Cohort Profile: The Bern Infant Lung Development Cohort

Childhood asthma resembles a complex syndrome rather than a single disease. Clinical manifestations include cough, shortness of breath and wheeze.1 Because of its high prevalence, it is of major public health relevance.2,3 Presentation and disease course of childhood wheezing disorders vary,4 and its phenotypes are difficult to distinguish in early childhood despite the demand for diverse therapeutic strategies.5 Current treatments have no sustained effect on development of lung function and cannot prevent tracking of reduced lung function.6 Risk factors for childhood wheeze and subsequent asthma include genes, environmental factors and their interaction:1,7,8 all these affect lung development directly or indirectly (Figure 1). Data on the association between lung development and respiratory symptoms9 in early childhood are mostly derived from small hospital-based studies. Larger epidemiological studies have been based on questionnaires and most studies have been conducted in older children,2 in high-risk populations10 or retrospectively.11 There is a lack of prospectively assessed lung function studies in unselected healthy infants that take into account genetic and environmental factors. However, in order to disentangle the complex interaction of these predisposing factors on lung development and childhood wheeze, relatively large groups of infants need to be studied, with repeated lung function measurements, assessment of environmental and hereditary factors and clinical outcomes. The ‘Bern Infant Lung Development’ (BILD) cohort aims to contribute towards closing this gap. It was set up in 1999 to study physiological properties of the respiratory system and environmental and genetic risk factors affecting lung development in healthy individuals from infancy through childhood in relation to wheeze.9 Proposed effect of environmental and genetic risk factors and their interaction on lung development and evolution of wheeze phenotypes. The Figure illustrates how genetic background, environmental exposures (ETS, air pollution, infections, allergens, active smoking) and their interaction might influence lung growth and development from branching of the airways to alveolarization. We propose a direct effect of these exposures on lung development, and an indirect effect via changes in the balance between inflammation, injury and repair mechanisms, leading to remodelling. Differences in these pathways might lead to different phenotypes of wheezing disorders Direct costs of the cohort are being paid by project grants from the Swiss National Science Foundation, the European Respiratory Society (ERS), the Austrian, German and Swiss Paediatric Respiratory Society and Swiss Governmental Anti-Tobacco Fund. The University Children’s Hospital in Bern, Switzerland, where the study centre is located, provides the infrastructure. All studies were approved by the local Ethics Research Committee. In a comprehensive approach, we search for early markers of common respiratory morbidity, including respiratory infections and asthma, by trying to disentangle predisposing and modifying factors of respiratory morbidity within the context of lung development. This includes the assessment of immune development and markers of airway inflammation in response to environmental triggers. The strengths of the BILD cohort are its hallmarks: the prospective approach with standardized data collection starting before birth in unselected children; the accurate and standardized measurements of lung function and markers of airway inflammation; and the detailed assessment of incidence and determinants of respiratory symptoms especially during the first year of life.12 To explain developing properties of lung and airways during the vulnerable phases, lung function is measured at the age of 1 month and at the age of 6 years, with further lung function measurements planned for the age of 12 years. We study the complex reaction of lung and airways to environmental triggers, which is possibly influenced both by inflammation and immune response. Here, we measure the association between exposure to environmental tobacco smoke (ETS), air pollution and lung function, markers of airway inflammation and components of the immune system. In addition, we prospectively assess viral pathogens of lower respiratory tract infections during the first year of life, as well as related respiratory symptoms and their severity. Data covering genetic risk factors for childhood asthma are rapidly increasing.13,14 However, little is known about their effect on lung development and childhood wheeze.14–16 This is particularly true for genes known, from animal models, to be involved in lung development. Therefore, we measure the effect of single-nucleotide polymorphisms in these genes in comparison with genes associated with clinical manifestation of childhood allergy, asthma or wheeze. Recruitment for the BILD cohort is ongoing; about 35 unselected healthy neonates enter the cohort every year. Study participants are born after April 1999 in the agglomeration of Bern, the capital of Switzerland. One-third of the study population comes from the rural surroundings, and two-thirds from the urban area of Bern, which still offers relatively rural living conditions compared with other European cities. Pregnant mothers are recruited at the four major maternity hospitals and practices of obstetricians in the agglomeration of Bern through advertisements and interviews. Interested families receive informative letters describing involved measurements and are contacted by the study centre. The following inclusion criteria apply: White ethnicity, term delivery (at least 37 weeks), ability of parents to speak one of the major Swiss languages (German, French), no severe maternal health problems, no maternal drug abuse other than nicotine, no known major birth defects or perinatal disease of the newborn, such as respiratory distress, airway malformation or other major respiratory diseases diagnosed after birth. From 1999 until the end of 2009, a total of 42 110 mothers gave birth at the four major maternity hospitals in the agglomeration of Bern. By the end of 2009, we recruited 364 study participants (see Table 1 for anthropometric data of infants with lung function data), and 107 have been followed-up so far at the age of 6 years (Table 2). The others have not yet reached this age. Anthropometric data of study participants in the BILD cohort with information on lung function (N = 344) at the age of 1 month Anthropometric data of study participants in the BILD cohort with information on lung function (N = 344) at the age of 1 month Number of participants initially recruited, number completing study Phases 1 and 2 and number of drop-outs during study Phases 1 and 2 from 1999–2009 in the BILD cohort Number of participants initially recruited, number completing study Phases 1 and 2 and number of drop-outs during study Phases 1 and 2 from 1999–2009 in the BILD cohort The study design of the BILD cohort is shown in Figure 2. It includes three study phases with three questionnaires, weekly telephone interviews during the first year of life, two visits to the study centre and two visits to the families’ homes at the time of the first lower respiratory infection. The BILD cohort: time-flow of recorded data, as well as of tests and procedures performed during the follow-up. Vt: tidal volume; FeNO: fraction of exhaled nitric oxide; MBW: multiple breath washout; FRC: functional residual capacity; LCI: lung clearance index; PCR: polymerase chain reaction; Rint: airway resistance by interrupter; Reff: effective airway resistance (measured by bodyplethysmography); FEV1: forced expiratory volume during the first second of expiration; MEF25-75: midexpiratory flow Study Phase 1 starts with recruitment. After birth, mid wives extract perinatal history from medical records, and take cord blood and first urine samples if eligibility is confirmed. At the age of 1 month, the infants visit the study centre. On this occasion, lung function measurements and maternal skin-prick tests are performed, and Questionnaire 1 is used to assess pre- and perinatal history. During the first year of life, study nurses perform regular weekly telephone calls with standardized interviews. After the first year of life, Study Phase 2 starts. The first follow-up is performed at the age of 6 years, when participants visit the study centre again to undergo lung function measurements and skin-prick tests. Questionnaires 2 and 3 assess the history during Study Phase 2. A further follow-up as part of Study Phase 3, also including lung function measurements and skin-prick tests, is planned for the age of 12 years. Attrition was low during Phase 1 and relatively low during Phase 2. We lost only 13 of 364 recruited infants (3.7%) during Phase 1 and only 31 of 138 children (22.5%) during Phase 2 (Table 2). Drop-outs were almost exclusively due to personal reasons (8 during Phase 1, 25 during Phase 2), and to families moving away (1 during Phase 1, 5 during Phase 2). Five children were excluded because of heart disease diagnosed after the neonatal period (four in Phase 1 and one in Phase 2). The data are derived from four sources: (i) hospital records; (ii) questionnaires; (iii) telephone interviews; and (iv) objective A detailed of data in the BILD cohort during Phases 1 and 2 is in Table of data and measurements in the BILD cohort during Phases 1 and 2 hospital during delivery of of of and of of expiratory of measured in blood from and or Questionnaires 2 and 3 infections and lower respiratory number and or of of effect of symptoms on and triggers, number and of asthma, problems, 12 to follow-up and of and of 12 to and used Respiratory symptoms and wheeze during and reduced standardized to symptoms into four to and with high for lower infections with severe respiratory symptoms as total number of with or of of cough, of cough, assessment of first time of cough, time of cough, of during 12 to of cough, of wheeze, of wheeze, assessment of first time of wheeze, time of wheeze, of wheeze, of or of and of at away due to in animal exposure at of of due to at assessment of exposure to active or number of and number of respiratory infections, infections, tract infections, infections, other infections during and during first year of active number of during and first year of and of at away due to in animal exposure at of of conditions of number of number of in active or number of until first major follow-up at the age of 6 years and active or number of until first major follow-up at the age of 6 years hospital during delivery of of of and of of expiratory of measured in blood from and or Questionnaires 2 and 3 infections and lower respiratory number and or of of effect of symptoms on and triggers, number and of asthma, problems, 12 to follow-up and of and of 12 to and used Respiratory symptoms and wheeze during and reduced standardized to symptoms into four to and with high for lower infections with severe respiratory symptoms as total number of with or of of cough, of cough, assessment of first time of cough, time of cough, of during 12 to of cough, of wheeze, of wheeze, assessment of first time of wheeze, time of wheeze, of wheeze, of or of and of at away due to in animal exposure at of of due to at assessment of exposure to active or number of and number of respiratory infections, infections, tract infections, infections, other infections during and during first year of active number of during and first year of and of at away due to in animal exposure at of of conditions of number of number of in active or number of until first major follow-up at the age of 6 years and active or number of until first major follow-up at the age of 6 years during with volume by respiratory and expiratory flow of fraction of exhaled nitric with a of (see lung volume and resistance (see Anthropometric data at study and measurements tidal (see with and volume by respiratory and expiratory flow of with a of and no (see lung volume and resistance (see lung volume forced expiratory and Anthropometric data at study and blood measured as with at first respiratory which is as with or wheeze, with or are by polymerase chain reaction based different respiratory of single polymorphisms of number in genes involved in lung growth of and of number in genes involved in lung growth and Swiss National of with of of of of at of Swiss of of of of at of of and at study of of and at study of during with volume by respiratory and expiratory flow of fraction of exhaled nitric with a of (see lung volume and resistance (see Anthropometric data at study and measurements tidal (see with and volume by respiratory and expiratory flow of with a of and no (see lung volume and resistance (see lung volume forced expiratory and Anthropometric data at study and blood measured as with at first respiratory which is as with or wheeze, with or are by polymerase chain reaction based different respiratory of single polymorphisms of number in genes involved in lung growth of and of number in genes involved in lung growth and Swiss National of with of of of of at of Swiss of of of of at of of and at study of of and at study of Study of birth, maternity birth birth multiple birth, birth and asthma, due to asthma or and and birth of birth and all from study and as well as of history Study of birth, maternity birth birth multiple birth, birth and asthma, due to asthma or and and birth of birth and all from study and as well as of history of data and measurements in the BILD cohort during Phases 1 and 2 hospital during delivery of of of and of of expiratory of measured in blood from and or Questionnaires 2 and 3 infections and lower respiratory number and or of of effect of symptoms on and triggers, number and of asthma, problems, 12 to follow-up and of and of 12 to and used Respiratory symptoms and wheeze during and reduced standardized to symptoms into four to and with high for lower infections with severe respiratory symptoms as total number of with or of of cough, of cough, assessment of first time of cough, time of cough, of during 12 to of cough, of wheeze, of wheeze, assessment of first time of wheeze, time of wheeze, of wheeze, of or of and of at away due to in animal exposure at of of due to at assessment of exposure to active or number of and number of respiratory infections, infections, tract infections, infections, other infections during and during first year of active number of during and first year of and of at away due to in animal exposure at of of conditions of number of number of in active or number of until first major follow-up at the age of 6 years and active or number of until first major follow-up at the age of 6 years hospital during delivery of of of and of of expiratory of measured in blood from and or Questionnaires 2 and 3 infections and lower respiratory number and or of of effect of symptoms on and triggers, number and of asthma, problems, 12 to follow-up and of and of 12 to and used Respiratory symptoms and wheeze during and reduced standardized to symptoms into four to and with high for lower infections with severe respiratory symptoms as total number of with or of of cough, of cough, assessment of first time of cough, time of cough, of during 12 to of cough, of wheeze, of wheeze, assessment of first time of wheeze, time of wheeze, of wheeze, of or of and of at away due to in animal exposure at of of due to at assessment of exposure to active or number of and number of respiratory infections, infections, tract infections, infections, other infections during and during first year of active number of during and first year of and of at away due to in animal exposure at of of conditions of number of number of in active or number of until first major follow-up at the age of 6 years and active or number of until first major follow-up at the age of 6 years during with volume by respiratory and expiratory flow of fraction of exhaled nitric with a of (see lung volume and resistance (see Anthropometric data at study and measurements tidal (see with and volume by respiratory and expiratory flow of with a of and no (see lung volume and resistance (see lung volume forced expiratory and Anthropometric data at study and blood measured as with at first respiratory which is as with or wheeze, with or are by polymerase chain reaction based different respiratory of single polymorphisms of number in genes involved in lung growth of and of number in genes involved in lung growth and Swiss National of with of of of of at of Swiss of of of of at of of and at study of of and at study of during with volume by respiratory and expiratory flow of fraction of exhaled nitric with a of (see lung volume and resistance (see Anthropometric data at study and measurements tidal (see with and volume by respiratory and expiratory flow of with a of and no (see lung volume and resistance (see lung volume forced expiratory and Anthropometric data at study and blood measured as with at first respiratory which is as with or wheeze, with or are by polymerase chain reaction based different respiratory of single polymorphisms of number in genes involved in lung growth of and of number in genes involved in lung growth and Swiss National of with of of of of at of Swiss of of of of at of of and at study of of and at study of Study of birth, maternity birth birth multiple birth, birth and asthma, due to asthma or and and birth of birth and all from study and as well as of history Study of birth, maternity birth birth multiple birth, birth and asthma, due to asthma or and and birth of birth and all from study and as well as of history Hospital these are used to extract information about maternal during the delivery and perinatal Questionnaires these assess information about health with an on respiratory and infections and and environmental Questionnaire 1 also information on pre- and perinatal risk factors including and maternal medical history. Questionnaires 2 and 3 assess the study history during Phase 2. Questionnaire 1 from a cohort Questionnaires 2 and 3 include for children from the Study of and in Childhood All questionnaires have been and with little Questionnaire 1 is as an for data during Questionnaires 2 and 3 are to parents in (see as Data at data A and as Data at telephone interviews these interviews are during the first year of to information about respiratory This includes a standardized with a high for lower infections (Table in and environmental exposures are also assessed in Table 5 for the study population with data from Phase 1). In the of a first lower the study nurses visit the families within 3 and perform two for by polymerase chain reaction used in weekly telephone interviews during the first year of used in weekly telephone interviews during the first year of Risk factors for respiratory disease of infants during Phase 1 of the BILD cohort This Table the of risk factors for respiratory disease of study participants during Phase 1 of the BILD during the first year of = information not be for 3 of drop-outs during Phase 1). maternal history of asthma or tests were performed in a of were in of than in of the common Risk factors for respiratory disease of infants during Phase 1 of the BILD cohort This Table the of risk factors for respiratory disease of study participants during Phase 1 of the BILD during the first year of = information not be for 3 of drop-outs during Phase 1). maternal history of asthma or tests were performed in a of were in of than in of the common measurements these measurements during infancy the a lung function at the age of 1 month in infants during measurements, multiple breath resistance At the age of 6 years, the lung function tests are performed, by and The fraction of exhaled nitric as a of airway inflammation, is measured at both All measurements are performed to by the and the Society tests are performed in mothers during the first visit and in infants at the age of 6 years. In to data from questionnaires, exposure during is assessed by the of the first urine after birth. to air pollution on the is measured by of the Swiss National including of with a of and as well as the of of pollution at the is measured in time by of with a of and and at the of To assess lung development in a large one tests that be performed in study In to the standardized data we have to of lung function measurements in and to the development and of lung function the of prospective birth we have properties of the airways in infants to wheeze.9 We that not only also airway a for the development of wheeze, infants with a history of wheeze airway This might be due to or at birth. This the of early of lung air pollution might be such an early By air pollution exposure during we that exposure to was associated with lung function in and that were associated with after birth, the of response in This was if mothers during of maternal is a risk for asthma, this to the that lung development and evolution of asthma might be which are both influenced by early We were the first to prospective data on respiratory symptoms in a cohort of unselected The incidence of symptoms was in infants of maternal was related to the number of after birth were associated with severe symptoms during the first year of in the of which was again if mothers during after birth might be an of respiratory symptoms and We the of viral pathogens respiratory infections during the first year of and that were most by and respiratory also with to the of viral 3 after incidence of we that a in children with lower infections from and hospital-based is also associated with respiratory disease in healthy Swiss and that in an in the the We were to towards the about the of environmental on airway We that during an effect on components of the immune system of the in cord blood were lower if mothers during The was most in and the of air pollution on as of for which large changes are after exposure to high pollution such as after we only small in cord blood of healthy term the effect of the collection on respiratory morbidity, we that low were only and high with the incidence and of respiratory symptoms during the first year of life, particularly in infants with The BILD with its data set of comprehensive lung function data, particularly during is an and to how predisposing factors affect lung development from through childhood and to risk of respiratory disease. with to the and lung function measurements in the BILD cohort a number of and data during these measurements in the BILD cohort have been To we measure lung function at age in a standardized the and on every subsequent in the are performed to the by the and we were for the of tidal at the age of 1 month, we used of as for There is still to lung function To exposure to air we have to assess exposure to air which is and yet been used in studies the effect of exposure to air pollution on lung The BILD cohort a prospective It includes data before and after birth, follow-up with weekly standardized interviews until the age of 1 year and a detailed at the age of 6 years. Lung function tests are performed at time covering the vulnerable phases of lung development of airways and during and This of pre- and perinatal risk factors from of risk such as exposure to airway all infants being healthy and of a age and all measurements in infants performed during within the cohort is such as and for older children are in the these are prospectively assessed and be in the of measurements at age. We have only during the especially during Phase 1, with other This is due to the regular particularly the weekly telephone interviews during the first year of The of such a detailed study is that it only be on a number of is not a major as all participants are recruited of exposures and outcomes. are assessed and from we have been to for known and further All involved families were recruited in maternity hospitals and only a of children born during the study period in the was the for was information about the participants are to be towards a This is the with most studies detailed In so far been a risk a risk for Therefore, we that most are for the it be in that not all be to all Swiss or European of the in is The Bern cohort studies are at the of Paediatric at Children’s University Hospital Bern, Switzerland. The provides information personal data, and The is of the University Hospital Switzerland. in or further information are to the Swiss National Science to to to and and to European Respiratory Society to Austrian, German and Swiss Paediatric Respiratory Society to We all study participants and their families in the of Bern for in the study and the of the four major maternity hospitals in the for and recruitment. We also the study nurses and and the lung function and for their and of