Cohort Profile Update: The Bern Basel Infant Lung Development Cohort

Abstract

The Bern Basel Infant Lung Development (BILD-) cohort was set up in 1999 to investigate risk factors related to childhood wheeze and asthma in healthy, term-born children in Switzerland. Over past decades, risk factors, respiratory morbidities and knowledge about underlying mechanisms have changed significantly. Nowadays, the BILD-cohort also includes risk groups with particular susceptibilities (e.g. preterm infants), and with exposure to novel environmental risk factors (e.g. COVID-19 and other respiratory infections, vaping). So far, a total of 1332 participants have entered the BILD-cohort after birth and are followed up regularly from infancy to adulthood (range of study age: 36.7 post-conceptional weeks to 21.4 years). Data collection includes new exposure factors, outcome measures (e.g. virus and microbiota diagnostics, magnetic resonance imaging, breath biomarkers) and follow-up time points. For collaborative projects and enquiries about data sharing, please contact Philipp Latzin [[email protected]] and Urs Frey [[email protected]]. This is an update on the Bern Basel Infant Lung Development (BILD-) cohort profile published in 2012.1 The BILD-cohort is a prospective birth cohort study with ongoing recruitment since 1999. The original aim of the BILD-cohort was to investigate hereditary and environmental risk factors (infections, allergic triggers, air pollution) related to impaired lung functional growth and subsequently childhood wheeze and asthma.1 Up to the first description in 2012, 364 unselected, healthy, term-born neonates were recruited in the predominantly rural area of Bern (Switzerland), of whom 107 children had been followed up at 6 years of age.1 Briefly, after recruitment during pregnancy, the BILD-cohort consists of weekly telephone interviews during the first year of life for assessment of respiratory symptoms and study visits at 1 month and 6 years of age, including questionnaires on exposure and respiratory outcomes and objective markers such as lung function tests and virus, inflammation and genetic diagnostics.1 The main aim of the BILD-cohort was to study risk factors and environmental exposure-outcome associations among children for the most common respiratory morbidities, namely childhood wheeze and asthma, in order to find early disease markers and potentially new aetiological factors.1 Since the start of the BILD-cohort in 1999, not only the risk factors have changed, but also resulting morbidities, clinical management and scientific landscape. There is increasing evidence that early life risk factors not only play a critical role in the development of asthma, but also in chronic airway disease of adulthood.2 This provides a potential window of opportunity for preventative measures, and indicates the importance of long-term respiratory follow-up and the need to understand underlying mechanisms.2 Some factors are supposed to impair lung growth directly, such as prematurity, and others seem to be mediated mainly through inflammatory processes such as recurrent infections, oxidative stress or direct toxicity (e.g. air pollution). The past decade, and the COVID-19 pandemic in particular, yielded new insights on the influence of viral infections on respiratory morbidity. It underlined that the impact of risk exposures, and responses might differ in infants at risk for chronic respiratory symptoms. For comprehensive assessment of early life risk factors and their long-term influence on lung development and respiratory health, the BILD-cohort started to collect new data. The BILD-cohort expanded at various levels to include new exposure factors and to improve the long-term assessment of pulmonary outcome and the underlying mechanisms (Figures 1 and 2). In order to enlarge the cohort, we extended to a second study centre, the University of Basel Children’s Hospital (Switzerland). Moreover, we matched and compared findings with cohorts with other risk profiles.3,4 Initially the BILD-cohort mainly focused on healthy infants; in the current phase we focus on risk groups. Comparing them with the healthy group allows us to assess the effect of environmental exposures on pulmonary outcomes and the underlying mechanisms via biomarkers. Schematic overview of the Bern Basel Infant Lung Development Cohort study: tracking of lung function trajectories and lung health. The Bern Basel Infant Lung Development (BILD) Cohort study tracks lung development and lung growth longitudinally by regular follow-ups of healthy term-born participants and particular risk groups from infancy up to early adulthood. Lung development and growth are assessed by measurement of lung function, as well as lung structure, respiratory symptoms, microbiota and biological responses. In parallel, we assess potential modifiers of the lung trajectories such as environmental and individual risk factors Overview of assessments and study procedures during the different study phases of the Bern Basel Infant Lung Development Cohort study. £ This figure has been adapted from our original cohort profile1 We started to include preterm infants (Pre-BILD). Prematurity is the most common disruptor of normal lung development and a relevant early life risk factor for respiratory morbidity in the elderly.2 It is long known that preterm infants have persisting alterations in lung mechanics, and recent evidence suggests that they might additionally be more susceptible to environmental pollution, possibly due to an impaired oxidative stress response.5 Improved neonatal care and survival rate over the past decades have changed the pathophysiology of the subsequent chronic lung disease, i.e. bronchopulmonary dysplasia (BPD).6 Long-term data are scarce, as preterm survivors are reaching adulthood now. We aim to investigate long-term effects of preterm birth on pulmonary outcomes, considering the associated perinatal and environmental factors. Infants born from asthmatic mothers are known to have higher risk for respiratory symptoms in early life.7 The mechanisms are still not entirely explored. A set of genetic factors has been described to be associated with respiratory symptoms in infancy and, in collaboration with another cohort, we demonstrated that compared with females, male infants from asthmatic mothers have impaired lung function at birth even before the onset of symptoms.3 Symptoms are more frequent if the mother’s asthma in pregnancy is poorly controlled, which underlines the important role of the intrauterine environment. In the current phase, we focus on the exploration of the underlying mechanisms. Children with COVID-19 and other respiratory infections: early life viral infections are associated with disadvantageous immune and microbiota profiles and an increased risk for later development of asthma.8 Since the COVID-19 pandemic, virus epidemiology changed, with initially decreasing viral infections due to control measures and a rebound of some viruses after relaxation of these measures.9 To assess the influence of the COVID-19 pandemic on virus epidemiology and respiratory health, as well as microbiota-virus interactions, we analyse viral profiles of anterior nasal swabs by multiplex polymerase chain reaction (PCR). Vaping adolescents: recently, the use of e-cigarettes besides or instead of classical tobacco use has become popular. Smoking adults probably benefit from switching to e-cigarettes, but long-term effects in adolescents are unknown.10 Few studies in adults have estimated the exposure to inhaled pollutants by biomonitoring the dose of toxins delivered by e-cigarettes, the effect on oxidative stress and, ultimately, respiratory symptoms and function.11 To assess the effect of e-cigarettes on lung health in adolescence, we started to recruit vaping adolescents (e-BILD). We present data for healthy term-born (BILD), preterm (Pre-BILD) and vaping participants (e-BILD) so far. BILD and Pre-BILD participants are recruited at both study centres on an ongoing basis, and e-BILD participants are recruited in Bern on a time-limited basis. Inclusion criteria for BILD are term-born (gestational age ≥37 weeks), White neonates without major birth defects or perinatal disease, whose parents speak one of the major Swiss languages (German, French) and whose mothers have no severe health problems or drug abuse except for smoking. For Pre-BILD, the same inclusion criteria apply to preterm (gestational age <37 weeks) children, and perinatal morbidities are not exclusive. Inclusion criteria for adolescents for e-BILD is daily vaping, excluding daily tobacco or cannabis use; e-BILD participants are recruited independently from BILD study participants, in vape shops, schools and via social media. In Bern, recruitment as described in the original cohort profile is ongoing since 1999 for BILD and Pre-BILD. Up to mid-2022, 650 term-born neonates were recruited. Of these, 618 performed a study visit during infancy, 374 at school age and 128 in adolescence (Table 1). In parallel, 263 preterm neonates have been recruited while they hospitalised at the University Children’s Hospital of Bern. Of these, 243 performed a study visit during infancy, 85 at school age and 91 in adolescence (Table 1). For e-BILD, recruitment started in 2021 and aims for 30 participants. So far, 14 vaping participants have been included (Table 1). In Bern, we additionally recruit preterm-born participants from the outpatient clinics since 2020, with retrospective collection of perinatal data from medical records. We have included 16 participants so far (Supplementary Table S1, available as Supplementary data at IJE online). The inclusion of study participants at a later stage allows for expansion of the study population. Anthropometric data of participants with lung function until mid-2022. Data are presented as n (%) or median (range), unless otherwise stated. Data include participants until mid-2022. No data presented for study Phase II, as none of the participants have been followed up at 3 years of age yet. BILD, Bern Basel Infant Lung Development Cohort; BMI, body mass index; NA, not applicable. Body weight is reported in z-scores in infancy and in kg at school age and adolescence. Z-scores for body weight and length in infancy were calculated based on Fenton growth charts for all participants with gestational age <37 weeks (Fenton et al, BMC Pediatr, 2013), and based on World Health Organization (WHO) growth charts for those with gestational age ≥37 weeks (WHO, Acta Paediatr Suppl, 2006); z-scores for body length and BMI at school age and in adolescence were calculated based on WHO growth charts (de Onis et al., Bull World Health Organ, 2007); if participants were aged >19 years at study visit, we set the age to 19 years to calculate z-scores. In Basel, recruitment is ongoing since 2012 for BILD and Pre-BILD. Up to mid-2022, 238 term-born and 181 preterm neonates have been included. Of these, 211 term-born and 158 preterm-born participants performed a study visit during infancy, and 76 and 64, respectively, at school age (Table 1). In Bern, the median (range) gestational age of the term-born group was 39.8 (37.0–42.3) weeks and 19% were born by caesarean section, compared with median gestational age of 28.8 (23.9–36.7) weeks and 65% caesarean section rate in the preterm group (Table 2). In Pre-BILD, 69% of the participants were diagnosed with BPD, with a median (range) duration of supplemental oxygen of 64 (0–508) days (Table 2). Population characteristics of participants included in infancy (study Phase I.) Data are presented as n (%) or median (range), unless otherwise stated. Data include participants until mid-2022. BPD, bronchopulmonary dysplasia; BILD, Bern Basel Infant Lung Development Cohort; CPAP, continuous positive airway pressure; O2, oxygen; C-section, caesarean section. Z-scores were calculated based on Fenton growth charts for all participants with gestational age <37 weeks (Fenton et al., BMC Pediatr, 2013), and based on World Health Organization (WHO) growth charts for those with gestational age ≥37 weeks (WHO, Acta Paediatr Suppl, 2006). In Basel, median (range) gestational age of the term-born group was 39.7 (37.0–42.0) weeks and 33% were born by cesarean section, compared with 32.9 (24.3–36.9) weeks and 75% cesarean section rate in the preterm group (Table 2). In Pre-BILD, 7% of the participants were diagnosed with BPD, with a median (range) duration of supplemental oxygen of 0 (0–308) days (Table 2). Drop-out rate in infancy was 2% in Bern (21/913 term-born and preterm infants) and 5% in Basel (19/419) (Supplementary Table S1, available as Supplementary data at IJE online). Between infancy and school age, 144 (16%) participants in Bern and 53 (13%) in Basel dropped out of the study (Supplementary Table S1, available as Supplementary data at IJE online). So far, follow-up in adolescence has only been established in Bern, where 89 (10%) participants dropped out between school age and adolescence (Supplementary Table S1, available as Supplementary data at IJE online). The BILD-cohort continues to collect information as described in the original cohort profile, with extended data collection for a more comprehensive and longitudinal follow-up.1 Study phase I starts with prenatal recruitment and ends with the first year of life (Figure 2). It includes: collection of perinatal data, blood and urine samples at birth; the first study visit at 4–6 weeks after birth with lung function, maternal skin prick testing and collection of bio samples (e.g. nasal swabs); followed by weekly assessment of respiratory symptoms, respiratory rate and nasal swabs during the first year of life. Phase II for the age of 1–6 years foresees a study visit at 3 years with lung function, skin prick testing, questionnaires and the collection of bio samples, followed by monthly nasal swabs at home during 1 year (Figure 2). Phase III from 6 years up to young adulthood includes 3-yearly study visits following the same protocol as in phase II, with additional lung imaging (Figure 2). The following gives an overview of new (i) exposure factors, (ii) outcome measures and (iii) time points that have been introduced since the original BILD-cohort description.1 In view of the new risk groups, we expanded the assessment of exposure factors including a wide range of perinatal exposures from medical records for Pre-BILD, extended questionnaires for novel environmental risk factors such as respiratory infections (including COVID-19) from infancy on, and substance use in adolescence (Table 3). For comprehensive assessment of the effect on lung health and the underlying mechanisms, we included new outcome measures. In 2011, weekly (during the first year of life) to monthly (after follow-up visits for 1 year) nasal swabs were introduced for assessment of viruses and microbiota (until mid-2022, >10 000 aliquots collected during infancy). In all infants with available plasma and serum samples, we assessed a signature of genomic, proteinomic and metabolomic cord blood markers related to intrauterine inflammation, oxidative stress, autophagy, cellular senescence and remodelling (Table 3; and Supplementary Table S2, available as Supplementary data at IJE online). These specific markers have been measured since 1999 in Bern and since 2012 in Basel. Additionally, metabolomic profiles have been assessed by mass spectrometry since 2020 in Basel. Novel outcomes relate to oxidative stress response markers in exhaled air at 1 month of age (until mid-2022, 42 infants from Basel with metabolomic profiles) and to structure-function relationship in the developing lung (Table 3).12 The latter involves additional measurements of lung function and structure, such as magnetic resonance tomography (MRI; Table 3 and Figure 2). MRI was introduced to the BILD-cohort in Bern in 2020 and is performed on a standard 1.5 Tesla scanner (MAGNETOM Aera; Siemens Healthineers, Erlangen, Germany) without sedation or application of contrast agents, including morphological and functional sequences based on the matrix pencil decomposition technique.13 For e-BILD, we included a questionnaire on consumers’ behaviour, as well as new urinary biomarkers to assess the exposure to inhalant intoxicants (volatile organic compounds, polycyclic aromatic hydrocarbons, oxidative stress metabolites), and nasal epithelial cell cultures to assess immunological response to viral exposure and inflammatory gene expression in 2021 (Table 3). Besides the original follow-up during the first year of life and at 6 years, we introduced additional study visits to ensure regular follow-up from infancy up to adulthood, aiming for a 3-year interval starting at 1 year of age (Figure 2). So far, we have not yet started the follow-up in study phase II (study visit at 3 years), and 3-yearly visits in phase III have been introduced in Bern but are not yet entirely harmonized throughout all groups (Table 1). For data management, paper forms such as questionnaires were changed to an electronic format. New data collection and measures of the Bern Basel Infant Lung Development Cohort study. Source: medical records (e.g. data on prenatal steroids, surfactant therapy, supplemental oxygen, respiratory support) Source: questionnaires Date of infection and vaccination Source: Questionnaires Date of infection and vaccination Source: Questionnaires Substance use prevalence and intensity/duration of use: tobacco and nicotine products including e-cigarettes, reason for use, nicotine addiction screening, alcohol including binge drinking, other illicit substances Source: SESI-MS Assessment of metabolic profiles measured in parallel to infant lung function and FeNO BILD, Bern Basel Infant Lung Development Cohort; DLCO, diffusing capacity of the lung for carbon monoxide; FeNO, fractional exhaled nitric oxide; MRI, magnet resonance imaging; NGS, next-generation sequencing; OLS, online data supplement; PCR, polymerase chain reaction; RNA, ribonucleic acid; SESI-MS, secondary electrospray ionization-high resolution mass spectrometry; WMS, whole metagenome shotgun sequencing. An overview of publications can be found on the cohort website [https://www.bild-cohort.ch/en/study/publications/]. Lung function data collected within the BILD-cohort has been used to validate, improve and compare new lung function techniques such as multiple-breath washout or volumetric Moreover, data from healthy participants have to The BILD-cohort to the description of the respiratory and with viral infections, and We that the of the respiratory microbiota over the first year of We found that infections during infancy were associated with a of The of infections was mainly associated with environmental factors and respiratory symptoms during infections were to The BILD-cohort the of early life factors with respiratory morbidity. We found that the and of respiratory symptoms in no was found with lung function at school no with respiratory morbidity in infancy, at school was associated with lung function in children and young adults independently of gestational The BILD-cohort knowledge to and air effects on lung function, respiratory symptoms and nasal microbiota after and exposure in infancy and at school the first longitudinal we evidence that exposure is associated with an increased risk of respiratory symptoms in healthy The BILD-cohort assessed the of different early markers to asthma and disease at school age, such as specific biomarkers in cord blood and based on during the first year of We found that preterm infants have different compared with term-born and are more susceptible to prenatal air Moreover, preterm-born children at school age first evidence for a normal the of The BILD-cohort is a study lung development and the influence of environmental risk factors in healthy, term-born children and children at risk for respiratory disease, the of healthy children with risk and disease groups. data nasal in the first year of a resolution of susceptible and regular follow-ups until adulthood, longitudinal tracking of lung function and continuous assessment of risk exposure and associated respiratory study procedures are performed in a between study as well as with other The the and the risk of by including with different the BILD-cohort has been since 1999, also opportunity to assess in exposure and outcome over to the time and This might a a White population. the prevalence for some risk exposures might be within the BILD-cohort compared with the Swiss (e.g. a prevalence of asthma compared with among Swiss and Moreover, due to the for instead of a of all we not response The long time involves in and of measurement and to of participants, which has to be In the longitudinal follow-up of the cohort of healthy and risk groups us to assess lung function trajectories from the stage of lung development to individual and environmental risk factors as potential modifiers allows us to understand which factors might the trajectories in which group of of lung function, structure, symptoms, microbiota and biological response to new preventative and in early time might improve lung function trajectories and to respiratory The BILD Cohort study is out at the of and of the University Hospital in Bern and at the University Hospital in Basel (Switzerland). The provides information contact data, study procedures and publications are Philipp of the of and of Bern University University of Bern, and Urs of the University of Basel Hospital Basel, Switzerland. in collaborative or information are to contact Philipp Latzin [[email protected]] and Urs Frey [[email protected]]. Urs Philipp Bern The study was by the of the of Bern and the of the of Basel (Switzerland), and was from participants or their I of the Supplementary data are available at IJE and were in the and of the study and of data, and the for important and were in and of the data and and the and were in and of the data and the for important This was by the Swiss to to and to The of the study had no role in study data data data of the or to the for The all the study participants for in the with the study and lung function and from both study and of Bern University and University of Basel Hospital Basel, for their with the Additionally, we to for with the data management and of Bern University as well as and University of Basel Hospital Basel, for their in the for the

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