[FG] Pediatric PulmonologyHead of Research Unit PD Dr. rer. nat.Edgar Delgado-Eckert Prof. Dr. med.Urs FreyOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 11 foundShow per page10 10 20 50 Air Pollution and Effects on Lung Functional Development and Respiratory Morbidity in At-Risk Infants Research Project | 4 Project MembersBACKGROUND AND RATIONALE: This is a direct continuation of SNF 182871/1, which investigated the impact of early-childhood environmental factors on lung functional growth and consequences for later respiratory morbidity in healthy term infants. We previously demonstrated that even low-level air pollution exposure during pregnancy and early childhood is associated with impaired lung functional growth in infancy and early childhood. Although the mechanisms are still unclear, they could be related to lung functional growth deficits or remodeling of the lung due to changes in the intrauterine environment. Air pollution is known to induce oxidative stress response and related autophagy and cellular senescence mechanisms, potentially playing a role in pollution-related lung pathology and in remodeling. As novel preliminary evidence in SNF 182871/1, we recently found that, in the cord blood of human infants, autophagy-related biomarkers are correlated with remodeling biomarkers. We also found that air pollution exposure during pregnancy is associated with biomarkers of autophagy and remodeling in the cord blood of healthy term infants. Interestingly, these mechanisms also play an important role in fetal development and preterm birth, and may thus theoretically contribute to the susceptibility of infants-and particularly preterm infants-to oxidative stress and air pollution effects. Indeed, as first evidence from SNF 182871/1, we also found an enhanced impact of air pollutants on lung function impairment of preterm infants. Furthermore, our own preliminary human data show that markers of autophagy, and remodeling already have significant differences between the cord blood of preterm infants compared to term infants at birth prior to early postnatal injury. Bringing this together, we hypothesize that the interaction of oxidative stress response, autophagy and remodeling could be a key mechanism involved in the complex host-environment interaction determining lung functional growth and related respiratory morbidity. Moreover, this response could be different in infants at risk for chronic respiratory symptoms, such preterm infants, infants born from asthmatic mothers or infants exposed to high levels of air pollution during pregnancy. OVERALL OBJECTIVES: We aim to expand the ongoing BILD cohort of (i) term infants with two risk subgroups, (ii) infants born preterm, and (iii) infants born to asthmatic mothers, and we will investigate the differences in response to prenatal air pollution in relation to the above key mechanisms. SPECIFIC AIMS: In comparison to healthy term infants, we will investigate in study phase 1, (i) whether the increased susceptibility of infants to prenatal air pollution in these three risk groups is related to differences in markers of oxidative stress response, autophagy, and remodeling in cord blood and in study phase 2, (ii) whether these pollution-related cord blood profiles are correlated to lung functional development and subsequent symptoms in the first year of life (primary outcomes) and at school age (secondary outcomes). We will replicate these findings in other birth cohorts from collaborators (Germany, Australia) with comparable outcome measures. METHODS: In our prospective BILD birth cohort of 1000 unselected healthy term infants, 400 preterm infants, and 200 infants from asthmatic mothers we will (i) estimate indoor and outdoor air pollution exposure during pregnancy and in early infancy, (ii) assess family, obstetric and birth history, cord-molecular biomarkers (metabolomics, gene expression, proteins), and infant lung function shortly after birth (including exhalomics) and at 6 years of age, as well as respiratory symptoms in the first year of life and at school age. EXPECTED RESULTS AND IMPACT: We expect a 26.03.2021 18:35:26 Page - 14 - significant correlation between air pollution exposure and oxidative stress response and lung remodeling in newborns with effects on lung function and clinical outcomes, the latter effects enhanced in the risk groups. Particularly for these risk groups, today's air pollution may already result in lung remodeling and subsequent impaired lung functional growth even at this early stage of life. Since early-life lung functional impairment often persists until school age and even late adulthood, it is a previously described early-life risk factor known to be associated with asthma in children and chronic obstructive respiratory airway diseases in the elderly. Thus, early-life environmental injury has a potentially very relevant impact on future global respiratory health, with unpredictable costs. We are one of the first groups to look into the impact of these air-pollution-induced mechanisms on oxidative stress response and lung remodeling, subsequent impairment of lung functional growth, and resulting human lung disease. Better understanding of these mechanisms might help the development of preventative and therapeutic strategies, particularly for at-risk infants. Impact of air pollution on profibrotic and autophagy related mechanisms involved in the development of the respiratory system in infants Research Project | 3 Project MembersWir wissen aus mehreren Studien, einschließlich der BILD-Studie, dass die Luftverschmutzung im frühen Kindesalter Auswirkungen auf die kindliche Entwicklung der Lunge hat. Untersuchungen in Ländern mit hoher Luftverschmutzung haben gezeigt, dass die Exposition mit bestimmten Luftschadstoffen zu einer Beeinträchtigung des Lungenwachstums und der Entwicklung von Asthma führen kann. Selbst eine geringe Luftverschmutzung während der Schwangerschaft kann Auswirkungen auf die Lungenfunktion eines Säuglings kurz nach der Geburt haben. Wir wollen untersuchen ob in dieser frühen Phase der Lungenentwicklung kurz vor und nach der Geburt das Lungengewebe durch Umweltreize geschädigt oder das Immunsystem beeinflusst wird. Auch wenn noch nicht ganz klar ist, wie dies geschieht, glauben wir, dass mehrere Faktoren dazu beitragen. Wir untersuchen beispielsweise die Rolle der erblichen Veranlagung, des Geburtsprozesses, der Ernährung, früher Infektionen und der Interaktion von Genen und Umweltschadstoffen. Jeder einzelne dieser Faktoren hat eine relativ geringe Auswirkung, aber zusammen können sie potentiell bestimmen, ob ein Kind Lungenkrankheiten oder Asthma entwickeln wird. In dieser aktuellen Phase unserer Studie interessiert uns vor allem, wie diese Umweltfaktoren das Wachstum, die Alterung, aber möglicherweise auch das vorzeitige Absterben von Lungenzellen beeinflussen. Dies könnte eine wertvolle zusätzliche Information sein, um zu verstehen, wie Umwelteinflüsse Wachstum und Entwicklung der Lunge beeinflussen. Predictive value of heart rate variability on cardiorespiratory events of preterm infants routinely immunised in the hospital Research Project | 2 Project MembersPreterm birth is a major challenge of health care systems across the globe, affecting about 10% of all infants born worldwide, resulting in almost 13 million preterm births per year. The autonomic nervous system of preterm infants is characterized by instability of heart rate and breathing, requiring continuous monitoring of vital signs over several months and long-term respiratory support. Cardiorespiratory events due to this instability, summarised under the term 'apnoea of prematurity' (AOP), affect at least 80% of very preterm infants born before 32 weeks of gestation. AOP may lead to severe hypoxaemia requiring immediate resuscitation and recent data show that repetitive episodes of AOP increase the risk of post-discharge death and long-term neurodevelopmental impairment. Most importantly, severity and frequency of AOP may drastically increase upon challenging the autonomic system by routine immunisation. It is, however, very important to provide timely immunisation and establish early immunity against typical vaccine-preventable diseases in preterm infants as they are particularly vulnerable to complications arising from those diseases. Current recommendations are to initially immunise preterm infants in the hospital under continuous monitoring of vital signs if the treating physician considers an infant to be at risk of post-immunisation AOP. However, there are no objective criteria to predict post-immunisation AOP. Although the first immunisation of very preterm infants typically takes place in the hospital under continuous monitoring of vital signs, immunisations of infants at risk of AOP are often delayed due to fear of AOP or may be initiated in non-intensive care settings (normal wards) where adequate respiratory support cannot be provided but may be needed due to post-immunisation AOP. Also, due to an international trend of early discharge home of preterm infants, immunisations may be arranged in the rooms of the family paediatrician without further monitoring of vital signs and no specific knowledge of the individual risk of post-immunisation AOP. Thus, developing of new biomarkers and objective criteria to better understand and assess the risk of post-immunisation AOP is urgently needed. We recently developed a systematic quality control algorithm for assessing heart rate variability data in a standardised manner and demonstrated that the sample entropy (SampEn) of interbeat intervals, a parameter of heart rate variability derived from nonlinear time series analysis, predicts cardiorespiratory stability in preterm infants. SampEn reflects the regularity of heart rate and the presence of spikes in a given time series of heart beats and has been validated to be a reliable predictor of incipient events such as sepsis. SampEn of heart rate can be obtained non-invasively from electrocardiogram monitors, which are routinely used to monitor preterm infants immunised in the hospital. We aim to evaluate whether real-time calculation of SampEn at a) 32 and 36 weeks corrected age, b) upon primary routine immunisation in the hospital, c) at discharge from the hospital after initial prematurity-related hospital stay, and d) on readmission for immunisation in the hospital based on previous post-immunisation AOP or referral of the family paediatrician has prognostic utility for the risk of post-immunisation AOP in very preterm infants. We will further assess whether immunisation itself initiates a step response in SampEn and compare SampEn values from preterm infants to those of term healthy infants to study maturational effects. The biomarker SampEn provides a unique opportunity to objectively prognosticate autonomic stability with the goal of optimising risk stratification and establishing timely immunisation in preterm infants. Such real-time display of SampEn thus could become a valuable tool to better understand autonomic regulation in preterm infants and guide physicians in providing an optimal level of care for immunisation based on personalised risk assessment in order to provide an adequate setting and staffing. This approach combines both novel scientific aspects on prognostic value of nonlinear time series analysis and pragmatic utility of SampEn for decision-making on within hospital risk-stratification and necessity of readmission for immunisation. Integrating the impact of genetic and environmental factors on trajectories of respiratory disease from birth to school age Research Project | 2 Project MembersNo Description available Synergetic Development of Steady State Imaging Concepts and Registration Methods for In-Vivo Functional and Morphological Magnetic Resonance Imaging of the Lung in Paediatric Pneumology Research Project | 3 Project MembersIt is well known that chronic disease of the lung in early childhood will affect lung growth and development, and thus determine long term respiratory morbidity in later age. Early detection of chronic lung disease and early treatment are the cornerstones of successful paediatric respiratory medicine in order to prevent alterations in lung growth and development. Typical paediatric disorders are not only cystic fibrosis, chronic lung disease of prematurity or severe asthma but also inborn alterations of the lung and thorax malformations. The University Children's Hospital in Basel (UKBB) is a competence centre for chronic respiratory disease as well as for inborn malformation of the chest and spine. Children with such disorders often show progression of lung fibrosis, severe ventilation inhomogeneities or bronchiectasis with increasing age. Targeted treatment, aims to prevent these severe complications. Normal chest X-ray, currently the gold standard, often fails to detect early signs of such lung fibrosis, severe ventilation inhomogeneities or bronchiectasis. To detect such structural abnormalities, multibreath gas washout lung function tests and plethysmography are used, whereas CO-diffusion tests are used to detect functional abnormalities in children. Often structural and functional monitoring is needed to adequately diagnose and monitor the disease progression in these children. The main drawback is the implied high radiation dose, particularly when used in yearly intervals. There is an urgent need for X-ray radiation free imaging methods to detect structural abnormalities. However, direct visualisation of the lung parenchyma with corresponding airspaces, associated with the bronchial structure, represents one of the remaining fundamental challenges with proton-based MRI. This issue can be overcome by the inhalation of hyperpolarised gases to visualise the airspaces rather than the parenchyma, but requires dedicated instrumentation and technology that is typically limited to research laboratories. Only recently, we were able to visualise, for the first time, directly the lung parenchyma and corresponding airspaces with high contrast-to-noise using a novel ultra-fast steady state imaging approach. Based on our initial experience with this novel imaging approach in combination with the required post-processing of the data (image registration), we will be able to non-invasively assess functional as well as structural aspects of the lung in children. Thanks to the strong track record of the UKBB in developmental physiology and physiological measurements of the lung, the current project will allow comparing such new MRI techniques to clinical routine lung function measurements immediately and seamlessly. In the proposed research we plan on developing the techniques allowing to expand the knowledge about lung function in children. In particular we aim at developing new MR pulse-sequences for lung imaging and the post-processing of the data to extract dynamic ventilation information (in 2D and 3D), as well as 2D perfusion maps. Indo-European Research Network in Mathematics for Health and Disease Research Project | 1 Project MembersHealth and disease are regulated, to a large extent, by our immune system. Current challenges for health and disease that would benefit from mathematical, statistical, and computational approaches to integrate experimental and clinical data include: (1) What are the relevant mechanisms of viral pathogenesis and immune responses, and how do these relate to a pathogenic and molecular characterisation of the virus, (2) What are the mechanisms that regulate immune cell differentiation and fate, as well as ageing, (3) How does receptor-mediated signalling correlate with cellular responses, and (4) How can we quantify the gene diversity of a species with pathogenic potential, such as M. tuberculosis. These questions can now be addressed with dual experimental/clinical and mathematical/computational approaches. In particular, modelling (mathematical and computational) helps to (i) interpret and integrate experimental data, (ii) frame and test hypotheses, (iii) suggest novel experiments allowing for more conclusive and quantitative interpretations of biological, immunological and disease-related processes, and (iv) help towards the 3Rs objectives to reduce, refine and develop replacement strategies as alternatives to animal testing. More concretely, the main research objective of this research network is to develop, by means of the Marie Curie Research Staff Exchange Scheme, four long-term directions in Mathematics for Health and Disease. Given the clinical and experimental expertise of the Indian, EU and Australian partners, and the mathematical and computational expertise of the Indian, EU, USA and Canadian partners, we plan (i) to develop mathematical and computational models of host-pathogen and virus dynamics, with a focus on pathogenic and molecular characterisation of HIV-1, and the distribution of virulence in intra-host HIV quasispecies, in order to understand if regulation of immune activation can be a potentially optimum way for disease management, (ii) to develop mathematical and computational models of immune cellular processes, such as differentiation and cellular fate, as well as ageing, validated by experimental data, with a focus on T cells, (iii) to develop stochastic mathematical models of receptor-mediated processes in health and disease, with a focus on the CCR5 receptor, VEGF receptor, T cell receptor and B cell receptor, and (iv) to develop statistical tools and methods, using evolutionary game theory, to characterise the genomic fluidity of human pathogens, in order to understand microbial pathogen evolution and what constitutes the boundary between commensal and pathogenic organisms. Influence of tobacco exposure on heart rate variability Research Project | 1 Project MembersThe aim of our study is to take a systems biology approach to HR variability using nonlinear correlation analysis techniques to identify changes in autonomic control with ETS and pollution exposure, particularly in at-risk individuals. We will investigate this aim in potentially 1,813 adults from the SAPALDIA study. IMI - EU Innovative Medicine Initiative IMI-BIOPRED:(Bio-Markers of Severe asthma) at University of Berne Research Project | 1 Project MembersNo Description available Impact of early environmental and genetic determinants on lung development from infancy to preschool age Research Project | 1 Project MembersBackground: The high prevalence of wheezing disorders in infants and preschool children has become a major health issue. Wheezing disorders can occur as a result of simple viral infections and are mostly episodic and transient in nature, but they may occur recurrently and be an expression of disturbed fetal growth or lung development or the consequence of early allergic bronchial asthma (multi-trigger wheeze). These different phenotypes are clinically often difficult to distinguish in infancy, however, they have different long term outcomes into school age. While genetic risk factors such as parental atopy (allergy) play an important role, environmental factors such as tobacco exposure, Western lifestyle or air pollution are also known risk factors for wheezing disorders in children. Our hypothesis raised in project 3200-052197.97/1, that different mechanisms may be responsible for the impairment of lung growth to those for the impairment of the immune, allergic or inflammatory system, has been recently reinforced in the literature. Many longitudinal studies show that this loss of lung function tracks throughout life, and impaired lung function at a young age is related to chronic respiratory morbidity in old age. This suggests that the determinants of impaired lung growth may be programmed in early life and that these programmers have a sustained impact on long term morbidity with its related burden for the health care system. Evidence that air pollution impairs lung growth has recently been demonstrated in school children. Based on this current cohort, we have recently shown for the first time that prenatal exposure to particulate matter air pollution is similarly related to impaired lung function shortly after birth. These effects are even more dramatic than in older children suggesting a particular vulnerability of fetuses and infants to pollutants. Aims: The aim of the current study is to test whether these lung functional changes at birth persist into school age, and whether there is genetic susceptibility of certain infants to develop impaired lung growth. Methods: In our prospective birth cohort, we have identified a variety of asthma genes in the cord blood which have been related to lung growth, as well as to susceptibility to environmental toxins. We will improve our pre- and postnatal exposure modelling to tobacco and air pollution of all infants according to the Swiss national air pollution monitoring system (NABEL). In this worldwide unique and optimal dataset of 400-500 infants (currently 420 included), we longitudinally measure lung function after birth and at 5-6 yrs and evaluate whether any impairment persist into childhood, are modified by genetic risk factors, atopy, exposure to air pollutants in the preschool age or the prospectively assessed number and type of viral infections during the first year of life. Additionally we will investigate whether infants exposed to pollutants during pregnancy will have higher prevalence allergic sensitisation and/or asthma at early school age. Significance: The consequence of today s air pollution on the fetal lung development has a unknown but potentially very relevant impact on global respiratory health in the future with unpredictable costs. If genetic and physiological mechanisms that lead to impaired lung growth at this early vulnerable phase of lung development are better understood, we will be better able to identify infants at risk and to develop environmental, preventative, and therapeutic strategies for infants and children at risk. Breastfeeding and the risk of childhodd asthma: a population-based study. Research Project | 1 Project MembersBreastfeeding and the risk of childhodd asthma: a population-based study. 12 12 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 11 foundShow per page10 10 20 50 Air Pollution and Effects on Lung Functional Development and Respiratory Morbidity in At-Risk Infants Research Project | 4 Project MembersBACKGROUND AND RATIONALE: This is a direct continuation of SNF 182871/1, which investigated the impact of early-childhood environmental factors on lung functional growth and consequences for later respiratory morbidity in healthy term infants. We previously demonstrated that even low-level air pollution exposure during pregnancy and early childhood is associated with impaired lung functional growth in infancy and early childhood. Although the mechanisms are still unclear, they could be related to lung functional growth deficits or remodeling of the lung due to changes in the intrauterine environment. Air pollution is known to induce oxidative stress response and related autophagy and cellular senescence mechanisms, potentially playing a role in pollution-related lung pathology and in remodeling. As novel preliminary evidence in SNF 182871/1, we recently found that, in the cord blood of human infants, autophagy-related biomarkers are correlated with remodeling biomarkers. We also found that air pollution exposure during pregnancy is associated with biomarkers of autophagy and remodeling in the cord blood of healthy term infants. Interestingly, these mechanisms also play an important role in fetal development and preterm birth, and may thus theoretically contribute to the susceptibility of infants-and particularly preterm infants-to oxidative stress and air pollution effects. Indeed, as first evidence from SNF 182871/1, we also found an enhanced impact of air pollutants on lung function impairment of preterm infants. Furthermore, our own preliminary human data show that markers of autophagy, and remodeling already have significant differences between the cord blood of preterm infants compared to term infants at birth prior to early postnatal injury. Bringing this together, we hypothesize that the interaction of oxidative stress response, autophagy and remodeling could be a key mechanism involved in the complex host-environment interaction determining lung functional growth and related respiratory morbidity. Moreover, this response could be different in infants at risk for chronic respiratory symptoms, such preterm infants, infants born from asthmatic mothers or infants exposed to high levels of air pollution during pregnancy. OVERALL OBJECTIVES: We aim to expand the ongoing BILD cohort of (i) term infants with two risk subgroups, (ii) infants born preterm, and (iii) infants born to asthmatic mothers, and we will investigate the differences in response to prenatal air pollution in relation to the above key mechanisms. SPECIFIC AIMS: In comparison to healthy term infants, we will investigate in study phase 1, (i) whether the increased susceptibility of infants to prenatal air pollution in these three risk groups is related to differences in markers of oxidative stress response, autophagy, and remodeling in cord blood and in study phase 2, (ii) whether these pollution-related cord blood profiles are correlated to lung functional development and subsequent symptoms in the first year of life (primary outcomes) and at school age (secondary outcomes). We will replicate these findings in other birth cohorts from collaborators (Germany, Australia) with comparable outcome measures. METHODS: In our prospective BILD birth cohort of 1000 unselected healthy term infants, 400 preterm infants, and 200 infants from asthmatic mothers we will (i) estimate indoor and outdoor air pollution exposure during pregnancy and in early infancy, (ii) assess family, obstetric and birth history, cord-molecular biomarkers (metabolomics, gene expression, proteins), and infant lung function shortly after birth (including exhalomics) and at 6 years of age, as well as respiratory symptoms in the first year of life and at school age. EXPECTED RESULTS AND IMPACT: We expect a 26.03.2021 18:35:26 Page - 14 - significant correlation between air pollution exposure and oxidative stress response and lung remodeling in newborns with effects on lung function and clinical outcomes, the latter effects enhanced in the risk groups. Particularly for these risk groups, today's air pollution may already result in lung remodeling and subsequent impaired lung functional growth even at this early stage of life. Since early-life lung functional impairment often persists until school age and even late adulthood, it is a previously described early-life risk factor known to be associated with asthma in children and chronic obstructive respiratory airway diseases in the elderly. Thus, early-life environmental injury has a potentially very relevant impact on future global respiratory health, with unpredictable costs. We are one of the first groups to look into the impact of these air-pollution-induced mechanisms on oxidative stress response and lung remodeling, subsequent impairment of lung functional growth, and resulting human lung disease. Better understanding of these mechanisms might help the development of preventative and therapeutic strategies, particularly for at-risk infants. Impact of air pollution on profibrotic and autophagy related mechanisms involved in the development of the respiratory system in infants Research Project | 3 Project MembersWir wissen aus mehreren Studien, einschließlich der BILD-Studie, dass die Luftverschmutzung im frühen Kindesalter Auswirkungen auf die kindliche Entwicklung der Lunge hat. Untersuchungen in Ländern mit hoher Luftverschmutzung haben gezeigt, dass die Exposition mit bestimmten Luftschadstoffen zu einer Beeinträchtigung des Lungenwachstums und der Entwicklung von Asthma führen kann. Selbst eine geringe Luftverschmutzung während der Schwangerschaft kann Auswirkungen auf die Lungenfunktion eines Säuglings kurz nach der Geburt haben. Wir wollen untersuchen ob in dieser frühen Phase der Lungenentwicklung kurz vor und nach der Geburt das Lungengewebe durch Umweltreize geschädigt oder das Immunsystem beeinflusst wird. Auch wenn noch nicht ganz klar ist, wie dies geschieht, glauben wir, dass mehrere Faktoren dazu beitragen. Wir untersuchen beispielsweise die Rolle der erblichen Veranlagung, des Geburtsprozesses, der Ernährung, früher Infektionen und der Interaktion von Genen und Umweltschadstoffen. Jeder einzelne dieser Faktoren hat eine relativ geringe Auswirkung, aber zusammen können sie potentiell bestimmen, ob ein Kind Lungenkrankheiten oder Asthma entwickeln wird. In dieser aktuellen Phase unserer Studie interessiert uns vor allem, wie diese Umweltfaktoren das Wachstum, die Alterung, aber möglicherweise auch das vorzeitige Absterben von Lungenzellen beeinflussen. Dies könnte eine wertvolle zusätzliche Information sein, um zu verstehen, wie Umwelteinflüsse Wachstum und Entwicklung der Lunge beeinflussen. Predictive value of heart rate variability on cardiorespiratory events of preterm infants routinely immunised in the hospital Research Project | 2 Project MembersPreterm birth is a major challenge of health care systems across the globe, affecting about 10% of all infants born worldwide, resulting in almost 13 million preterm births per year. The autonomic nervous system of preterm infants is characterized by instability of heart rate and breathing, requiring continuous monitoring of vital signs over several months and long-term respiratory support. Cardiorespiratory events due to this instability, summarised under the term 'apnoea of prematurity' (AOP), affect at least 80% of very preterm infants born before 32 weeks of gestation. AOP may lead to severe hypoxaemia requiring immediate resuscitation and recent data show that repetitive episodes of AOP increase the risk of post-discharge death and long-term neurodevelopmental impairment. Most importantly, severity and frequency of AOP may drastically increase upon challenging the autonomic system by routine immunisation. It is, however, very important to provide timely immunisation and establish early immunity against typical vaccine-preventable diseases in preterm infants as they are particularly vulnerable to complications arising from those diseases. Current recommendations are to initially immunise preterm infants in the hospital under continuous monitoring of vital signs if the treating physician considers an infant to be at risk of post-immunisation AOP. However, there are no objective criteria to predict post-immunisation AOP. Although the first immunisation of very preterm infants typically takes place in the hospital under continuous monitoring of vital signs, immunisations of infants at risk of AOP are often delayed due to fear of AOP or may be initiated in non-intensive care settings (normal wards) where adequate respiratory support cannot be provided but may be needed due to post-immunisation AOP. Also, due to an international trend of early discharge home of preterm infants, immunisations may be arranged in the rooms of the family paediatrician without further monitoring of vital signs and no specific knowledge of the individual risk of post-immunisation AOP. Thus, developing of new biomarkers and objective criteria to better understand and assess the risk of post-immunisation AOP is urgently needed. We recently developed a systematic quality control algorithm for assessing heart rate variability data in a standardised manner and demonstrated that the sample entropy (SampEn) of interbeat intervals, a parameter of heart rate variability derived from nonlinear time series analysis, predicts cardiorespiratory stability in preterm infants. SampEn reflects the regularity of heart rate and the presence of spikes in a given time series of heart beats and has been validated to be a reliable predictor of incipient events such as sepsis. SampEn of heart rate can be obtained non-invasively from electrocardiogram monitors, which are routinely used to monitor preterm infants immunised in the hospital. We aim to evaluate whether real-time calculation of SampEn at a) 32 and 36 weeks corrected age, b) upon primary routine immunisation in the hospital, c) at discharge from the hospital after initial prematurity-related hospital stay, and d) on readmission for immunisation in the hospital based on previous post-immunisation AOP or referral of the family paediatrician has prognostic utility for the risk of post-immunisation AOP in very preterm infants. We will further assess whether immunisation itself initiates a step response in SampEn and compare SampEn values from preterm infants to those of term healthy infants to study maturational effects. The biomarker SampEn provides a unique opportunity to objectively prognosticate autonomic stability with the goal of optimising risk stratification and establishing timely immunisation in preterm infants. Such real-time display of SampEn thus could become a valuable tool to better understand autonomic regulation in preterm infants and guide physicians in providing an optimal level of care for immunisation based on personalised risk assessment in order to provide an adequate setting and staffing. This approach combines both novel scientific aspects on prognostic value of nonlinear time series analysis and pragmatic utility of SampEn for decision-making on within hospital risk-stratification and necessity of readmission for immunisation. Integrating the impact of genetic and environmental factors on trajectories of respiratory disease from birth to school age Research Project | 2 Project MembersNo Description available Synergetic Development of Steady State Imaging Concepts and Registration Methods for In-Vivo Functional and Morphological Magnetic Resonance Imaging of the Lung in Paediatric Pneumology Research Project | 3 Project MembersIt is well known that chronic disease of the lung in early childhood will affect lung growth and development, and thus determine long term respiratory morbidity in later age. Early detection of chronic lung disease and early treatment are the cornerstones of successful paediatric respiratory medicine in order to prevent alterations in lung growth and development. Typical paediatric disorders are not only cystic fibrosis, chronic lung disease of prematurity or severe asthma but also inborn alterations of the lung and thorax malformations. The University Children's Hospital in Basel (UKBB) is a competence centre for chronic respiratory disease as well as for inborn malformation of the chest and spine. Children with such disorders often show progression of lung fibrosis, severe ventilation inhomogeneities or bronchiectasis with increasing age. Targeted treatment, aims to prevent these severe complications. Normal chest X-ray, currently the gold standard, often fails to detect early signs of such lung fibrosis, severe ventilation inhomogeneities or bronchiectasis. To detect such structural abnormalities, multibreath gas washout lung function tests and plethysmography are used, whereas CO-diffusion tests are used to detect functional abnormalities in children. Often structural and functional monitoring is needed to adequately diagnose and monitor the disease progression in these children. The main drawback is the implied high radiation dose, particularly when used in yearly intervals. There is an urgent need for X-ray radiation free imaging methods to detect structural abnormalities. However, direct visualisation of the lung parenchyma with corresponding airspaces, associated with the bronchial structure, represents one of the remaining fundamental challenges with proton-based MRI. This issue can be overcome by the inhalation of hyperpolarised gases to visualise the airspaces rather than the parenchyma, but requires dedicated instrumentation and technology that is typically limited to research laboratories. Only recently, we were able to visualise, for the first time, directly the lung parenchyma and corresponding airspaces with high contrast-to-noise using a novel ultra-fast steady state imaging approach. Based on our initial experience with this novel imaging approach in combination with the required post-processing of the data (image registration), we will be able to non-invasively assess functional as well as structural aspects of the lung in children. Thanks to the strong track record of the UKBB in developmental physiology and physiological measurements of the lung, the current project will allow comparing such new MRI techniques to clinical routine lung function measurements immediately and seamlessly. In the proposed research we plan on developing the techniques allowing to expand the knowledge about lung function in children. In particular we aim at developing new MR pulse-sequences for lung imaging and the post-processing of the data to extract dynamic ventilation information (in 2D and 3D), as well as 2D perfusion maps. Indo-European Research Network in Mathematics for Health and Disease Research Project | 1 Project MembersHealth and disease are regulated, to a large extent, by our immune system. Current challenges for health and disease that would benefit from mathematical, statistical, and computational approaches to integrate experimental and clinical data include: (1) What are the relevant mechanisms of viral pathogenesis and immune responses, and how do these relate to a pathogenic and molecular characterisation of the virus, (2) What are the mechanisms that regulate immune cell differentiation and fate, as well as ageing, (3) How does receptor-mediated signalling correlate with cellular responses, and (4) How can we quantify the gene diversity of a species with pathogenic potential, such as M. tuberculosis. These questions can now be addressed with dual experimental/clinical and mathematical/computational approaches. In particular, modelling (mathematical and computational) helps to (i) interpret and integrate experimental data, (ii) frame and test hypotheses, (iii) suggest novel experiments allowing for more conclusive and quantitative interpretations of biological, immunological and disease-related processes, and (iv) help towards the 3Rs objectives to reduce, refine and develop replacement strategies as alternatives to animal testing. More concretely, the main research objective of this research network is to develop, by means of the Marie Curie Research Staff Exchange Scheme, four long-term directions in Mathematics for Health and Disease. Given the clinical and experimental expertise of the Indian, EU and Australian partners, and the mathematical and computational expertise of the Indian, EU, USA and Canadian partners, we plan (i) to develop mathematical and computational models of host-pathogen and virus dynamics, with a focus on pathogenic and molecular characterisation of HIV-1, and the distribution of virulence in intra-host HIV quasispecies, in order to understand if regulation of immune activation can be a potentially optimum way for disease management, (ii) to develop mathematical and computational models of immune cellular processes, such as differentiation and cellular fate, as well as ageing, validated by experimental data, with a focus on T cells, (iii) to develop stochastic mathematical models of receptor-mediated processes in health and disease, with a focus on the CCR5 receptor, VEGF receptor, T cell receptor and B cell receptor, and (iv) to develop statistical tools and methods, using evolutionary game theory, to characterise the genomic fluidity of human pathogens, in order to understand microbial pathogen evolution and what constitutes the boundary between commensal and pathogenic organisms. Influence of tobacco exposure on heart rate variability Research Project | 1 Project MembersThe aim of our study is to take a systems biology approach to HR variability using nonlinear correlation analysis techniques to identify changes in autonomic control with ETS and pollution exposure, particularly in at-risk individuals. We will investigate this aim in potentially 1,813 adults from the SAPALDIA study. IMI - EU Innovative Medicine Initiative IMI-BIOPRED:(Bio-Markers of Severe asthma) at University of Berne Research Project | 1 Project MembersNo Description available Impact of early environmental and genetic determinants on lung development from infancy to preschool age Research Project | 1 Project MembersBackground: The high prevalence of wheezing disorders in infants and preschool children has become a major health issue. Wheezing disorders can occur as a result of simple viral infections and are mostly episodic and transient in nature, but they may occur recurrently and be an expression of disturbed fetal growth or lung development or the consequence of early allergic bronchial asthma (multi-trigger wheeze). These different phenotypes are clinically often difficult to distinguish in infancy, however, they have different long term outcomes into school age. While genetic risk factors such as parental atopy (allergy) play an important role, environmental factors such as tobacco exposure, Western lifestyle or air pollution are also known risk factors for wheezing disorders in children. Our hypothesis raised in project 3200-052197.97/1, that different mechanisms may be responsible for the impairment of lung growth to those for the impairment of the immune, allergic or inflammatory system, has been recently reinforced in the literature. Many longitudinal studies show that this loss of lung function tracks throughout life, and impaired lung function at a young age is related to chronic respiratory morbidity in old age. This suggests that the determinants of impaired lung growth may be programmed in early life and that these programmers have a sustained impact on long term morbidity with its related burden for the health care system. Evidence that air pollution impairs lung growth has recently been demonstrated in school children. Based on this current cohort, we have recently shown for the first time that prenatal exposure to particulate matter air pollution is similarly related to impaired lung function shortly after birth. These effects are even more dramatic than in older children suggesting a particular vulnerability of fetuses and infants to pollutants. Aims: The aim of the current study is to test whether these lung functional changes at birth persist into school age, and whether there is genetic susceptibility of certain infants to develop impaired lung growth. Methods: In our prospective birth cohort, we have identified a variety of asthma genes in the cord blood which have been related to lung growth, as well as to susceptibility to environmental toxins. We will improve our pre- and postnatal exposure modelling to tobacco and air pollution of all infants according to the Swiss national air pollution monitoring system (NABEL). In this worldwide unique and optimal dataset of 400-500 infants (currently 420 included), we longitudinally measure lung function after birth and at 5-6 yrs and evaluate whether any impairment persist into childhood, are modified by genetic risk factors, atopy, exposure to air pollutants in the preschool age or the prospectively assessed number and type of viral infections during the first year of life. Additionally we will investigate whether infants exposed to pollutants during pregnancy will have higher prevalence allergic sensitisation and/or asthma at early school age. Significance: The consequence of today s air pollution on the fetal lung development has a unknown but potentially very relevant impact on global respiratory health in the future with unpredictable costs. If genetic and physiological mechanisms that lead to impaired lung growth at this early vulnerable phase of lung development are better understood, we will be better able to identify infants at risk and to develop environmental, preventative, and therapeutic strategies for infants and children at risk. Breastfeeding and the risk of childhodd asthma: a population-based study. Research Project | 1 Project MembersBreastfeeding and the risk of childhodd asthma: a population-based study. 12 12
Air Pollution and Effects on Lung Functional Development and Respiratory Morbidity in At-Risk Infants Research Project | 4 Project MembersBACKGROUND AND RATIONALE: This is a direct continuation of SNF 182871/1, which investigated the impact of early-childhood environmental factors on lung functional growth and consequences for later respiratory morbidity in healthy term infants. We previously demonstrated that even low-level air pollution exposure during pregnancy and early childhood is associated with impaired lung functional growth in infancy and early childhood. Although the mechanisms are still unclear, they could be related to lung functional growth deficits or remodeling of the lung due to changes in the intrauterine environment. Air pollution is known to induce oxidative stress response and related autophagy and cellular senescence mechanisms, potentially playing a role in pollution-related lung pathology and in remodeling. As novel preliminary evidence in SNF 182871/1, we recently found that, in the cord blood of human infants, autophagy-related biomarkers are correlated with remodeling biomarkers. We also found that air pollution exposure during pregnancy is associated with biomarkers of autophagy and remodeling in the cord blood of healthy term infants. Interestingly, these mechanisms also play an important role in fetal development and preterm birth, and may thus theoretically contribute to the susceptibility of infants-and particularly preterm infants-to oxidative stress and air pollution effects. Indeed, as first evidence from SNF 182871/1, we also found an enhanced impact of air pollutants on lung function impairment of preterm infants. Furthermore, our own preliminary human data show that markers of autophagy, and remodeling already have significant differences between the cord blood of preterm infants compared to term infants at birth prior to early postnatal injury. Bringing this together, we hypothesize that the interaction of oxidative stress response, autophagy and remodeling could be a key mechanism involved in the complex host-environment interaction determining lung functional growth and related respiratory morbidity. Moreover, this response could be different in infants at risk for chronic respiratory symptoms, such preterm infants, infants born from asthmatic mothers or infants exposed to high levels of air pollution during pregnancy. OVERALL OBJECTIVES: We aim to expand the ongoing BILD cohort of (i) term infants with two risk subgroups, (ii) infants born preterm, and (iii) infants born to asthmatic mothers, and we will investigate the differences in response to prenatal air pollution in relation to the above key mechanisms. SPECIFIC AIMS: In comparison to healthy term infants, we will investigate in study phase 1, (i) whether the increased susceptibility of infants to prenatal air pollution in these three risk groups is related to differences in markers of oxidative stress response, autophagy, and remodeling in cord blood and in study phase 2, (ii) whether these pollution-related cord blood profiles are correlated to lung functional development and subsequent symptoms in the first year of life (primary outcomes) and at school age (secondary outcomes). We will replicate these findings in other birth cohorts from collaborators (Germany, Australia) with comparable outcome measures. METHODS: In our prospective BILD birth cohort of 1000 unselected healthy term infants, 400 preterm infants, and 200 infants from asthmatic mothers we will (i) estimate indoor and outdoor air pollution exposure during pregnancy and in early infancy, (ii) assess family, obstetric and birth history, cord-molecular biomarkers (metabolomics, gene expression, proteins), and infant lung function shortly after birth (including exhalomics) and at 6 years of age, as well as respiratory symptoms in the first year of life and at school age. EXPECTED RESULTS AND IMPACT: We expect a 26.03.2021 18:35:26 Page - 14 - significant correlation between air pollution exposure and oxidative stress response and lung remodeling in newborns with effects on lung function and clinical outcomes, the latter effects enhanced in the risk groups. Particularly for these risk groups, today's air pollution may already result in lung remodeling and subsequent impaired lung functional growth even at this early stage of life. Since early-life lung functional impairment often persists until school age and even late adulthood, it is a previously described early-life risk factor known to be associated with asthma in children and chronic obstructive respiratory airway diseases in the elderly. Thus, early-life environmental injury has a potentially very relevant impact on future global respiratory health, with unpredictable costs. We are one of the first groups to look into the impact of these air-pollution-induced mechanisms on oxidative stress response and lung remodeling, subsequent impairment of lung functional growth, and resulting human lung disease. Better understanding of these mechanisms might help the development of preventative and therapeutic strategies, particularly for at-risk infants.
Impact of air pollution on profibrotic and autophagy related mechanisms involved in the development of the respiratory system in infants Research Project | 3 Project MembersWir wissen aus mehreren Studien, einschließlich der BILD-Studie, dass die Luftverschmutzung im frühen Kindesalter Auswirkungen auf die kindliche Entwicklung der Lunge hat. Untersuchungen in Ländern mit hoher Luftverschmutzung haben gezeigt, dass die Exposition mit bestimmten Luftschadstoffen zu einer Beeinträchtigung des Lungenwachstums und der Entwicklung von Asthma führen kann. Selbst eine geringe Luftverschmutzung während der Schwangerschaft kann Auswirkungen auf die Lungenfunktion eines Säuglings kurz nach der Geburt haben. Wir wollen untersuchen ob in dieser frühen Phase der Lungenentwicklung kurz vor und nach der Geburt das Lungengewebe durch Umweltreize geschädigt oder das Immunsystem beeinflusst wird. Auch wenn noch nicht ganz klar ist, wie dies geschieht, glauben wir, dass mehrere Faktoren dazu beitragen. Wir untersuchen beispielsweise die Rolle der erblichen Veranlagung, des Geburtsprozesses, der Ernährung, früher Infektionen und der Interaktion von Genen und Umweltschadstoffen. Jeder einzelne dieser Faktoren hat eine relativ geringe Auswirkung, aber zusammen können sie potentiell bestimmen, ob ein Kind Lungenkrankheiten oder Asthma entwickeln wird. In dieser aktuellen Phase unserer Studie interessiert uns vor allem, wie diese Umweltfaktoren das Wachstum, die Alterung, aber möglicherweise auch das vorzeitige Absterben von Lungenzellen beeinflussen. Dies könnte eine wertvolle zusätzliche Information sein, um zu verstehen, wie Umwelteinflüsse Wachstum und Entwicklung der Lunge beeinflussen.
Predictive value of heart rate variability on cardiorespiratory events of preterm infants routinely immunised in the hospital Research Project | 2 Project MembersPreterm birth is a major challenge of health care systems across the globe, affecting about 10% of all infants born worldwide, resulting in almost 13 million preterm births per year. The autonomic nervous system of preterm infants is characterized by instability of heart rate and breathing, requiring continuous monitoring of vital signs over several months and long-term respiratory support. Cardiorespiratory events due to this instability, summarised under the term 'apnoea of prematurity' (AOP), affect at least 80% of very preterm infants born before 32 weeks of gestation. AOP may lead to severe hypoxaemia requiring immediate resuscitation and recent data show that repetitive episodes of AOP increase the risk of post-discharge death and long-term neurodevelopmental impairment. Most importantly, severity and frequency of AOP may drastically increase upon challenging the autonomic system by routine immunisation. It is, however, very important to provide timely immunisation and establish early immunity against typical vaccine-preventable diseases in preterm infants as they are particularly vulnerable to complications arising from those diseases. Current recommendations are to initially immunise preterm infants in the hospital under continuous monitoring of vital signs if the treating physician considers an infant to be at risk of post-immunisation AOP. However, there are no objective criteria to predict post-immunisation AOP. Although the first immunisation of very preterm infants typically takes place in the hospital under continuous monitoring of vital signs, immunisations of infants at risk of AOP are often delayed due to fear of AOP or may be initiated in non-intensive care settings (normal wards) where adequate respiratory support cannot be provided but may be needed due to post-immunisation AOP. Also, due to an international trend of early discharge home of preterm infants, immunisations may be arranged in the rooms of the family paediatrician without further monitoring of vital signs and no specific knowledge of the individual risk of post-immunisation AOP. Thus, developing of new biomarkers and objective criteria to better understand and assess the risk of post-immunisation AOP is urgently needed. We recently developed a systematic quality control algorithm for assessing heart rate variability data in a standardised manner and demonstrated that the sample entropy (SampEn) of interbeat intervals, a parameter of heart rate variability derived from nonlinear time series analysis, predicts cardiorespiratory stability in preterm infants. SampEn reflects the regularity of heart rate and the presence of spikes in a given time series of heart beats and has been validated to be a reliable predictor of incipient events such as sepsis. SampEn of heart rate can be obtained non-invasively from electrocardiogram monitors, which are routinely used to monitor preterm infants immunised in the hospital. We aim to evaluate whether real-time calculation of SampEn at a) 32 and 36 weeks corrected age, b) upon primary routine immunisation in the hospital, c) at discharge from the hospital after initial prematurity-related hospital stay, and d) on readmission for immunisation in the hospital based on previous post-immunisation AOP or referral of the family paediatrician has prognostic utility for the risk of post-immunisation AOP in very preterm infants. We will further assess whether immunisation itself initiates a step response in SampEn and compare SampEn values from preterm infants to those of term healthy infants to study maturational effects. The biomarker SampEn provides a unique opportunity to objectively prognosticate autonomic stability with the goal of optimising risk stratification and establishing timely immunisation in preterm infants. Such real-time display of SampEn thus could become a valuable tool to better understand autonomic regulation in preterm infants and guide physicians in providing an optimal level of care for immunisation based on personalised risk assessment in order to provide an adequate setting and staffing. This approach combines both novel scientific aspects on prognostic value of nonlinear time series analysis and pragmatic utility of SampEn for decision-making on within hospital risk-stratification and necessity of readmission for immunisation.
Integrating the impact of genetic and environmental factors on trajectories of respiratory disease from birth to school age Research Project | 2 Project MembersNo Description available
Synergetic Development of Steady State Imaging Concepts and Registration Methods for In-Vivo Functional and Morphological Magnetic Resonance Imaging of the Lung in Paediatric Pneumology Research Project | 3 Project MembersIt is well known that chronic disease of the lung in early childhood will affect lung growth and development, and thus determine long term respiratory morbidity in later age. Early detection of chronic lung disease and early treatment are the cornerstones of successful paediatric respiratory medicine in order to prevent alterations in lung growth and development. Typical paediatric disorders are not only cystic fibrosis, chronic lung disease of prematurity or severe asthma but also inborn alterations of the lung and thorax malformations. The University Children's Hospital in Basel (UKBB) is a competence centre for chronic respiratory disease as well as for inborn malformation of the chest and spine. Children with such disorders often show progression of lung fibrosis, severe ventilation inhomogeneities or bronchiectasis with increasing age. Targeted treatment, aims to prevent these severe complications. Normal chest X-ray, currently the gold standard, often fails to detect early signs of such lung fibrosis, severe ventilation inhomogeneities or bronchiectasis. To detect such structural abnormalities, multibreath gas washout lung function tests and plethysmography are used, whereas CO-diffusion tests are used to detect functional abnormalities in children. Often structural and functional monitoring is needed to adequately diagnose and monitor the disease progression in these children. The main drawback is the implied high radiation dose, particularly when used in yearly intervals. There is an urgent need for X-ray radiation free imaging methods to detect structural abnormalities. However, direct visualisation of the lung parenchyma with corresponding airspaces, associated with the bronchial structure, represents one of the remaining fundamental challenges with proton-based MRI. This issue can be overcome by the inhalation of hyperpolarised gases to visualise the airspaces rather than the parenchyma, but requires dedicated instrumentation and technology that is typically limited to research laboratories. Only recently, we were able to visualise, for the first time, directly the lung parenchyma and corresponding airspaces with high contrast-to-noise using a novel ultra-fast steady state imaging approach. Based on our initial experience with this novel imaging approach in combination with the required post-processing of the data (image registration), we will be able to non-invasively assess functional as well as structural aspects of the lung in children. Thanks to the strong track record of the UKBB in developmental physiology and physiological measurements of the lung, the current project will allow comparing such new MRI techniques to clinical routine lung function measurements immediately and seamlessly. In the proposed research we plan on developing the techniques allowing to expand the knowledge about lung function in children. In particular we aim at developing new MR pulse-sequences for lung imaging and the post-processing of the data to extract dynamic ventilation information (in 2D and 3D), as well as 2D perfusion maps.
Indo-European Research Network in Mathematics for Health and Disease Research Project | 1 Project MembersHealth and disease are regulated, to a large extent, by our immune system. Current challenges for health and disease that would benefit from mathematical, statistical, and computational approaches to integrate experimental and clinical data include: (1) What are the relevant mechanisms of viral pathogenesis and immune responses, and how do these relate to a pathogenic and molecular characterisation of the virus, (2) What are the mechanisms that regulate immune cell differentiation and fate, as well as ageing, (3) How does receptor-mediated signalling correlate with cellular responses, and (4) How can we quantify the gene diversity of a species with pathogenic potential, such as M. tuberculosis. These questions can now be addressed with dual experimental/clinical and mathematical/computational approaches. In particular, modelling (mathematical and computational) helps to (i) interpret and integrate experimental data, (ii) frame and test hypotheses, (iii) suggest novel experiments allowing for more conclusive and quantitative interpretations of biological, immunological and disease-related processes, and (iv) help towards the 3Rs objectives to reduce, refine and develop replacement strategies as alternatives to animal testing. More concretely, the main research objective of this research network is to develop, by means of the Marie Curie Research Staff Exchange Scheme, four long-term directions in Mathematics for Health and Disease. Given the clinical and experimental expertise of the Indian, EU and Australian partners, and the mathematical and computational expertise of the Indian, EU, USA and Canadian partners, we plan (i) to develop mathematical and computational models of host-pathogen and virus dynamics, with a focus on pathogenic and molecular characterisation of HIV-1, and the distribution of virulence in intra-host HIV quasispecies, in order to understand if regulation of immune activation can be a potentially optimum way for disease management, (ii) to develop mathematical and computational models of immune cellular processes, such as differentiation and cellular fate, as well as ageing, validated by experimental data, with a focus on T cells, (iii) to develop stochastic mathematical models of receptor-mediated processes in health and disease, with a focus on the CCR5 receptor, VEGF receptor, T cell receptor and B cell receptor, and (iv) to develop statistical tools and methods, using evolutionary game theory, to characterise the genomic fluidity of human pathogens, in order to understand microbial pathogen evolution and what constitutes the boundary between commensal and pathogenic organisms.
Influence of tobacco exposure on heart rate variability Research Project | 1 Project MembersThe aim of our study is to take a systems biology approach to HR variability using nonlinear correlation analysis techniques to identify changes in autonomic control with ETS and pollution exposure, particularly in at-risk individuals. We will investigate this aim in potentially 1,813 adults from the SAPALDIA study.
IMI - EU Innovative Medicine Initiative IMI-BIOPRED:(Bio-Markers of Severe asthma) at University of Berne Research Project | 1 Project MembersNo Description available
Impact of early environmental and genetic determinants on lung development from infancy to preschool age Research Project | 1 Project MembersBackground: The high prevalence of wheezing disorders in infants and preschool children has become a major health issue. Wheezing disorders can occur as a result of simple viral infections and are mostly episodic and transient in nature, but they may occur recurrently and be an expression of disturbed fetal growth or lung development or the consequence of early allergic bronchial asthma (multi-trigger wheeze). These different phenotypes are clinically often difficult to distinguish in infancy, however, they have different long term outcomes into school age. While genetic risk factors such as parental atopy (allergy) play an important role, environmental factors such as tobacco exposure, Western lifestyle or air pollution are also known risk factors for wheezing disorders in children. Our hypothesis raised in project 3200-052197.97/1, that different mechanisms may be responsible for the impairment of lung growth to those for the impairment of the immune, allergic or inflammatory system, has been recently reinforced in the literature. Many longitudinal studies show that this loss of lung function tracks throughout life, and impaired lung function at a young age is related to chronic respiratory morbidity in old age. This suggests that the determinants of impaired lung growth may be programmed in early life and that these programmers have a sustained impact on long term morbidity with its related burden for the health care system. Evidence that air pollution impairs lung growth has recently been demonstrated in school children. Based on this current cohort, we have recently shown for the first time that prenatal exposure to particulate matter air pollution is similarly related to impaired lung function shortly after birth. These effects are even more dramatic than in older children suggesting a particular vulnerability of fetuses and infants to pollutants. Aims: The aim of the current study is to test whether these lung functional changes at birth persist into school age, and whether there is genetic susceptibility of certain infants to develop impaired lung growth. Methods: In our prospective birth cohort, we have identified a variety of asthma genes in the cord blood which have been related to lung growth, as well as to susceptibility to environmental toxins. We will improve our pre- and postnatal exposure modelling to tobacco and air pollution of all infants according to the Swiss national air pollution monitoring system (NABEL). In this worldwide unique and optimal dataset of 400-500 infants (currently 420 included), we longitudinally measure lung function after birth and at 5-6 yrs and evaluate whether any impairment persist into childhood, are modified by genetic risk factors, atopy, exposure to air pollutants in the preschool age or the prospectively assessed number and type of viral infections during the first year of life. Additionally we will investigate whether infants exposed to pollutants during pregnancy will have higher prevalence allergic sensitisation and/or asthma at early school age. Significance: The consequence of today s air pollution on the fetal lung development has a unknown but potentially very relevant impact on global respiratory health in the future with unpredictable costs. If genetic and physiological mechanisms that lead to impaired lung growth at this early vulnerable phase of lung development are better understood, we will be better able to identify infants at risk and to develop environmental, preventative, and therapeutic strategies for infants and children at risk.
Breastfeeding and the risk of childhodd asthma: a population-based study. Research Project | 1 Project MembersBreastfeeding and the risk of childhodd asthma: a population-based study.
