Comment

Severe childhood asthma: a common international approach?

Among patients with asthma, reliance on the type/dose of prescribed medication and symptom control does not adequately capture those at risk of adverse outcomes, and we need biomarkers for risk and treatment stratification that are consistently accurate, readily quantifiable, and reproducible. Most patients with severe asthma, regardless of age, have predominant type-2 inflammation-mediated disease, making airway/blood eosinophils, fractional exhaled nitric oxide, periostin, and/or allergic sensitization potentially important biomarkers for severe disease. In both adult and pediatric asthma, there is scope to improve prediction of severe attacks by using a composite type-2 biomarker of blood eosinophils and fractional exhaled nitric oxide. Technological advances in component-resolved diagnostics microarray technologies coupled with the development of interpretation software offer a possibility to use component-resolved diagnostics as biomarkers of asthma severity among sensitized patients with asthma. Genetic predisposition and polygenic risk scores of relevant traits (eg, lung function, host immune responses, biomarkers of exposure from the indoor and outdoor environment, infection, and microbial dysbiosis) may also contribute to prediction algorithms. We challenge the idea that asthma can be accurately defined in an individual patient by a discrete and static “endotype” (eg, type-2–high asthma). As we traverse the new era of molecular endotyping in asthma, we need to understand how relevant mechanisms impact patient outcomes, and in parallel develop new tools and approaches to stratify therapies and define individual patient trajectories.

Over the past years, advanced in vitro pulmonary platforms have witnessed exciting developments that are pushing beyond traditional preclinical cell culture methods. Here, we discuss ongoing efforts in bridging the gap between in vivo and in vitro interfaces and identify some of the bioengineering challenges that lie ahead in delivering new generations of human-relevant in vitro pulmonary platforms. Notably, in vitro strategies using foremost lung-on-chips and biocompatible “soft” membranes have focused on platforms that emphasize phenotypical endpoints recapitulating key physiological and cellular functions. We review some of the most recent in vitro studies underlining seminal therapeutic screens and translational applications and open our discussion to promising avenues of pulmonary therapeutic exploration focusing on liposomes. Undeniably, there still remains a recognized trade-off between the physiological and biological complexity of these in vitro lung models and their ability to deliver assays with throughput capabilities. The upcoming years are thus anticipated to see further developments in broadening the applicability of such in vitro systems and accelerating therapeutic exploration for drug discovery and translational medicine in treating respiratory disorders.

Stability of asthma is a clinical phenotype of the disease based on long-term evaluation of control of asthma symptoms and its exacerbations. A relationship between airway inflammation and clinical classification of asthma based on stability criterion has not been well studied.

The purpose of our study was to analyze the inflammation profile of stable and unstable asthma in adolescents treated with moderate and high doses of inhaled corticosteroids.

139 young asthmatics of 16.8 (3.25) years were classified in the stable group (N = 72) and unstable group (N = 67) after a 3-month prospective observation. Inflammatory markers including cytogram of the induced sputum (IS), fractional exhaled nitric oxide (FeNO) and bronchial hyperresponsiveness (BHR) following provocation with hypertonic saline and exercises, as well as clinical and spirometric parameters in both groups were compared.

75% of patients with unstable asthma revealed elevated percentage of eosinophils in the induced sputum (>2.5%), and mean values were significantly higher in comparison with stable asthma: 2.0 (0,5–4,2) vs 5,5 (2,6–11,3), p < 0,001. Bronchial hyperresponsiveness was markedly higher in unstable asthma, especially in asthma with eosinophilic profile; statistically significant differences also related to functional pulmonary tests. In multivariate analysis, asthma instability was significantly associated with sEos (p = 0.005), BHR (p = 0.001) but not FeNO (p = 0.24).

Eosinophilic inflammation, relatively resistant to high doses of inhaled corticosteroids, is a dominant type of inflammation in unstable asthma in adolescents. Asthma instability is also associated with higher bronchial hyperresponsiveness and lower spirometric parameters. In the light of the new studies and progress in biological methods of therapy of eosinophilic inflammation, unstable asthma, especially in case of severe course, requires extended diagnostics with determination of inflammatory phenotype.

Lung diseases impose a significant socioeconomic burden and are a leading cause of morbidity and mortality worldwide. Moreover, respiratory medicine, unlike several other therapeutic areas, faces a disappointingly low number of new approved therapies. This is partly due to lack of reliable in vitro or in vivo models that can reproduce organ-level complexity and pathophysiological responses of human lung. Here, we examine new opportunities in application of recently emerged organ-on-chip technology to model human lung alveolus and small airway in preclinical drug development and biomarker discovery. We also discuss challenges that need to be addressed in coming years to further enhance the physiological and clinical relevance of these microsystems, enable their increased accessibility, and support their leap into personalized medicine.

There is no agreed upon definition of systemic corticosteroid response in asthmatic children. Moreover, pediatric severe therapy-resistant asthma (STRA) is heterogeneous, and thus response to steroids is unlikely to be uniform in all patients.

We sought to evaluate the utility of a multidomain approach incorporating symptoms, lung function, and inflammation to determine steroid responsiveness in pediatric patients with STRA.

Eighty-two children (median age, 12 years) with STRA received a clinically indicated dose of intramuscular steroid. Changes in 4 separate domains were assessed 4 weeks after intramuscular triamcinolone acetonide: normalization of (1) symptoms (Asthma Control Test score, >19/25 or 50% increase), (2) spirometric results (FEV₁ ≥80% of predicted value or ≥15% increase), (3) fraction of exhaled nitric oxide levels (<24 ppb), and (4) sputum eosinophil counts (<2.5%). Fifty-four of 82 children had complete data in all 4 domains.

Twenty-three (43%) of 54 children had a symptom response, 29 (54%) of 54 had a lung function response, 28 (52%) of 54 had a fraction of exhaled nitric oxide response, and 29 (54%) of 54 had a sputum eosinophil response. Although a similar proportion of children responded to systemic corticosteroids in each domain, there were no reliable predictors of a response pattern. Seven (13%) of 54 were complete responders (response in all domains), 8 (15%) of 54 were nonresponders (no response in any domain), and 39 (72%) of 54 were partial responders (response in ≥1 domain).

A multidomain evaluation of systemic steroid responsiveness using pragmatic clinical assessments confirms childhood STRA is heterogeneous and that a complete response in symptoms and inflammatory and physiologic parameters is rare. Individual response patterns to systemic steroids might be useful in guiding the choice of add-on therapies in each child as a step toward achieving personalized medicine.