The EXIMIOUS project—Mapping exposure-induced immune effects: connecting the exposome and the immunome

External exposome; Immune-mediated diseases; ImmunomeExposoma extern; Malalties immunomediades; ImmunomaExposoma externo; Enfermedades inmunomediadas; InmunomaImmune-mediated, noncommunicable diseases—such as autoimmune and inflammatory diseases—are chronic disorders, in which the interaction between environmental exposures and the immune system plays an important role. The prevalence and societal costs of these diseases are rising in the European Union. The EXIMIOUS consortium—gathering experts in immunology, toxicology, occupational health, clinical medicine, exposure science, epidemiology, bioinformatics, and sensor development—will study eleven European study populations, covering the entire lifespan, including prenatal life. Innovative ways of characterizing and quantifying the exposome will be combined with high-dimensional immunophenotyping and -profiling platforms to map the immune effects (immunome) induced by the exposome. We will use two main approaches that “meet in the middle”—one starting from the exposome, the other starting from health effects. Novel bioinformatics tools, based on systems immunology and machine learning, will be used to integrate and analyze these large datasets to identify immune fingerprints that reflect a person’s lifetime exposome or that are early predictors of disease. This will allow researchers, policymakers, and clinicians to grasp the impact of the exposome on the immune system at the level of individuals and populations.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 874707

Is asthma a risk factor for COVID-19? Are phenotypes important?

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Infeccions respiratòries i tuberculosi; Asma i al·lèrgiaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; COVID-19; Infecciones respiratorias y tuberculosis; Asma y alergiaCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Respiratory infections and tuberculosis; Asthma and allergyThese results reaffirm the idea that asthma does not appear to be a risk factor for the development of #COVID19. However, most of the asthma patients in this study had a non-T2 phenotype

Risk factors for the development of bronchiectasis in patients with asthma

Asthma; Medical researchAsma; Investigación médicaAsma; Recerca mèdicaThough asthma and bronchiectasis are two different diseases, their coexistence has been demonstrated in many patients. The aim of the present study is to compare the characteristics of asthmatic patients with and without bronchiectasis and to assess risk factors for the development of this condition. Two hundred and twenty-four moderate-severe asthmatic patients were included. The severity of bronchiectasis was assessed by Reiff and FACED parameters. Logistic regression was used to identify independent factors associated with bronchiectasis. Bronchiectasis was identified in 78 asthma patients. In severe asthma patients, its prevalence was 56.9%. Bronchiectasis was defined as mild in81% of patients using modified Reiff criteria and in 74% using FACED criteria. Asthmatic patients with bronchiectasis had decreasing FEV1, FVC and FEV1/FVC (p = 0.002, 0.005 and 0.014 respectively), presented more frequent asthma exacerbations (p < 0.001) and worse asthma control (ACT 21 vs 16pts, p < 0.001). Factors independently associated with bronchiectasis were older age (42–65 years: OR, 3.99; 95% CI 1.60 to 9.95, P = 0.003; ≥ 65 years: OR, 2.91; 95% CI 1.06 to 8.04, P = 0.039), severe asthma grade (OR, 8.91; 95% CI 3.69 to 21.49; P < 0.001) and frequency of asthma exacerbations (OR, 4.43; 95% CI 1.78 to 11.05; P < 0.001). In patients with severe asthma, age of asthma onset (OR, 1.02; 95% CI 1.01 to 1.04; P = 0.015) and asthma exacerbations (OR, 4.88; 95% CI 1.98 to 12.03; P = 0.001) were independently associated with the development of bronchiectasis. The prevalence of bronchiectasis in severe asthmatic patients is high. Age of asthma onset and exacerbations were independent factors associated with the occurrence of bronchiectasis.The study was partially supported by FIS PI15/01900 (Fondo Europeo de Desarrollo Regional (FEDER) and Fundacio Catalana de Pneumología (FUCAP). MJC is supported by the Miguel Servet program of the Instituto de Salud Carlos III (MSII17/00025). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Association of rhinitis with asthma prevalence and severity

Asthma; Comorbidities; Risk factorsAsma; Comorbilitats; Factors de riscAsma; Comorbilidades; Factores de riesgoAsthma and rhinitis often co-exist in the same patient. Although some authors observed a higher prevalence and/or greater severity of asthma in patients with rhinitis, this view is not homogeneous and the debate continues. The aim of our study is to describe the prevalence of rhinitis in children and adolescents and to analyse their relationship with the prevalence of asthma. A multicentre study was conducted using the methodology of the International Study of Asthma and Allergies in Childhood (ISAAC). The target population of the study was all those school children aged 6–7 and 13–14 years from 6 of the main health catchment areas of Galicia (1.9 million inhabitants). The schools required were randomly selected, and all children in the targeted age ranges were included. Multiple logistic regression was used to obtain adjusted prevalence odds ratios (OR) between asthma symptoms of the schoolchildren and rhinitis prevalence. The results were adjusted for parental smoking habits, maternal education level, cat and dog exposure, and obesity. A total of 21,420 valid questionnaires were finally obtained. Rhinitis was associated with a significant increase in the prevalence of asthma in both age groups. The highest OR were 11.375 for exercise induced asthma (EIA) for children with recent rhinoconjunctivitis and 9.807 for children with recent rhinitis in 6–7 years old group. The prevalence OR’s are higher in EIA and severe asthmatics. Rhinitis in children and adolescents is associated with a higher prevalence and severity of asthma.This work was funded by the Maria Jose Jove Foundation

Expansion of different subpopulations of CD26−/low T cells in allergic and non-allergic asthmatics

Asthma; Allergy; CD26Asma; Al·lèrgia; CD26Asma; Alergia; CD26CD26 displays variable levels between effector (TH17 ≫ TH1 > TH2 > Treg) and naïve/memory (memory > naïve) CD4+ T lymphocytes. Besides, IL-6/IL-6R is associated with TH17-differentiation and asthma severity. Allergic/atopic asthma (AA) is dominated by TH2 responses, while TH17 immunity might either modulate the TH2-dependent inflammation in AA or be an important mechanism boosting non-allergic asthma (NAA). Therefore, in this work we have compared the expression of CD26 and CD126 (IL-6Rα) in lymphocytes from different groups of donors: allergic (AA) and non-allergic (NAA) asthma, rhinitis, and healthy subjects. For this purpose, flow cytometry, haematological/biochemical, and in vitro proliferation assays were performed. Our results show a strong CD26-CD126 correlation and an over-representation of CD26- subsets with a highly-differentiated effector phenotype in AA (CD4+CD26-/low T cells) and NAA (CD4-CD26- γδ-T cells). In addition, we found that circulating levels of CD26 (sCD26) were reduced in both AA and NAA, while loss of CD126 expression on different leukocytes correlated with higher disease severity. Finally, selective inhibition of CD26-mRNA translation led to enhanced T cell proliferation in vitro. These findings support that CD26 down-modulation could play a role in facilitating the expansion of highly-differentiated effector T cell subsets in asthma

Multi-ancestry genome-wide association study of asthma exacerbations

Asthma exacerbations; Single-nucleotide polymorphismExacerbaciones del asma; Polimorfismo de un solo nucleótidoExacerbacions de l'asma; Polimorfisme d'un sol nucleòtidBackground Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. Methods A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10−5) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. Results One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 × 10−6 and replication: ORT allele = 0.89, p = 5.35 × 10−3) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10−5 and replication: ORC allele = 0.89, p = 1.30 × 10−2). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. Conclusions This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.This work was funded by the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033, and the European Regional Development Fund “ERDF A way of making Europe” by the European Union (SAF2017-83417R), by MCIN/AEI/10.13039/501100011033 (PID2020-116274RB-I00) and by the Allergopharma-EAACI award 2021. This study was also supported by the SysPharmPedia grant from the ERACoSysMed 1st Joint Transnational Call from the European Union under the Horizon 2020. GALA II and SAGE studies were supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professor in Pharmaceutical Sciences II, the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL117004, R01HL128439, R01HL135156, X01HL134589, R01HL141992, and R01HL141845), National Institute of Health and Environmental Health Sciences (R01ES015794 and R21ES24844); the National Institute on Minority Health and Health Disparities (NIMHD) (P60MD006902, R01MD010443, and R56MD013312); the National Institute of General Medical Sciences (NIGMS) (RL5GM118984); the Tobacco-Related Disease Research Program (24RT-0025 and 27IR-0030); and the National Human Genome Research Institute (NHGRI) (U01HG009080) to EGB. The PACMAN study was funded by a strategic alliance between GlaxoSmithKline and Utrecht Institute for Pharmaceutical Sciences. The Slovenia study was financially supported by the Slovenian Research Agency (research core funding No. P3-0067) and from SysPharmPediA grant, co-financed by the Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106). The SHARE Bioresource (GoSHARE) and SHARE have ongoing funding from NHS Research Scotland and were established by funding from The Wellcome Trust Biomedical Resource [Grant No. 099177/Z/12/Z]. Genotyping of samples from BREATHE, PAGES, and GoSHARE was funded by AC15/00015 and conducted at the Genotyping National Centre (CeGEN) CeGen-PRB3-ISCIII; supported by ISCIII and European Regional Development Fund (ERDF) (PT17/0019). ALSPAC was supported by the UK Medical Research Council and Wellcome (102215/2/13/2) and the University of Bristol. The Swedish Heart-Lung Foundation, the Swedish Research Council, and Region Stockholm (ALF project and database maintenance) funded the BAMSE study. The PASS study was funded by the NHS Chair of Pharmacogenetics via the UK Department of Health. U-BIOPRED was funded by the Innovative Medicines Initiative (IMI) Joint Undertaking, under grant agreement no. 115010, resources for which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and kind contributions from companies in the European Federation of Pharmaceutical Industries and Associations (EFPIA). Genotyping of samples from GEMAS and MEGA studies was funded by the Spanish Ministry of Science and Innovation (SAF2017-87417R) at the Spanish National Cancer Research Centre, in the Human Genotyping lab, a member of CeGen, PRB3, and was supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The genotyping of GEMAS was also partially funded by Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC19/17). The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. ALLIANCE Cohort was funded by grants from the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) as part of the German Centre for Lung Research (DZL) funding. The Hartford-Puerto Rico study was funded by the U.S. National Institutes of Health (grant HL07966 to JCC). MP-Y was funded by the Ramón y Cajal Program (RYC-2015-17205) by MCIN/AEI/10.13039/501100011033 and by the European Social Fund “ESF Investing in your future”. MP-Y and JV were supported by CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain (CB/06/06/1088). EH-L was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” (PRE2018-083837). JP-G was supported by a fellowship awarded by Spanish Ministry of Universities (FPU19/02175). AE-O reports funding from the Spanish Ministry of Science, Innovation, and Universities (MICIU) and Universidad de La Laguna (ULL). NH-P was supported by a Medium-Term Research Fellowship by the European Academy of Allergy and Clinical Immunology (EAACI) and a Long-Term Research Fellowship by the European Respiratory Society (ERS) (LTRF202101-00861). UP and MG were supported by the Ministry of Education, Science and Sport of the Republic of Slovenia, grant PERMEABLE (contract number C3330-19-252012). SCSGES results were contributed by authors FTC and YYS. FTC has received research support from the Singapore Ministry of Education Academic Research Fund, Singapore Immunology Network (SIgN), National Medical Research Council (NMRC) (Singapore), Biomedical Research Council (BMRC) (Singapore), and the Agency for Science Technology and Research (A*STAR) (Singapore); Grant Numbers: N-154-000-038-001, R-154-000-191-112, R-154-000-404-112, R-154-000-553-112, R-154-000-565-112, R-154-000-630-112, R-154-000-A08-592, R-154-000-A27-597, R-154-000-A91-592, R-154-000-A95-592, R-154-000-B99-114, BMRC/01/1/21/18/077, BMRC/04/1/21/19/315, SIgN-06-006, SIgN-08-020, NMRC/1150/2008, and H17/01/a0/008. F.T.C. has received consulting fees from Sime Darby Technology Centre; First Resources Ltd; Genting Plantation, and Olam International, outside the submitted work. YYS has received research support from the NUS Resilience & Growth Postdoctoral Fellowships with grant number: R-141-000-036-281. QY conducted the analysis from Hartford-Puerto Rico and United Kingdom Biobank studies. QY was funded by the U.S. National Institutes of Health (HL138098)

Metodos no invasivos de medición de la inflamación en las neumonitis por hipersensibilidad : utilidad del esputo inducido

El diagnòstic de la pneumonitis per hipersensibilitat requereix en ocasions la realització de tècniques diagnòstiques invasives que de vegades no són possibles de practicar donat el deteriorament de la capacitat funcional que presenta el pacient. L'ús de noves tècniques d'estudi de la inflamació pulmonar, a través de mètodes no invasius, podrien ser d'utilitat en el diagnòstic i seguiment d'aquesta entitat. En el present estudi, plantegem el valor de l'estudi de l'esput induït en el diagnòstic de la pneumonitis per hipersensibilitat, així com la seva possible utilitat en el context de les proves de provocació bronquial específiques.El diagnóstico de la neumonitis por hipersensibilidad requiere en ocasiones la realización de técnicas diagnósticas invasivas que en ocasiones no son posibles de practicar dado el deterioro de la capacidad funcional que presenta el paciente. El empleo de nuevas técnicas de estudio de la inflamación pulmonar, a través de métodos no invasivos, podrían ser de utilidad en el diagnóstico y seguimiento de esta entidad. En el presente estudio, planteamos el valor del estudio del esputo inducido en el diagnóstico de la neumonitis por hipersensibilidad, así como su posible utilidad en el contexto de las pruebas de provocación bronquial específica

Asbestos Exposure and Severity of COVID-19

COVID-19; Asbestos exposure; Occupational exposureCOVID-19; Exposició a l'amiant; Exposició laboralCOVID-19; Exposición al amianto; Exposición laboralBackground: The aim of this study was to analyse the relationship between occupational exposure to asbestos and the severity of SARS-CoV-2 infection. Methods: We evaluated patients who survived admission in our centre for COVID-19 pneumonia. Demographic, analytical, and clinical variables were collected during admission. After discharge, a previously validated occupational exposure to asbestos questionnaire was administered. Spirometry, CO diffusion test, the 6-min walk test, and high-resolution chest CT were performed. Patients who required respiratory support (oxygen, CPAP, or NIV) were considered severe. Results: In total, 293 patients (mean age 54 + 13 years) were included. Occupational exposure to asbestos was detected in 67 (24%). Patients with occupational exposure to asbestos had a higher frequency of COVID-19 pneumonia requiring respiratory support (n = 52, 77.6%) than their unexposed peers (n = 139, 61.5%) (p = 0.015). Asbestos exposure was associated with COVID-19 severity in the univariate but not in the multivariate analysis. No differences were found regarding follow-up variables including spirometry and the DLCO diffusion, the 6-min walk test, and CT alterations. Conclusions: In hospitalised patients with COVID-19 pneumonia, those with occupational exposure to asbestos more frequently needed respiratory support. However, an independent association between asbestos exposure and COVID-19 severity could not be confirmed.M.-J.C. is a member of the Miguel Servet research program of the Carlos III Health Institute (MSII17/00025). This project was funded by Instituto de Salud Carlos III (PI20/01134) and Fondo Europeo de Desarrollo Regional (FEDER). The sponsors played no part in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript

Influence of the environment on the characteristics of asthma

Environmental sciences; Health careCiències ambientals; Atenció sanitàriaCiencias Ambientales; Atención sanitariaFew studies have compared the prevalence of asthma in urban and rural settings or explored the issue of whether these two manifestations of the disease may represent different phenotypes. The aim of this study was: (a) to establish whether the prevalence of asthma differs between rural and urban settings, and b) to identify differences in the clinical presentation of asthma in these two environments. Descriptive epidemiological study involving individuals aged 18 or over from a rural (n = 516) and an urban population (n = 522). In the first phase, individuals were contacted by letter in order to organize the administration of a first validated questionnaire (Q1) designed to establish the possible prevalence of bronchial asthma. In the second phase, patients who had presented association patterns in the set of variables related to asthma in Q1 completed a second validated questionnaire (Q2), designed to identify the characteristics of asthma. According to Q1, the prevalence of asthma was 15% (n = 78) and 11% (n = 59) in rural and urban populations respectively. Sixty-five individuals with asthma from the rural population and all 59 individuals from the urban population were contacted and administered the Q2. Thirty-seven per cent of the individuals surveyed had previously been diagnosed with bronchial asthma (35% in the rural population and 40% in the urban setting). In the urban asthmatic population there was a predominance of women, a greater personal history of allergic rhinitis and a family history of allergic rhinitis and/or eczema. Asthma was diagnosed in adulthood in 74.8% of the patients, with no significant differences between the two populations. Regarding symptoms, cough (morning, daytime and night) and expectoration were more frequent in the urban population. The prevalence of asthma does not differ between urban and rural settings. The differences in exposure that characterize each environment may lead to different manifestations of the disease and may also affect its severity.MJC is supported by the Miguel Servet program of the Instituto de Salud Carlos III (MSII17/00025). This project received funding from the Fundació Catalana de Pneumologia (FUCAP), FIS PI18/00344, Fondo Europeo de Desarrollo Regional (FEDER) and Menarini. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Analysis of Differentially Expressed MicroRNAs in Serum and Lung Tissues from Individuals with Severe Asthma Treated with Oral Glucocorticoids

Biomarker; Individuals with severe asthma; Oral corticosteroidsBiomarcador; Persones amb asma greu; Corticosteroides oralsBiomarcador; Personas con asma grave; Corticosteroides oralesNowadays, microRNAs (miRNAs) are increasingly used as biomarkers due to their potential contribution to the diagnosis and targeted treatment of a range of diseases. The aim of the study was to analyze the miRNA expression profiles in serum and lung tissue from patients with severe asthma treated with oral corticosteroids (OCS) and those without OCS treatment. For this purpose, serum and lung tissue miRNAs of OCS and non-OCS asthmatic individuals were evaluated by miRNAs-Seq, and subsequently miRNA validation was performed using RT-qPCR. Additionally, pathway enrichment analysis of deregulated miRNAs was conducted. We observed altered expression by the next-generation sequencing (NGS) of 11 miRNAs in serum, of which five (hsa-miR-148b-3p, hsa-miR-221-5p, hsa-miR-618, hsa-miR-941, and hsa-miR-769-5p) were validated by RT-qPCR, and three miRNAs in lung tissue (hsa-miR-144-3p, hsa-miR-144-5p, and hsa-miR-451a). The best multivariate logistic regression model to differentiate individuals with severe asthma, treated and untreated with OCS, was to combine the serum miRNAs hsa-miR-221-5p and hsa-miR-769-5p. Expression of hsa-miR-148b-3p and hsa-miR-221-5p correlated with FEV1/FVC (%) and these altered miRNAs act in key signaling pathways for asthma disease and the regulated expression of some genes (FOXO3, PTEN, and MAPK3) involved in these pathways. In conclusion, there are miRNA profiles differentially expressed in OCS-treated individuals with asthma and could be used as biomarkers of OCS treatment.This work was supported by ISCIII—Instituto de Salud Carlos III, FIS (Fondo de Investigación Sanitaria—Spanish Health Research Fund) grants PI18/00167, PI21/00896, and FI19/00067; Ciber de Enfermedades Respiratorias (CIBERES); RTC-2017-6501-1 (Ministerio de Ciencia, Innovación y Universidades), a Carlos III Institute of Health Initiative; and FEDER funds (Fondo Europeo de Desarrollo Regional)