Household aeroalergens in the inception of infant atopy and asthma

Aquesta tesi doctoral consisteix en una sèrie de deu articles (8 publicats y 2 en premsa) basats en dades recollides a l'estudi AMICS (Asthma Multicentre Infant Cohort Study), portat a terme a Ashford (UK) a Barcelona y a Menorca. A més dels propis articles, s'inclouen una introducció i una discussió generals per a mostrar de forma conjunta les troballes i posar-les en el context de l'evidència científica actual. També s'inclou un apartat sobre les implicacions dels resultats obtinguts tant per la recerca etiològica de l'asma com per a la salut pública, així com una llista de recomanacions finals. Des de l'any 1997 soc el responsable del estudi de cohort AMICS a Menorca, que ha comptat amb diverses beques del Ministeri de Sanitat i Consum, de la Comunitat Europea i d'una fundació privada. L'objectiu inicial principal del projecte europeu era mesurar el paper del aeroal.lergens domèstics més comuns en el procés d'iniciació de l'atòpia i l'asma. La cohort de Menorca va ampliar el seus objectius incloent dades addicionals sobre dieta i nivells d'organoclorats a la sang. El projecte continua a Menorca i en el moment de presentar la tesi s'està realitzant el seguiment del 9 anys.The present doctoral thesis consists of a series of ten articles (8 published and 2 in press) based on data collected from the Asthma Multicentre Infant Cohort Study (AMICS), carried out in Ashford (UK) and Barcelona and Menorca (Spain). In addition to the articles themselves, a general introduction and a general discussion are included to put together the findings of the articles in the light of present scientific evidence. A section on the implications for the etiologic research of asthma and for public health and a list of final conclusions are also included. I have been responsible of the AMICS cohort in Menorca since its origin in 1997, which has been funded by different grants from the Spanish Ministry of Health, the European Commission and a private foundation. The main initial objective of the European project was to measure the role of common domestic aeroallergens in the inception of atopy and asthma. The Menorca cohort extended its objectives including additional data on dietary habits and blood levels of organochlorine compounds. The project continues in Menorca and at the moment of presenting this thesis the 9 years follow-up work is being carried out

Prenatal concentrations of polychlorinated biphenyls, DDE, and DDT and overweight in children: a prospective birth cohort study

Background: Recent experimental evidence suggests that prenatal exposure to endocrine-disrupting chemicals (EDCs) may increase postnatal obesity risk and that these effects may be sex or diet dependent. Objectives: We explored whether prenatal organochlorine compound (OC) concentrations [polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyltrichloroethane (DDT)] were associated with overweight at 6.5 years of age and whether child sex or fat intakes modified these associations. Methods: We studied 344 children from a Spanish birth cohort established in 1997–1998. Overweight at 6.5 years was defined as a body mass index (BMI) z-score ≥ 85th percentile of the World Health Organization reference. Cord blood OC concentrations were measured and treated as categorical variables (tertiles). Children’s diet was assessed by food frequency questionnaire. Relative risks (RRs) were estimated using generalized linear models. Results: After multivariable adjustment, we found an increased RR of overweight in the third tertile of PCB exposure [RR = 1.70; 95% confidence interval (CI): 1.09, 2.64] and the second tertile of DDE exposure (RR = 1.67; 95% CI: 1.10, 2.55), but no association with DDT exposure in the population overall. Associations between overweight and PCB and DDE concentrations were strongest in girls (p-interaction between 0.01 and 0.28); DDT was associated with overweight only in boys. For DDT we observed stronger associations in children with fat intakes at or above compared with below the median, but this interaction was not significant (p-interaction > 0.05). Conclusions: This study suggests that prenatal OC exposures may be associated with overweight in children and that sex and high-fat intake may influence susceptibility.This study was funded by grants from the Spanish Ministry of Health (FIS-97/0588 and FIS-00/0021-02), the Instituto Carlos III (Red INMA G03176 and predoctoral grant PFIS 2010, Register FI10/00399), the Fundació La Caixa (00/007-00), the RecerCaixa (Register 2010ACUP 00349), and the European Commission (Concerted Action, contract QLK4-2000-00263

Prenatal exposure to persistent organic pollutants and markers of obesity and cardiometabolic risk in Spanish adolescents

Background: Prenatal exposure to persistent organic pollutants (POPs) has been linked to cardiometabolic (CM) risk factors in childhood, but there are no studies evaluating the persistence of these associations into adolescence, a period of relevant changes in endocrine-dependent organ systems and rapid increases in lean and fat mass. We examined the associations of prenatal POP exposures with body mass index (BMI) from age 4 to 18 years, and with other CM risk markers in adolescence. Methods: We analysed 379 children from the Spanish INMA-Menorca birth cohort study with measured cord blood POP concentrations. We calculated BMI z-scores at ages 4, 6, 11, 14 and 18 years using the WHO growth reference. Body fat % was measured at 11 and 18 years and waist-to-height ratio (WHtR) and blood pressure (BP) at 11, 14 and 18 years. We measured CM biomarkers in fasting blood collected at age 14 years and calculated a CM-risk score as the sum of the sex-, and age-specific z-scores for waist circumference, mean arterial BP, homeostatic model assessment of insulin resistance, fasting blood triglycerides, and high-density lipoprotein cholesterol (HDL-C) (n = 217). Generalised estimating equations and multivariate linear regression models assessed the associations with repeated and single time-point measures, respectively. Results: Hexachlorobenzene (HCB) exposure in the third tertile, compared to the first tertile, was associated with higher BMI (β = 0.24; 95% CI: 0.01, 0.47) and WHtR z-score (β = 0.27; 95% CI: 0.04, 0.51). A continuous increase in HCB was associated with an elevated body fat % (β per 10-fold increase = 4.21; 95% CI: 0.51, 7.92), systolic BP (β = 0.32; 95% CI: 0.02, 0.64) and diastolic BP z-score (β = 0.32; 95% CI: 0.02, 0.62) across all ages, and with higher CM-risk score (β = 1.59; 95% CI: 0.02, 3.18) and lipid biomarkers (total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C)) at 14 years. Dichlorodiphenyltrichloroethane (p,p'-DDT) exposure was non-monotonically associated with BMI and systolic BP. p,p'-DDE and Σ-polychlorinated biphenyls (PCBs) (sum of congeners 118, 138, 153, 180) were not associated with adiposity or BP. p,p'-DDT exposure was associated with an increased CM-risk score, and ΣPCBs concentrations with LDL-C in all adolescents and with total cholesterol only in girls (p-sex interaction = 0.05). Conclusion: This first longitudinal study from 4 to 18 years suggests that the previously reported POP associations with child BMI persist later in adolescence and that prenatal POP exposures are associated with major risk factors for adult CM syndrome.This study received funding from the European Community’s Horizon 2020 programme under grant agreement no 825712, the Oberon project. The Menorca cohort was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263

The development of the MeDALL core questionnaires for a harmonized follow-up assessment of eleven European birth cohorts on asthma and allergies

Background: Numerous birth cohorts have been initiated in the world over the past 30 years using heterogeneous methods to assess the incidence, course and risk factors of asthma and allergies. The aim of the present work is to provide the stepwise proceedings of the development and current version of the harmonized MeDALL-Core Questionnaire (MeDALL-CQ) used prospectively in 11 European birth cohorts. Methods: The harmonization of questions was accomplished in 4 steps: (i) collection of variables from 14 birth cohorts, (ii) consensus on questionnaire items, (iii) translation and back-translation of the harmonized English MeDALL-CQ into 8 other languages and (iv) implementation of the harmonized follow-up. Results: Three harmonized MeDALL-CQs (2 for parents of children aged 4-9 and 14-18, 1 for adolescents aged 14-18) were developed and used for a harmonized follow-up assessment of 11 European birth cohorts on asthma and allergies with over 13,000 children. Conclusions: The harmonized MeDALL follow-up produced more comparable data across different cohorts and countries in Europe and will offer the possibility to verify results of former cohort analyses. Thus, MeDALL can become the starting point to stringently plan, conduct and support future common asthma and allergy research initiatives in Europe.Mechanisms of the Development of Allergy (MeDALL) is funded by the European Union in the 7th Framework program, grant agreement No. 26135

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010–2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda

Maternal circulating Vitamin D3 levels during pregnancy and behaviour across childhood

Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D3, children obtained higher social competence scores (coefficient = 0.77; 95% CI = 0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed.We thank all the investigators who have collected information and samples from the participants. Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundació La marató de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017. Asturias: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), FIS-PI042018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI18/00909, CIBERESP, Obra Social Cajastur/Fundación Liberbank and UNIVERSIDAD DE OVIEDO. Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090 and FIS-PI13/02187), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)

Television viewing duration during childhood and long- association with adolescent neuropsychological outcomes

This study is aiming to evaluate the association between television viewing during childhood and long-term adolescent neuropsychological outcomes and the potential explanatory pathways. This is a longitudinal study based on 278 children participating in the INMA birth cohort (1998) in Menorca Island, Spain. The exposure is parent-reported duration of child television viewing (hours per week) at 6 and 9 years of age. Neuropsychological outcomes were assessed at 14 years of age using the N-back test. Behavioral outcomes at 14 years of age were assessed using the Strengths and Difficulties Questionnaire (SDQ) and school performance was assessed by the global school score. Regression models were developed to quantify the associations between duration of television viewing and neuropsychological outcomes adjusted for child and parents' characteristics. The average of weekly TV viewing from 6 to 9 years was 9.2 h (SD: 4.1). Only N-back test outcomes exhibited statistically significant differences in crude models. Children viewing > 14 h per week tended to show larger latencies in working memory reaction time (HRT in ms), beta (CI) = 53 (0-107). After adjusting for potential social confounders, the association weakened and became non-significant but adverse trends were slightly preserved. Early life TV viewing was not associated with adolescent neuropsychological outcomes after adjustment for potential confounders. Further research including larger and exhaustive population-based cohort studies is required in order to verify our conclusions.All phases of the study was supported for grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), (FIS 97/0588, 00/0021-2, PI061756, PS0901958 and CP14/00108), Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000- 00263. Payam Dadvand is funded by a Ramón y Cajal fellowship (RYC- 2012-10995) awarded by the Spanish Ministry of Economy and Competitiveness. Miguel Servet (MS) fellowship (MS14/00108) awarded by the Spanish Institute of Health Carlos III (Ministry of Economy and/nCompetitiveness)

The INMA-INfancia y Medio Ambiente-(Environment and Childhood) project: more than 10 years contributing to environmental and neuropsychological research

BACKGROUND: In 2003 the INMA-INfancia y Medio Ambiente (Environment and Childhood) project, a Spanish national network of birth cohorts including more than 3500 participants, was set up with the aim to assess the health impacts of pre- and postnatal environmental exposures on children. The project has published more than 60 papers on maternal and environmental factors related to neuropsychological development in children, one of the main research interests within the project. With the present review, we evaluate the evidence provided by the INMA project on this topic and discuss how the data can contribute to cover the challenges that children's environmental health research will face in the coming years. RESULTS: The INMA project has contributed to provide increasing evidence of the association between prenatal exposure to persistent organic pollutants (POPs) and child neuropsychological development, but it has also shown, using innovative methodologies, that postnatal exposure to these compounds does not play a role in this association. The project has also contributed to show the detrimental influence of certain air pollutants on child neuropsychological development, as well as how a balanced maternal fish intake can protect from the potential adverse effects of prenatal exposure to mercury. Also, the project has contributed to the understanding of impacts of nutritional factors including supplement intake and vitamin D levels during pregnancy and the role of breastfeeding on the neuropsychological benefits. CONCLUSIONS: INMA findings underscore the importance of continued research on the delineation of the sensitive windows of exposure both during pregnancy and postnatally and on the combined effects of environmental exposures, denoted the exposome. In terms of health policy, INMA findings have important implications for the development of public health policies to advance the health and development of children.This study was supported Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, 97/0588, 00/0021-2, PI04/1436, PI06/1756, PI08/1151, PS09/01958, PI12/01890, PI14/00677, MS13/00054, CP13/00054 including FIS-FEDER funds 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314, 09/02311, 09/02647, 11/0178, 11/02591, 11/02038, 13/1944, 13/2032, 13/02429, 14/0891, 14/1687, and 16/1288) and Miguel Servet-FEDER MS15/00025, Spanish Ministry of Health - CIBERESP (FIS-97/1102, FIS-PS09/00362, FIS-07/0252, FIS-PI11/00610, FISPI07/0252, FISPI11/0610, FIS-PI04/2018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI06/0867, FIS-PS09/00090, FIS-PI13/02187, PI13/02406, MS13/00054), Spanish Ministry of Economy and Competitiveness (SAF2012-32991 incl. FEDER funds), EU Comission (QLK4-CT-2000-00263, QLK4-1999-01422, QLK4-2002-00603 and CONTAMED FP7-ENV-212502, FP7-ENV-2011 cod 282957, 261357, 308333 and 603794 and HEALTH.2010.2.4.5-1), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR (2009 SGR501, 2014 SGR 822), Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221), Consejería de Salud de la Junta de Andalucía (grant number 183/07 and SAS-PI-0675-2010), Conselleria de Sanitat, Generalitat Valenciana, Andalusia Regional Government – Consejería de Salud (Grants P09-CTS-5488 Project of Excellence, and SAS PI-0133-2007; PI-0675–2010), Agence Nationale de Securite Sanitaire de l’Alimentation de l’Environnement et du Travail (1262C0010), beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, Fundació La Caixa (97/009-00 and 00/077-00), Fundació La Marató de TV3 (090430), Obra Social Cajastur/Fundación Liberbank and University of Oviedo, and annual agreements with the municipalities of the area of study (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain

Maternal circulating Vitamin D3 levels during pregnancy and behaviour across childhood

Vitamin D deficiency during critical periods of development could lead to persistent brain alterations. We aimed to assess the association between maternal vitamin D3, the major circulatory form of vitamin D, at pregnancy and neurodevelopmental outcomes during childhood, namely: behavioural problems, Attention Deficit and Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) symptoms, and social competence. This study included 2,107 mother-child pairs of a Spanish population-based birth cohort. Maternal plasma vitamin D3 was measured in pregnancy. The outcomes were measured through questionnaires at 5, 8, 14, and 18 years old. We ran multivariate regression models adjusted for potential confounding variables. We found that per each 10 ng/mL increment of maternal vitamin D3, children obtained higher social competence scores (coefficient = 0.77; 95% CI = 0.19, 1.35) at 5 years old. However, we observed null associations between maternal vitamin D3 and total behavioural problems and ADHD and ASD symptoms in children from 5 to 18 years old. Further studies carried out in countries where the population is exposed to lower vitamin D levels are needed.We thank all the investigators who have collected information and samples from the participants. Menorca: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; 97/0588; 00/0021-2; PI061756; PS0901958; PI14/00677 incl. FEDER funds), CIBERESP, Beca de la IV convocatoria de Ayudas a la Investigación en Enfermedades Neurodegenerativas de La Caixa, and EC Contract No. QLK4-CT-2000-00263. Sabadell: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds; CPII/00018), CIBERESP, Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat de Catalunya-AGAUR 2009 SGR 501, Fundació La marató de TV3 (090430), EU Commission (261357). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. Valencia: This study was funded by Grants from UE (FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1), Spain: ISCIII (G03/176; FIS-FEDER: PI11/01007, PI11/02591, PI11/02038, PI12/00610, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, and PI17/00663; Miguel Servet-FEDER CP11/00178, CP15/00025, and MSII16/00051), Generalitat Valenciana: FISABIO (UGP 15-230, UGP-15-244, and UGP-15-249), and Alicia Koplowitz Foundation 2017. Asturias: This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), FIS-PI042018, FIS-PI09/02311, FIS-PI13/02429, FIS-PI18/00909, CIBERESP, Obra Social Cajastur/Fundación Liberbank and UNIVERSIDAD DE OVIEDO. Gipuzkoa: This study was funded by grants from Instituto de Salud Carlos III (FIS-PI06/0867, FIS-PI09/00090 and FIS-PI13/02187), CIBERESP, Department of Health of the Basque Government (2005111093, 2009111069, 2013111089 and 2015111065), and the Provincial Government of Gipuzkoa (DFG06/002, DFG08/001 and DFG15/221) and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain)

Early-life house dust mite allergens, childhood mite sensitization, and respiratory outcomes.

BACKGROUND: Exposure to indoor allergens during early life may play a role in the development of the immune system and inception of asthma. OBJECTIVE: To describe the house dust mite (HDM) allergen concentrations in bedroom dust during early life and to evaluate its associations with HDM sensitization, wheezing, and asthma, from birth to school age, in 5 geographically spread European birth cohorts. METHODS: We included 4334 children from INMA-Menorca (Spain), BAMSE (Sweden), LISAplus and MAS (Germany), and PIAMA-NHS (the Netherlands). Dust samples were collected from bedrooms during early life and analyzed for Dermatophagoides pteronyssinus (Der p1) and Dermatophagoides farinae (Der f1). HDM concentrations were divided into four categories. Sensitization was determined by specific IgE. Wheezing and asthma information up to 8/10 years was collected through questionnaires. We performed mixed-effects logistic regression models and expressed associations as odds ratios with 95% confidence intervals. RESULTS: House dust mite concentrations varied across cohorts. Mean allergen concentrations were highest in INMA-Menorca (geometric mean (GM) Der p1 = 3.3 μg/g) and LISAplus (GM Der f1 = 2.1 μg/g) and lowest in BAMSE (GM Der p1 = 0.1 μg/g, Der f1 = 0.3 μg/g). Moderate and high HDM concentrations were significantly (P-values < 0.05) associated with 50-90% higher prevalence of HDM sensitization. No significant associations were observed with respiratory outcomes./nCONCLUSION: Our study based on geographically spread regions, a large sample size, and a wide range of allergen concentration shows that HDM allergen concentrations vary across regions and that exposure during early life plays a role in the development of allergic sensitization but not in the development of respiratory outcomes