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Precision Medicine in Childhood Asthma

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 32359

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Special Issue Editors

Dr. Anthony Bosco

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Guest Editor

Associate Research Scientist, Asthma & Airway Disease Research Center, the University of Arizona, Tucson, AZ 85721, USA
Interests: systems biology; immunology; genomics; childhood asthma; asthma exacerbations; personalised medicine; bioinformatics; network analysis

Dr. Anya C. Jones

E-Mail Website
Guest Editor

Telethon Kids Institute, University of Western Australia, Perth, Australia
Interests: systems immunology; personalised medicine; childhood asthma; bioinformatics; network analysis; personalised transcriptomics

Special Issue Information

Dear Colleagues,

Asthma is a highly complex and heterogeneous disease that is characterized by chronic airway inflammation, together with recurrent episodes of wheezing, breathlessness, chest tightness, and variable airflow obstruction. Whilst it is now recognized that both children and adults with asthma can be stratified into distinct clinical phenotypes on the basis of a range of clinical and biological risk factors, the treatment of asthma has traditionally focused on a one-size-fits all approach. We believe that three major advances are poised to disrupt this paradigm and revolutionize the treatment of childhood asthma in the future. The first advance is the development of new therapies that target specific molecular pathways. The second advance is the advent of molecular profiling technologies that can identify molecular phenotypes of asthma across multiple layers of biological regulation (genome, epigenome, transcriptome, proteome, metabolome, microbiome) and more recently at single cell resolution. The third advance pertains to the development of sophisticated bioinformatics tools that can cluster subjects into molecular phenotypes and unveil the underlying molecular networks and causal pathways that drive these phenotypes. Towards this goal, new studies are urgently needed that embed these ground-breaking technologies into pediatric asthma cohorts and/or clinical trials and to pave the way for linking molecular phenotypes with targeted therapies that are tailored to the unique biology of each individual child.

We are pleased to invite you contribute to this Special Issue on Precision Medicine in Childhood Asthma. This Special Issue aims to highlight the application of genomics and bioinformatics to elucidate childhood asthma phenotypes, obtain mechanistic insights into disease biology, and link these to targeted therapies. We welcome original research articles and reviews.

We look forward to receiving your contributions.

Dr. Anthony Bosco
Dr. Anya C. Jones
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Precision medicine
Childhood asthma
Systems biology
Asthma endotypes
Asthma exacerbations
Innate immunity
Microbiome
Wheeze
Atopy

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Published Papers (9 papers)

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Research

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13 pages, 2768 KiB

Open AccessArticle

AI-Driven Cell Tracking to Enable High-Throughput Drug Screening Targeting Airway Epithelial Repair for Children with Asthma

by Alphons Gwatimba, Tim Rosenow, Stephen M. Stick, Anthony Kicic, Thomas Iosifidis and Yuliya V. Karpievitch

J. Pers. Med. 2022, 12(5), 809; https://doi.org/10.3390/jpm12050809 - 17 May 2022

Cited by 1 | Viewed by 2281

Abstract

The airway epithelium of children with asthma is characterized by aberrant repair that may be therapeutically modifiable. The development of epithelial-targeting therapeutics that enhance airway repair could provide a novel treatment avenue for childhood asthma. Drug discovery efforts utilizing high-throughput live cell imaging of patient-derived airway epithelial culture-based wound repair assays can be used to identify compounds that modulate airway repair in childhood asthma. Manual cell tracking has been used to determine cell trajectories and wound closure rates, but is time consuming, subject to bias, and infeasible for high-throughput experiments. We therefore developed software, EPIC, that automatically tracks low-resolution low-framerate cells using artificial intelligence, analyzes high-throughput drug screening experiments and produces multiple wound repair metrics and publication-ready figures. Additionally, unlike available cell trackers that perform cell segmentation, EPIC tracks cells using bounding boxes and thus has simpler and faster training data generation requirements for researchers working with other cell types. EPIC outperformed publicly available software in our wound repair datasets by achieving human-level cell tracking accuracy in a fraction of the time. We also showed that EPIC is not limited to airway epithelial repair for children with asthma but can be applied in other cellular contexts by outperforming the same software in the Cell Tracking with Mitosis Detection Challenge (CTMC) dataset. The CTMC is the only established cell tracking benchmark dataset that is designed for cell trackers utilizing bounding boxes. We expect our open-source and easy-to-use software to enable high-throughput drug screening targeting airway epithelial repair for children with asthma. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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20 pages, 5327 KiB

Open AccessArticle

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze

by Thomas Iosifidis, Erika N. Sutanto, Samuel T. Montgomery, Patricia Agudelo-Romero, Kevin Looi, Kak-Ming Ling, Nicole C. Shaw, Luke W. Garratt, Jessica Hillas, Kelly M. Martinovich, Elizabeth Kicic-Starcevich, Shyan Vijayasekaran, Francis J. Lannigan, Paul J. Rigby, Darryl A. Knight, Stephen M. Stick and Anthony Kicic

J. Pers. Med. 2021, 11(12), 1323; https://doi.org/10.3390/jpm11121323 - 7 Dec 2021

Cited by 6 | Viewed by 2966

Abstract

The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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19 pages, 6697 KiB

Open AccessArticle

Personal Network Inference Unveils Heterogeneous Immune Response Patterns to Viral Infection in Children with Acute Wheezing

by Laura A. Coleman, Siew-Kim Khoo, Kimberley Franks, Franciska Prastanti, Peter Le Souëf, Yuliya V. Karpievitch, Ingrid A. Laing and Anthony Bosco

J. Pers. Med. 2021, 11(12), 1293; https://doi.org/10.3390/jpm11121293 - 3 Dec 2021

Cited by 3 | Viewed by 2087

Abstract

Human rhinovirus (RV)-induced exacerbations of asthma and wheeze are a major cause of emergency room presentations and hospital admissions among children. Previous studies have shown that immune response patterns during these exacerbations are heterogeneous and are characterized by the presence or absence of robust interferon responses. Molecular phenotypes of asthma are usually identified by cluster analysis of gene expression levels. This approach however is limited, since genes do not exist in isolation, but rather work together in networks. Here, we employed personal network inference to characterize exacerbation response patterns and unveil molecular phenotypes based on variations in network structure. We found that personal gene network patterns were dominated by two major network structures, consisting of interferon-response versus FCER1G-associated networks. Cluster analysis of these structures divided children into subgroups, differing in the prevalence of atopy but not RV species. These network structures were also observed in an independent cohort of children with virus-induced asthma exacerbations sampled over a time course, where we showed that the FCER1G-associated networks were mainly observed at late time points (days four–six) during the acute illness. The ratio of interferon- and FCER1G-associated gene network responses was able to predict recurrence, with low interferon being associated with increased risk of readmission. These findings demonstrate the applicability of personal network inference for biomarker discovery and therapeutic target identification in the context of acute asthma which focuses on variations in network structure. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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15 pages, 1476 KiB

Open AccessArticle

Role of Sex on the Genetic Susceptibility to Childhood Asthma in Latinos and African Americans

by Antonio Espuela-Ortiz, Esther Herrera-Luis, Fabián Lorenzo-Díaz, Donglei Hu, Celeste Eng, Jesús Villar, Jose R. Rodriguez-Santana, Esteban G. Burchard and María Pino-Yanes

J. Pers. Med. 2021, 11(11), 1140; https://doi.org/10.3390/jpm11111140 - 3 Nov 2021

Cited by 8 | Viewed by 2716

Abstract

Asthma is a respiratory disease whose prevalence changes throughout the lifespan and differs by sex, being more prevalent in males during childhood and in females after puberty. In this study, we assessed the influence of sex on the genetic susceptibility to childhood asthma in admixed populations. Sex-interaction and sex-stratified genome-wide association studies (GWAS) were performed in 4291 Latinos and 1730 African Americans separately, and results were meta-analyzed. Genome-wide (p ≤ 9.35 × 10⁻⁸) and suggestive (p ≤ 1.87 × 10⁻⁶) population-specific significance thresholds were calculated based on 1000 Genomes Project data. Additionally, protein quantitative trait locus (pQTL) information was gathered for the suggestively associated variants, and enrichment analyses of the proteins identified were carried out. Four independent loci showed interaction with sex at a suggestive level. The stratified GWAS highlighted the 17q12-21 asthma locus as a contributor to asthma susceptibility in both sexes but reached genome-wide significance only in females (p-females < 9.2 × 10⁻⁸; p-males < 1.25 × 10⁻²). Conversely, genetic variants upstream of ligand-dependent nuclear receptor corepressor-like gene (LCORL), previously involved in height determination and spermatogenesis, were associated with asthma only in males (minimum p = 5.31 × 10⁻⁸ for rs4593128). Enrichment analyses revealed an overrepresentation of processes related to the immune system and highlighted differences between sexes. In conclusion, we identified sex-specific polymorphisms that could contribute to the differences in the prevalence of childhood asthma between males and females. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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16 pages, 1268 KiB

Open AccessArticle

A System Pharmacology Multi-Omics Approach toward Uncontrolled Pediatric Asthma

by Mahmoud I. Abdel-Aziz, Anne H. Neerincx, Susanne J. H. Vijverberg, Simone Hashimoto, Paul Brinkman, Mario Gorenjak, Antoaneta A. Toncheva, Susanne Harner, Susanne Brandstetter, Christine Wolff, Javier Perez-Garcia, Anna M. Hedman, Catarina Almqvist, Paula Corcuera-Elosegui, Javier Korta-Murua, Olaia Sardón-Prado, Maria Pino-Yanes, Uroš Potočnik, Michael Kabesch, Aletta D. Kraneveld, Anke H. Maitland-van der Zee and on behalf of the SysPharmPediA Consortium Show full author list Hide full author list

J. Pers. Med. 2021, 11(6), 484; https://doi.org/10.3390/jpm11060484 - 28 May 2021

Cited by 12 | Viewed by 4311

Abstract

There is a clinical need to identify children with poor asthma control as early as possible, to optimize treatment and/or to find therapeutic alternatives. Here, we present the “Systems Pharmacology Approach to Uncontrolled Pediatric Asthma” (SysPharmPediA) study, which aims to establish a pediatric cohort of moderate-to-severe uncontrolled and controlled patients with asthma, to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach. In this multicenter observational case–control study, moderate-to-severe asthmatic children (age; 6–17 years) were included from four European countries (Netherlands, Germany, Spain, and Slovenia). Subjects were classified based on asthma control and number of exacerbations. Demographics, current and past patient/family history, and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics, and metabolomics were evaluated from multiple samples. In all, 145 children were included in this cohort, 91 with uncontrolled (median age = 12 years, 43% females) and 54 with controlled asthma (median age = 11.7 years, 37% females). The two groups did not show statistically significant differences in age, sex, and body mass index z-score distribution. Comprehensive information and diverse noninvasive biosampling procedures for various omics analyses will provide the opportunity to delineate underlying pathophysiological mechanisms of moderate-to-severe uncontrolled pediatric asthma. This eventually might reveal novel biomarkers, which could potentially be used for noninvasive personalized diagnostics and/or treatment. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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Review

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22 pages, 855 KiB

Open AccessEditor’s ChoiceReview

From Skin Barrier Dysfunction to Systemic Impact of Atopic Dermatitis: Implications for a Precision Approach in Dermocosmetics and Medicine

by Laura Maintz, Thomas Bieber, Helen D. Simpson and Anne-Laure Demessant-Flavigny

J. Pers. Med. 2022, 12(6), 893; https://doi.org/10.3390/jpm12060893 - 28 May 2022

Cited by 15 | Viewed by 4742

Abstract

Atopic dermatitis (AD) affects up to 20% of children and is considered the starting point of the atopic march with the development of food allergy, asthma, and allergic rhinitis. The heterogeneous phenotype reflects distinct and/or overlapping pathogenetic mechanisms with varying degrees of epidermal barrier disruption, activation of different T cell subsets and dysbiosis of the skin microbiome. Here, we review current evidence suggesting a systemic impact of the cutaneous inflammation in AD together with a higher risk of asthma and other comorbidities, especially in severe and persistent AD. Thus, early therapy of AD to restore the impaired skin barrier, modified microbiome, and target type 2 inflammation, depending on the (endo)phenotype, in a tailored approach is crucial. We discuss what we can learn from the comorbidities and the implications for preventive and therapeutic interventions from precision dermocosmetics to precision medicine. The stratification of AD patients into biomarker-based endotypes for a precision medicine approach offers opportunities for better long-term control of AD with the potential to reduce the systemic impact of a chronic skin inflammation and even prevent or modify the course, not only of AD, but possibly also the comorbidities, depending on the patient’s age and disease stage. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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14 pages, 693 KiB

Open AccessReview

Precision Medicine and Childhood Asthma: A Guide for the Unwary

by Mark L. Everard

J. Pers. Med. 2022, 12(1), 82; https://doi.org/10.3390/jpm12010082 - 10 Jan 2022

Cited by 3 | Viewed by 2217

Abstract

Many thousands of articles relating to asthma appear in medical and scientific journals each year, yet there is still no consensus as to how the condition should be defined. Some argue that the condition does not exist as an entity and that the term should be discarded. The key feature that distinguishes it from other respiratory diseases is that airway smooth muscles, which normally vary little in length, have lost their stable configuration and shorten excessively in response to a wide range of stimuli. The lungs’ and airways’ limited repertoire of responses results in patients with very different pathologies experiencing very similar symptoms and signs. In the absence of objective verification of airway smooth muscle (ASM) lability, over and underdiagnosis are all too common. Allergic inflammation can exacerbate symptoms but given that worldwide most asthmatics are not atopic, these are two discrete conditions. Comorbidities are common and are often responsible for symptoms attributed to asthma. Common amongst these are a chronic bacterial dysbiosis and dysfunctional breathing. For progress to be made in areas of therapy, diagnosis, monitoring and prevention, it is essential that a diagnosis of asthma is confirmed by objective tests and that all co-morbidities are accurately detailed. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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28 pages, 2058 KiB

Open AccessEditor’s ChoiceReview

Multi-Omics Profiling Approach to Asthma: An Evolving Paradigm

by Yadu Gautam, Elisabet Johansson and Tesfaye B. Mersha

J. Pers. Med. 2022, 12(1), 66; https://doi.org/10.3390/jpm12010066 - 7 Jan 2022

Cited by 37 | Viewed by 6039

Abstract

Asthma is a complex multifactorial and heterogeneous respiratory disease. Although genetics is a strong risk factor of asthma, external and internal exposures and their interactions with genetic factors also play important roles in the pathophysiology of asthma. Over the past decades, the application of high-throughput omics approaches has emerged and been applied to the field of asthma research for screening biomarkers such as genes, transcript, proteins, and metabolites in an unbiased fashion. Leveraging large-scale studies representative of diverse population-based omics data and integrating with clinical data has led to better profiling of asthma risk. Yet, to date, no omic-driven endotypes have been translated into clinical practice and management of asthma. In this article, we provide an overview of the current status of omics studies of asthma, namely, genomics, transcriptomics, epigenomics, proteomics, exposomics, and metabolomics. The current development of the multi-omics integrations of asthma is also briefly discussed. Biomarker discovery following multi-omics profiling could be challenging but useful for better disease phenotyping and endotyping that can translate into advances in asthma management and clinical care, ultimately leading to successful precision medicine approaches. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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15 pages, 1147 KiB

Open AccessReview

Airway Wall Remodeling in Childhood Asthma—A Personalized Perspective from Cell Type-Specific Biology

by Lei Fang and Michael Roth

J. Pers. Med. 2021, 11(11), 1229; https://doi.org/10.3390/jpm11111229 - 19 Nov 2021

Cited by 8 | Viewed by 2717

Abstract

Airway wall remodeling is a pathology occurring in chronic inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, and fibrosis. In 2017, the American Thoracic Society released a research statement highlighting the gaps in knowledge and understanding of airway wall remodeling. The four major challenges addressed in this statement were: (i) the lack of consensus to define “airway wall remodeling” in different diseases, (ii) methodologic limitations and inappropriate models, (iii) the lack of anti-remodeling therapies, and (iv) the difficulty to define endpoints and outcomes in relevant studies. This review focuses on the importance of cell-cell interaction, especially the bronchial epithelium, in asthma-associated airway wall remodeling. The pathology of “airway wall remodeling” summarizes all structural changes of the airway wall without differentiating between different pheno- or endo-types of asthma. Indicators of airway wall remodeling have been reported in childhood asthma in the absence of any sign of inflammation; thus, the initiation event remains unknown. Recent studies have implied that the interaction between the epithelium with immune cells and sub-epithelial mesenchymal cells is modified in asthma by a yet unknown epigenetic mechanism during early childhood. Full article

(This article belongs to the Special Issue Precision Medicine in Childhood Asthma)

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