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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. Because of its high prevalence, it is of major public health relevance. Presentation and disease course of childhood wheezing disorders vary, and its phenotypes are difficult to distinguish in early childhood despite the demand for diverse therapeutic strategies. Current treatments have no sustained effect on development of lung function and cannot prevent tracking of reduced lung function. Risk factors for childhood wheeze and subsequent asthma include genes, environmental factors and their interaction: all these affect lung development directly or indirectly (Figure 1). Data on the association between lung development and respiratory symptoms 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, in high-risk populations or retrospectively. 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. How is it funded?


What does it cover?
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][15][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.

Who is in the sample?
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. 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  Year  1999  2000  2001  2002  2003  2004  2005  2006  2007  2008  2009   Total until  31/12/2009   Prenatally recruited  26  40  20  21  46  44  37  29  30  45  25  364   Completed study phase 1  23  37  19  20  45  44  36  28  29  44  25  350   Completed study phase 2  ------28  14  11  18  36  107   Drop-outs during study phase 1  3  3  1  1  1  0  1  1  1  1  1  14   Drop-outs after study phase 1  ------8  8  7  1 8 32 How often have they been followed-up? What is attrition like?
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. 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).

What has been measured?
The data are derived from four sources: (i) hospital records; (ii) questionnaires; (iii) telephone interviews; and (iv) objective measurements. A detailed description of data collected in the BILD cohort during Phases 1 and 2 is given in Table 3.
Hospital records (i): these are used to extract information about maternal warning signs during the delivery and perinatal data.
Questionnaires (ii): these assess information about health conditions, with an emphasis on respiratory and atopic symptoms, infections and sociodemographic and environmental exposures. Questionnaire 1 also collects information on pre-and perinatal risk factors including family and maternal past medical history. Questionnaires 2 and 3 assess the study participant's history during Phase 2. While    alimentation, later diet Maternal and paternal hay fever, atopic dermatitis, asthma, therapy due to asthma or difficulty breathing Demographic and socio-economic information: mother and father: names, birth dates, occupation throughout study, nationality, religion, country of birth and language, all home addresses from pregnancy throughout study Families' paediatrician name and address as well as of general practitioner, family history THE BERN INFANT LUNG DEVELOPMENT COHORT Questionnaire 1 contains validated questions from a preschool cohort study, 17,18 Questionnaires 2 and 3 include questions for school-age children from the International Study of Asthma and Allergies in Childhood (ISAAC). 19 All questionnaires have been validated and used, with little variation since 1999. Questionnaire 1 is programmed as an online database for data entry during interview, Questionnaires 2 and 3 are distributed to parents in paper form (see available as Supplementary Data at IJE online data A and B available as Supplementary Data at IJE online).
Weekly telephone interviews (iii): these interviews are carried out during the first year of life to collect information about respiratory symptoms. This includes a standardized score with a high sensitivity for lower respiratory-tract infections (Table 4). 20 Changes in socio-demographic and environmental exposures are also assessed (listed in Table 5 for the study population with data from Phase 1). In the event of a first lower respiratory-tract infection, the study nurses visit the families twice within 3 weeks and perform two anterior nasal swabs for virus diagnostics by polymerase chain reaction (PCR).
Objective measurements (iv): these measurements during infancy include, besides the mentioned virus diagnostics, a lung function test at the age of 1 month in unsedated infants during quiet natural sleep (tidal breathing measurements, multiple breath washouts, interrupter resistance measurements). At the age of 6 years, the same lung function tests are performed, supplemented by spirometry and bodyplethysmography. The fraction of exhaled nitric oxide (FeNO), as a marker of airway inflammation, is measured at both time-points. All measurements are performed according to current standards by the ERS and the American Thoracic Society (ATS). [21][22][23][24] Skin-prick tests are performed in mothers during the first visit and in infants at the age of 6 years.
In addition to data from questionnaires, ETS exposure during pregnancy is objectively assessed by the analysis of the first urine after birth. Exposure to outdoor air pollution on the community level is measured by monitoring stations of the Swiss National Air Pollution Network (NABEL), including daily mean levels of particles with a 50% cut-off aerodynamic diameter of 10 mm (PM 10 ) and nitrogen dioxide (NO 2 ), as well as the daily maximum of mean hourly levels of ozone (O 3 ). Air pollution at the individual level is measured in selected time periods by mobile passive samplers (daily mean levels of particles with a 50% cut-off aerodynamic diameter of 2.5 mm (PM 2.5 ) and PM 10 ) and stationary passive samplers at the measurement sites (daily mean levels of NO 2 ).

What has been found? Key findings and publications
Development and standardization of non-invasive lung function tests To assess lung development in a large infant cohort, one needs non-invasive tests that can be performed in uncooperative study participants. In addition to the standardized data collection, we have significantly added to current ERS/ATS standards of lung function measurements in infants 23,24 and to the development and standardization of additional non-invasive lung function techniques. 9, Early programmers of lung development Since the beginning of our prospective birth cohort, we have investigated physical properties of the airways in infants prone to wheeze. 9 We showed that not only bronchoconstriction, but also impaired airway growth, plays a role for the development of wheeze. 27,29 Even without current wheeze, infants with a past history of wheeze display altered airway wall mechanics. This might be due to remodelling or independent developmental differences already present at birth. This emphasizes the importance of early programmers of lung development. 30,49,50 Outdoor air pollution might be such an early programmer. By modelling outdoor air pollution exposure during pregnancy, we found that exposure to PM 10 was associated with altered lung function in newborns and that NO 2 levels were associated with elevated FeNO levels after birth, indicating the induction of inflammatory response in infants. This was enhanced if mothers smoked during pregnancy but independent of maternal atopy. 12 Although atopy is a risk factor for allergic asthma, this adds to the hypothesis that lung development and evolution of allergic asthma might be partly independent processes, which are both influenced by early programmers. 25,51 Prevalence, risk factors and prognosis of respiratory symptoms in early life We were among the first to present prospective data on respiratory symptoms in a cohort of unselected infants. The incidence of symptoms was increased in infants of asthmatic mothers, whereas maternal hay fever was inversely related to the number of symptoms. 52 High FeNO levels after birth were associated with severe symptoms during the first year of life in the offspring of atopic mothers, which was again pronounced if mothers smoked during pregnancy. 53 Thus, FeNO after birth might be an important predictor of later respiratory symptoms and morbidity.

The role of viral triggers for early respiratory-tract infections
We analysed the pattern of viral pathogens causing respiratory infections during the first year of life and found that rhinoviruses were most common, followed by corona, parainfluenza and respiratory syncytial viruses. Patterns differed also with regard to the amount of viral shedding 3 weeks after incidence of symptoms. [54][55][56] Additionally, we showed that Human Bocavirus (HBoV), a picornavirus isolated in children with lower respiratory-tract infections from several retrospective and hospital-based studies, is also associated with respiratory disease in healthy Swiss infants, and reported that HBoV circulates in an endemic fashion in the community, thus confirming the worldwide distribution. 54 Early mechanisms and markers related to airway inflammation, the development of the immune system and childhood wheezing disorders We were able to add towards the knowledge about the effects of environmental triggers on airway inflammation. We found that smoking during pregnancy has an effect on components of the innate immune system of the offspring. Total leucocyte counts in cord blood were significantly lower if mothers smoked during pregnancy. The decrease was most prominent in neutrophils, monocytes, dendritic cells and lymphocytes. 57 Investigating the impact of outdoor air pollution on cytokine levels as of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), IL-10, for which large changes are seen after exposure to high pollution levels such as after bushfires, we found only small effects in cord blood of healthy term infants. 58,59 Assessing the quantitative effect of the acute-phase plasma collection mannose-binding lectin (MBL) on respiratory morbidity, we found that low levels were only weakly associated, and high levels more strongly associated, with the incidence and severity of respiratory symptoms during the first year of life, particularly in infants with asthmatic parents. 60 What are the main strengths and weaknesses?
The BILD cohort, with its unique data set of comprehensive lung function data, particularly during infancy, is an integrative and interdisciplinary framework to analyse how predisposing factors affect lung development from pregnancy through childhood and to predict later risk of respiratory disease. Especially with regard to the costly and time-consuming lung function measurements in infants, the BILD cohort has a number of methodological strengths, and normative data collected during these measurements in the BILD cohort have been published meanwhile. 61 To ensure comparability, we measure lung function at any age in a standardized way, using the same technique and equipment on every subsequent occasion in the same order. Measurements are performed according to the latest recommendations by the ERS and ATS; often we were even stricter. For instance, for the analysis of tidal breathing at the age of 1 month, we used 100 instead of 30 breaths as currently recommended, for better accuracy. 21 There is still enough flexibility to develop new lung function testing methods. 32,36 To validate exposure to air pollutants, we have started to assess individual exposure to air pollutants using passive samplers, which is expensive and has yet been rarely used in studies assessing the effect of long-term exposure to air pollution on lung function. The BILD cohort has a prospective design. It includes data assessments before and after birth, close follow-up with weekly standardized telephonic interviews until the age of 1 year and a detailed reassessment at the age of 6 years. Lung function tests are performed at several time points covering the vulnerable phases of lung development (growth of airways and alveoli) during gestation and childhood. This facilitates disentangling effects of pre-and perinatal risk factors from those of post-natal risk factors, such as exposure to airway pollutants.
With all included infants being healthy and of a narrow age range and all measurements in infants performed during quiet natural sleep, comparability within the cohort is given. Confounders such as physical activity, obesity and hypoxia important for older children are negligible in the studied infants. Nevertheless, these influences are prospectively assessed and will be included in the analysis of measurements at school age. We have only minimal attrition during the study, especially during Phase 1, comparing favourably with other studies. 62 This is probably due to the regular follow-up, particularly the weekly telephone interviews during the first year of life. The drawback of such a detailed time-consuming study is that it can only be done on a limited number of participants.
Selection bias is not a major issue, as all participants are recruited prenatally without knowledge of exposures and outcomes. These are assessed and analysed independently from each other. So far, we have been able to adjust for known biological, time-variant and further possible confounders.
All involved families were recruited in maternity hospitals and only a minority of children born during the study period in the region was recruited. Although the main reason for non-participation was lacking information about the study, participants are likely to be biased towards a well-educated middle-class population. This is the case with most studies involving detailed measurements. In our analyses, social class has so far neither been a risk factor nor a risk modifier for outcome measures. Therefore, although we believe that most results are fairly representative for the general population, it must be kept in mind that not all findings can be extrapolated to all Swiss or European children. Replication of the findings in independent cohorts is desirable.
Can I get hold of the data? Where can I find out more?
The Bern cohort studies are carried out at the Department of Paediatric Pulmonology at Children's University Hospital Bern, Switzerland. The department's homepage provides information regarding personal contact data, team members and publications (http://www.kinderkliniken.insel.ch/kiheil-pneumologie.html). The principal investigator is Prof. Dr Urs Frey, MD PhD, head of the University Children's Hospital (UKBB), Basel, Switzerland. Researchers interested in collaborative work or further information are invited to contact the principal investigator, Urs Frey, urs.frey@ukbb.ch.

Supplementary Data
Supplementary Data are available at IJE online. We also thank the study nurses Monika Graf, Barbara Hofer and Christine Becher and the lung function technicians Gisela Wirz and Sandra Luescher for their invaluable assistance and support.
Conflict of interest: None declared.