge on diagnosis and management of severe uncontrolled asthma in childhood. We describe a practical approach to differentiate children with difficult-to-treat asthma from those with true severe therapy-resistant asthma. Moreover, the recent advances in the understanding of the pathogenetic mechanisms and inflammatory mediators involved in asthma have paved the way for the development of a precision medicine approach. In this context, we analyze approved personalized therapies for severe uncontrolled asthma, focusing on the pediatric indications.

Lung clearance index and steroid response in pediatric severe asthma.

Lung clearance index (LCI) is a measure of airway disease that has been shown to be abnormal in asthma. We hypothesized that LCI would be higher (worse) in children with severe therapy-resistant asthma (STRA) compared with difficult asthma (DA) and healthy controls and that LCI would fall in response to parenteral steroids in STRA. Sixty-four children with asthma who were prescribed high-dose asthma therapy (GINA steps 4 or 5) performed LCI and spirometry. Forty-three had STRA and 21 DA. Thirty-nine of forty-three STRA patients attended for a clinically indicated bronchoscopy during which an intramuscular injection of triamcinolone was given. LCI, spirometry, and fractional exhaled nitric oxide (FeNO) were performed on the day of the bronchoscopy and repeated 4 weeks later. LCI was more abnormal in STRA (median: 7.40, range: 5.58-12.34) than in DA (6.55, 5.77-7.75), P = .0006, and healthy controls (6.53, 5.57-7.35), P = .005. In contrast to the first second forced expired volume (FEV1 ), LCI improved following systemic steroids; of 20 STRA patients with an abnormal LCI at baseline, 13 improved following triamcinolone. LCI and FeNO responses were concordant. There is a subgroup of children with STRA in whom LCI is elevated who improve following parenteral steroids. LCI may be a valuable additional domain in assessing steroid response in pediatric asthma.

An approach to the management of children with problematic severe asthma.

Children with poor asthma control despite high levels of prescribed treatment are described as having problematic severe asthma. Most of these children have steroid sensitive disease which improves with adherence to daily inhaled corticosteroids and after having removed modifiable factors like poor inhalation technique, persistent adverse environmental exposures and psychosocial factors. These children are described as having “difficult-to-treat asthma” while children with persistent symptoms despite above-mentioned factors having been addressed are described as having “severe therapy-resistant asthma”. In this review, we will describe the 6-step approach to the diagnosis and management of a child with problematic severe asthma adopted by The Royal Brompton Hospital (London, UK). The role of a multidisciplinary team is crucial for identification and treatment of modifiable factors and comorbidities in order to avoid invasive examinations and useless pharmacological treatments. The current knowledge on add-on therapies will be discussed.

Modified Shuttle Test Distance Correlates With Peak Oxygen Uptake in Children and Adolescents With Severe Therapy-Resistant Asthma.

IntroductionSeveral tests may be used to assess exercise intolerance in severe therapy-resistant asthma (STRA), including the gold standard cardiopulmonary exercise test (CPET) and the modified shuttle test (MST).ObjectiveTo correlate the distance achieved in the MST with peak oxygen uptake (VO2peak) and to compare the maximal heart rate (HRmax) obtained in both tests in children and adolescents with STRA.MethodsThis is a cross-sectional study, with 19 children and adolescents with STRA. Demographic, anthropometric, clinical data, and spirometric values were collected. CPET and the MST were performed in two consecutive visits. HRmax, pulse oxygen saturation, and dyspnea were compared between tests. The distance achieved in the MST was correlated with VO2peak.ResultsNineteen patients with a mean age of 11.5 ± 2.5 years were included. The mean HRmax (bpm) achieved was 180.8 ± 12.10 for the MST and 187.6 ± 9.35 for CPET, whereas the mean HRmax as a percentage of predicted (HRmax%) was 90.7 ± 6.5 for the MST and 93.8 ± 4.5 for CPET. A difference of only 6 bpm was found for HRmax (p = 0.10) and of 3% for HRmax% (p = 0.06) between tests. A strong correlation was found between the MST (r = 0.79; p = 0.001) and VO2peak measured through CPET. However, there were no correlations between the MST and both body mass index (r = −0.14; p = 0.564) and forced expiratory volume in the first second – FEV1 (r = −0.02; p = 0.917).ConclusionThe results demonstrate that the MST distance strongly correlates with VO2peak, measured through CPET, and the main physiological variable responses were similar between both tests. Our results provide additional data for the use of the MST to assess exercise capacity in children and adolescents with STRA.