Transcriptomic evaluation of skin tape-strips in children with allergic asthma uncovers epidermal barrier dysfunction and asthma-associated biomarkers abnormalities.

INTRODUCTION: Tape-strips, a minimally invasive method validated for the evaluation of several skin diseases, may help identify asthma-specific biomarkers in the skin of children with allergic asthma. METHODS: Skin tape-strips were obtained and analyzed with RNA-Seq from children with moderate allergic asthma (MAA) (n = 11, mean age 7.00; SD = 1.67), severe allergic asthma (SAA) (n = 9, mean age 9.11; SD = 2.37), and healthy controls (HCs) (n = 12, mean age 7.36; SD = 2.03). Differentially expressed genes (DEGs) were identified by fold change ≥2 with a false discovery rate <0.05. Transcriptomic biomarkers were analyzed for their accuracy in distinguishing asthma from HCs, their relationships with asthma-related outcomes (exacerbation rate, lung function-FEV1, IOS-R5-20, and lung inflammation-FeNO), and their links to skin (barrier and immune response) and lung (remodeling, metabolism, aging) pathogenetic pathways. RESULTS: RNA-Seq captured 1113 in MAA and 2117 DEGs in SAA. Epidermal transcriptomic biomarkers for terminal differentiation (FLG/filaggrin), cell adhesion (CDH19, JAM2), lipid biosynthesis/metabolism (ACOT2, LOXL2) were significantly downregulated. Gene set variation analysis revealed enrichment of Th1/IFNγ pathways (p < .01). MAA and SAA shared downregulation of G-protein-coupled receptor (OR4A16, TAS1R3), upregulation of TGF-ß/ErbB signaling-related (ACVR1B, EGFR, ID1/2), and upregulation of mitochondrial-related (HIGD2A, VDAC3, NDUFB9) genes. Skin transcriptomic biomarkers correlated with the annualized exacerbation rate and with lung function parameters. A two-gene classifier (TSSC4-FAM212B) was able to differentiate asthma from HCs with 100% accuracy. CONCLUSION: Tape-strips detected epithelial barrier and asthma-associated signatures in normal-appearing skin from children with allergic asthma and may serve as an alternative to invasive approaches for evaluating asthma endotypes.

Multidimensional endotyping using nasal proteomics predicts molecular phenotypes in the asthmatic airways.

BACKGROUND: Unsupervised clustering of biomarkers derived from noninvasive samples such as nasal fluid is less evaluated as a tool for describing asthma endotypes. OBJECTIVE: We sought to evaluate whether protein expression in nasal fluid would identify distinct clusters of patients with asthma with specific lower airway molecular phenotypes. METHODS: Unsupervised clustering of 168 nasal inflammatory and immune proteins and Shapley values was used to stratify 43 patients with severe asthma (endotype of noneosinophilic asthma) using a 2 "modeling blocks" machine learning approach. This algorithm was also applied to nasal brushings transcriptomics from U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes). Feature reduction and functional gene analysis were used to compare proteomic and transcriptomic clusters. Gene set variation analysis provided enrichment scores of the endotype of noneosinophilic asthma protein signature within U-BIOPRED sputum and blood. RESULTS: The nasal protein machine learning model identified 2 severe asthma endotypes, which were replicated in U-BIOPRED nasal transcriptomics. Cluster 1 patients had significant airway obstruction, small airways disease, air trapping, decreased diffusing capacity, and increased oxidative stress, although only 4 of 18 were current smokers. Shapley identified 20 cluster-defining proteins. Forty-one proteins were significantly higher in cluster 1. Pathways associated with proteomic and transcriptomic clusters were linked to TH1, TH2, neutrophil, Janus kinase-signal transducer and activator of transcription, TLR, and infection activation. Gene set variation analysis of the nasal protein and gene signatures were enriched in subjects with sputum neutrophilic/mixed granulocytic asthma and in subjects with a molecular phenotype found in sputum neutrophil-high subjects. CONCLUSIONS: Protein or gene analysis may indicate molecular phenotypes within the asthmatic lower airway and provide a simple, noninvasive test for non-type 2 immune response asthma that is currently unavailable.

Advances and highlights in asthma in 2021.

Last year brought a significant advance in asthma management, unyielding to the pressure of the pandemics. Novel key findings in asthma pathogenesis focus on the resident cell compartment, epigenetics and the innate immune system. The precision immunology unbiased approach was supplemented with novel tools and greatly facilitated by the use of artificial intelligence. Several randomised clinical trials and good quality real-world evidence shed new light on asthma treatment and supported the revision of several asthma guidelines (GINA, Expert Panel Report 3, ERS/ATS guidelines on severe asthma) and the conception of new ones (EAACI Guidelines for the use of biologicals in severe asthma). Integrating asthma management within the broader context of Planetary Health has been put forward. In this review, recently published articles and clinical trials are summarised and discussed with the goal to provide clinicians and researchers with a concise update on asthma research from a translational perspective.

The Concept of One Health for Allergic Diseases and Asthma.

The worldwide prevalence of allergic disease is rising as a result of complex gene-environment interactions that shape the immune system and host response. Climate change and loss of biodiversity are existential threats to humans, animals, plants, and ecosystems. While there is significant progress in the development of targeted therapeutic options to treat allergies and asthma, these approaches are inadequate to meet the challenges faced by climate change. The exposomic approach is needed with the recognition of the bidirectional effect between human beings and the environment. All stakeholders need to work together toward mitigating the effects of climate change and promoting a One Health concept in order to decrease the burden of asthma and allergy and to improve immune health. Healthcare professionals should strive to incorporate One Health counseling, environmental health precepts, and advocacy into their practice.

Precision medicine in the allergy clinic: the application of component resolved diagnosis.

INTRODUCTION: A precise diagnosis is key for the optimal management of allergic diseases and asthma. In vivo or in vitro diagnostic methods that use allergen extracts often fail to identify the molecules eliciting the allergic reactions. AREAS COVERED: Component-resolved diagnosis (CRD) has solved most of the limitations of extract-based diagnostic procedures and is currently valuable tool for the precision diagnosis in the allergy clinic, for venom and food allergy, asthma, allergic rhinitis, and atopic dermatitis. Its implementation in daily practice facilitates: a) the distinction between genuine multiple sensitizations and cross-reactive sensitization in polysensitized patients; b) the prediction of a severe, systemic reaction in food or insect venom allergy; c) the optimal selection of allergen immunotherapy based on the patient sensitization profile. This paper describes its main advantages and disadvantages, cost-effectiveness and future perspectives. EXPERT OPINION: The diagnostic strategy based on CRD is part of the new concept of precision immunology, which aims to improve the management of allergic diseases.

Mechanisms of allergen immunotherapy supporting its disease-modifying effect.

Allergen immunotherapy (AIT) is considered the only disease-modifying treatment available at present for allergic disorders. Its main benefits include improvement of symptoms, decreased need for pharmacotherapy, prevention of new sensitizations and sustained effect after AIT completion. The key pillars of AIT-induced tolerance include a shift from Th2 to Th1 response, an increase of regulatory T and B cells, pro-inflammatory effector cell downregulation and IgE suppression, in addition to IgG4, IgA and IgD induction. AIT may also induce trained immunity, characterized by a durable decrease in group 2 of innate lymphoid cells (ILCs) and increased ILC1 and ILC3s. Understanding the immune mechanisms of AIT is essential for validating biomarkers for the prediction of AIT response and for achieving AIT success.

In the last decades, allergic diseases have become a public health concern worldwide. Currently, their treatment is mainly based on medications that control the symptoms or decrease future disease risk. The only disease-modifying treatment available for allergic diseases is allergen immunotherapy (AIT). Its main benefits include improvement of symptoms, prevention of new sensitizations and sustained effect after therapy completion. The allergen tolerance induced by AIT is explained by an increase in the number of regulatory immune cells, which reduce inflammation, and a progressive decrease in pro-inflammatory immune cells and IgE synthesis. Better understanding of the mechanisms of AIT is essential for improving efficacy and safety.

Overactive bladder: A review and update.

Overactive bladder syndrome is a chronic, disabling condition with physical, psychological and social consequences that significantly affects the quality of life of millions of patients worldwide. The economic impact of this disorder is crucial. Overactive bladder syndrome is a little-known condition, with different manifestations from patient to patient, which causes a great deal of frustration to the medical staff involved. The patient requires a clear explanation and the full support of the attending physician. It is extremely important to establish a correct diagnosis and an effective individualized treatment. The collaboration and understanding of these patients are extremely important aspects. Improving the quality of life in these patients is the main purpose in managing this condition. There are several treatment modalities that may be used progressively, with favorable albeit inconsistent results. This condition remains extremely challenging for specialists and, unfortunately, always one of maximum interest.

Critical Points on the Use of Biologicals in Allergic Diseases and Asthma.

Improved understanding of the contribution of immune-inflammatory mechanisms in allergic diseases and asthma has encouraged development of biologicals and small molecules specifically targeting the innate and adaptive immune response. There are several critical points impacting the efficacy of this stratified approach, from the complexity of disease endotypes to the effectiveness in real-world settings. We discuss here how these barriers can be overcome to facilitate the development of implementation science for allergic diseases and asthma.

Genetics and epigenetics of allergy.

PURPOSE OF REVIEW: Allergic diseases are prototypic examples for gene × environment-wide interactions. This review considers the current evidence for genetic and epigenetic mechanisms in allergic diseases and highlights barriers and facilitators for the implementation of these novel tools both for research and clinical practice. RECENT FINDINGS: The value of whole-genome sequencing studies and the use of polygenic risk score analysis in homogeneous well characterized populations are currently being tested. Epigenetic mechanisms are known to play a crucial role in the pathogenesis of allergic disorders, especially through mediating the effects of the environmental factors, well recognized risk modifiers. There is emerging evidence for the immune-modulatory role of probiotics through epigenetic changes. Direct or indirect targeting of epigenetic mechanisms affect expression of the genes favouring the development of allergic diseases and can improve tissue biology. The ability to specifically edit the epigenome, especially using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology, holds the promise of enhancing understanding of how epigenetic modifications function and enabling manipulation of cell phenotype for research or therapeutic purposes. SUMMARY: Additional research in the role of genetic and epigenetic mechanisms in relation to allergic diseases' endotypes is needed. An international project characterizing the human epigenome in relation to allergic diseases is warranted.

Advances in allergen immunotherapy for asthma.

PURPOSE OF REVIEW: Allergen immunotherapy (AIT) is a well-known disease-modifying intervention for allergic diseases. Its benefit in allergic asthma, ranging from prevention to facilitating asthma control, is yet to be clarified. RECENT FINDINGS: In 2017, following several well-designed randomised controlled trials (RCTs) with house-dust mites (HDM) sublingual (SLIT) tablets in asthma, global initiative for asthma (GINA) guidelines highlighted the need to treat the allergic component of asthma. In 2019, the European Academy of Allergy and Clinical Immunology published the first comprehensive guidelines for HDM AIT in allergic asthma, formulating separate recommendations for subcutaneous, SLIT drops, and SLIT tablets. Significant steps were undertaken in understanding the mechanisms of allergic asthma, facilitating the stratified approach for selecting responders and in translating the immune-modulation effect in achieving long-term control of the chronic inflammation in asthma. SUMMARY: Currently existing guidelines recommend AIT as a therapeutic option in controlled or partially controlled HDM allergic asthma. Limited data are available for pollen, molds and pets, as well as for the severe allergic asthma population. The challenge for the future research will be to clarify the subendotypes of allergic asthma responding to AIT, the mechanisms facilitating its' preventive and disease-modifying effect, the optimal duration of the treatment, and route of administration.