The paradigm shift in allergy consultations through a digital ecosystem.

In Spain, specialist outpatient care traditionally relied on in-person consultations at public hospitals, leading to long wait times and limited clinical analysis in appointment assignments. However, the emergence of Information and Communication Technologies (ICTs) has transformed patient care, creating a seamless healthcare ecosystem. At the Allergy Department, we aimed to share our experience in transitioning form a traditional linear model of patient flow across different healthcare levels to the implementation of a digital ecosystem. By telemedicine, we can prioritize individuals based on clinical relevance, promptly and efficiently addressing potentially life-threatening conditions such as severe uncontrolled asthma or hymenoptera venom anaphylaxis. Furthermore, our adoption of telephone consultations has markedly reduced the need for in-person hospital visits, while issues with unstable patients are swiftly addressed via WhatsApp. This innovative approach not only enhances efficiency but also facilitates the dissemination of personalized medical information through various channels, contributing to public awareness and education, particularly regarding allergies. Concerns related to confidentiality, data privacy, and the necessity for informed consent must thoroughly be addressed. Also, to ensure the success of ICT integration, it is imperative to focus on the quality of educational information, its efficient dissemination, and anticipate potential unforeseen consequences. Sharing experiences across diverse health frameworks and medical specialties becomes crucial in refining these processes, drawing insights from the collective experiences of others. This collaborative effort aims to contribute to the ongoing development of a more effective and sustainable healthcare system.

Molecular Mapping of Allergen Exposome among Different Atopic Phenotypes.

Climate change and exposure to environmental pollutants play a key role in the onset and aggravation of allergic diseases. As different climate-dependent patterns of molecular immunoglobulin E (IgE) reactivity have been regionally described, we sought to investigate the evolving allergen exposome in distinctive allergic phenotypes and subtropical weather conditions through a Precision Allergy Molecular Diagnosis (PAMD@) model. Concurrent sensitization to several house dust mites (HDM) and storage mite molecules were broadly dominant in the investigated cohort, followed by the major cat allergen Fel d 1, and regardless of the basal allergic disease. Although a complex repertoire of allergens was recognized, a steadily increasing number of IgE binding molecules was associated with the complexity of the underlying atopic disease. Besides the highly prevalent IgE responses to major HDM allergens, Der p 21, Der p 5, and Der p 7 also showed up as serodominant molecules, especially in subjects bothered by asthma and atopic dermatitis. The accurate characterization of the external exposome at the molecular level and their putative role as clinically relevant allergens is essential to elucidate the phenotypic diversity of atopic disease in terms of personalized diagnosis and therapy.

Human genetics influences microbiome composition involved in asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4 

Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

INTRODUCTION AND OBJECTIVES: Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. MATERIALS AND METHODS: In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS: In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS: AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.

The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment.

BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.

Admixture mapping of severe asthma exacerbations in Hispanic/Latino children and youth.

BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.

Real-Life Performance of Mepolizumab in T2-High Severe Refractory Asthma with the Overlapping Eosinophilic-Allergic Phenotype.

Severe asthma (SA) is categorized into multiple overlapping phenotypes and clinical characteristics driven by complex mechanistic inflammatory pathways. Mepolizumab is a human monoclonal antibody effectively targeting interleukin-5 in severe eosinophilic asthma. However, the eligibility of biologics in coincident SA phenotypes is still unclear. We assessed the efficacy and safety of mepolizumab in real-life patients with the overlapping T2-high SA endotype. This was a phase IV, single-centre observational cohort study including patients with severe refractory T2-high asthma in treatment with mepolizumab. After 12 months of treatment with mepolizumab, significant improvements (p < 0.0001) in asthma control and lung function were recorded. Rates of clinically significant annual asthma exacerbation were also decreased by 71.22% after 52-week therapy with mepolizumab (p < 0.001) associated with a reduction in the mean daily dose of oral corticosteroids. Two patients (3.27%) had to discontinue mepolizumab due to musculoskeletal disorders with no severe safety issues reported. The use of mepolizumab as an add-on therapy in routine clinical practice was safely associated with significant clinical and functional in the overlapping eosinophilic-and-allergic SA phenotype. The current data should support clinical and therapeutic decision-making in this T2-high SA endotype.

Dupilumab modulates specific IgE mite responses at the molecular level in severe T2-high atopic dermatitis: A real-world experience.

Background: Atopic dermatitis (AD) is regarded as a chronic systemic disease which is characterized by a robust overexpression of type 2 related cytokines, with increased total IgE levels and a concomitant sensitization to common allergens. Dupilumab, a fully human monoclonal antibody (mAb) to IL-4Rα that inhibits both IL-4 and IL-13 signaling, has previously shown a marked and rapid improvement when treating the moderate-to-severe forms of AD. We sought to evaluate the real-world evidence (RWE) of dupilumab in the modulation of total and specific IgE (sIgE) serum levels to a panel of molecular house dust mites (HDM) and storage mites (SM) allergens in patients with severe AD. Methods: Demographic and clinical data for severe AD adult patients receiving dupilumab treatment (300 mg every 2 weeks) were reviewed. Mean (standard deviations SD) values and percent changes from baseline in total and sIgE to the complete HDM and SM extracts, and 14 individual molecular allergens were measured over 52 weeks. Results: Significant (p < 0.05) changes in mean total IgE levels were observed from baseline to week-52 after treatment with dupilumab. Despite no changes were found in sIgE against the extract of HDM during the 52-week treatment with dupilumab, baseline mean levels from 7 out of 14 individual molecular mite allergens -Der p 1, Der p 2, Der p 5, Der p 7, Der p 21, Der p 23, and Lep d 2- were significantly (p < 0.05) decreased-after 52 weeks of treatment with dupilumab. Conclusions: Dupilumab therapy for 52 weeks resulted in a profound reduction in blood levels of total IgE and allergen-specific IgE to both HDM and SM at the molecular level in adults with severe AD under RWE conditions. The potential benefits of these concomitant immunomodulatory effects after treatment with dupilumab should be explored to a greater extent.

Mite Molecular Profile in the Th2-Polarized Moderate-to-Severe Persistent Asthma Endotype Subjected to High Allergen Exposure.

BACKGROUND: The association among the IgE responses to prevailing groups of house dust mite (HDM) allergens in the concurrent asthma phenotypes has not been determined. OBJECTIVE: The aim of the present study lays on a component-resolved diagnosis (CRD) model to investigate the mite molecular signature in subjects with type-2 inflammation asthma. METHODS: We selected patients showing a clinically relevant sensitization to HDMs with moderate-to-severe persistent asthma. Skin prick test (SPT) with standardized mite extracts, a broad customized CRD serum sIgE panel including 9 Dermatophagoides pteronyssinus allergens and the related protein allergenic characterization, was investigated in all serum samples. RESULTS: Ninety out of 93 (96.77%) patients with a positive SPT to HDM showed a concordant sIgE (≥0.35 kUA/L) to the crude extract of D. pteronyssinus. Major allergens (Der p 2, Der p 23, and Der p 1) were present in >70% of all subjects, with mid-tier allergens (Der p 5, Der p 7, and Der p 21) reaching up to 51% in the present cohort. A complex pleomorphic repertoire of HDM molecules recognized by IgE was depicted, including 38 distinct profiles. CONCLUSIONS AND CLINICAL RELEVANCE: The proposed CRD panel approach, containing the most prevalent HDM allergens, appeared to be sufficient to obtain a precise D. pteronyssinus molecular diagnosis in asthmatics with a climate-dependent high-mite allergen exposure and coexisting sensitization. A dominant role of both major and mid-tier allergens has been confirmed in moderate and severe persistent asthmatics with the preponderant Th2-high endotype.

The Genomics and Metagenomics of Asthma Severity (GEMAS) Study: Rationale and Design.

Asthma exacerbations are a major contributor to the global disease burden, but no significant predictive biomarkers are known. The Genomics and Metagenomics of Asthma Severity (GEMAS) study aims to assess the role of genomics and the microbiome in severe asthma exacerbations. Here, we present the design of GEMAS and the characteristics of patients recruited from March 2018 to March 2020. Different biological samples and demographic and clinical variables were collected from asthma patients recruited by allergy and pulmonary medicine units in several hospitals from Spain. Cases and controls were defined by the presence/absence of severe asthma exacerbations in the past year (oral corticosteroid use, emergency room visits, and/or asthma-related hospitalizations). A total of 137 cases and 120 controls were recruited. After stratifying by recruitment location (i.e., Canary Islands and Basque Country), cases and controls did not differ for most demographic and clinical variables (p > 0.05). However, cases showed a higher proportion of characteristics inherent to asthma exacerbations (impaired lung function, severe disease, uncontrolled asthma, gastroesophageal reflux, and use of asthma medications) compared to controls (p < 0.05). Similar results were found after stratification by recruitment unit. Thereby, asthma patients enrolled in GEMAS are balanced for potential confounders and have clinical characteristics that support the phenotype definition. GEMAS will improve the knowledge of potential biomarkers of asthma exacerbations.