Cohort Profile Update: The Bern Basel Infant Lung Development Cohort

The original cohort

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

What is the reason for the new focus and new data collection?

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.

What will be the new areas of research?

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.

Risk groups with particular susceptibility to environmental risk factors

• 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.

Risk groups exposed to novel environmental risk factors

• 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).

Who is in the cohort?

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.

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).

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).

What has been measured?

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.

What has it found? Key findings and publications

An overview of publications can be found on the cohort website [https://www.bild-cohort.ch/en/study/publications/].

New lung function techniques: development, validation, normative data

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 capnography.¹⁴ Moreover, data from healthy participants have contributed to generate normative values.¹⁵

Upper respiratory tract microbiota and virus infections

The BILD-cohort contributed to the description of the upper respiratory tract microbiota, its dynamics and interaction with viral infections, and air-pollution-induced alterations.^16–20 We showed that the bacterial density of the upper respiratory tract microbiota increased, whereas microbial diversity decreased over the first year of life.¹⁶ We found that rhinovirus (RV) infections during infancy were associated with a loss of diversity.¹⁷ The frequency of RV infections was mainly associated with environmental factors and respiratory symptoms during RV infections were linked to host determinants.^19,20

Early life factors and environmental exposures

The BILD-cohort investigated the association of several early life factors with respiratory morbidity. We found that breastfeeding reduced the incidence and severity of respiratory symptoms in infancy; however, no association was found with lung function at school age.^4,21,22 Caesarean delivery showed no association with respiratory morbidity in infancy, nor at school age.²³ Low birthweight, however, was associated with lung function impairment in children and young adults independently of gestational age.²⁴ The BILD-cohort added knowledge to age- and dose-dependent air pollution effects on lung function, respiratory symptoms and nasal microbiota after pre- and postnatal exposure in infancy and at school age.^18,25,26 As the first longitudinal study, we provided evidence that pollen exposure is associated with an increased risk of respiratory symptoms in healthy infants.²⁷

Biomarkers as predictors of atopic disease and asthma

The BILD-cohort assessed the ability of different early markers to predict asthma and atopic disease at school age, such as specific biomarkers in cord blood and phenotypes based on symptom dynamics during the first year of life.^27–30

Preterm birth

We found that preterm infants have different breathing patterns compared with term-born controls, and are more susceptible to prenatal air pollution.^5,31 Moreover, former preterm-born children at school age showed first evidence for a functionally normal alveolar compartment, supporting the hypothesis of continued alveolarization.³²

What are the main strengths and weaknesses?

The BILD-cohort is a prospective, multicentre study investigating lung development and the influence of environmental risk factors in healthy, term-born children and children at risk for respiratory disease, allowing the comparison of unselected healthy children with risk and disease groups. Weekly data (telephone interviews, nasal swabs) in the first year of life, providing a dense resolution of this particularly susceptible period, and regular follow-ups until adulthood, allow longitudinal tracking of lung function and continuous assessment of risk exposure and associated respiratory morbidities. All study procedures are performed in a standardized way, ensuring comparability between study centres, as well as with other studies. The multicentre approach enhances the power and minimizes the risk of selection bias by including areas with different exposures. As the BILD-cohort has been running continuously since 1999, it also offers unique opportunity to assess changes in exposure and outcome over time.

Participation requires access to the study, time and compliance. This might introduce a selection bias towards a well-educated, White middle-class population. Thus, the prevalence for some risk exposures might be lower within the BILD-cohort compared with the general Swiss population (e.g. a 3% prevalence of asthma compared with 10% among Swiss and European schoolchildren).^33,34 Moreover, due to the call for participation instead of a systematic enquiry of all pregnant women, we do not know exact response rates. The long time span involves changes in hard- and software of measurement devices and leads to dropouts of participants, which has to be taken into account when analysing results.

In summary, the longitudinal follow-up of the well-characterized cohort of healthy individuals and risk groups enables us to assess lung function trajectories from the stage of lung development to maximal growth. Assessing individual and environmental risk factors as potential modifiers allows us to understand which factors might change the trajectories in which group of individuals. Holistic capture of lung function, structure, symptoms, microbiota and biological response helps to identify new preventative and therapeutic options which, applied in early time windows, might improve lung function trajectories and help to avert respiratory disease.

Can I get hold of the data? Where can I find out more?

The BILD Cohort study is carried out at the Division of Pediatric Respiratory Medicine and Allergology of the University Hospital in Bern (Switzerland) and at the University Children's Hospital in Basel (Switzerland). The cohort’s homepage provides information regarding personal contact data, team members, study procedures and previous publications [https://www.bild-cohort.ch]. Principal investigators are Prof. Dr Philipp Latzin, MD PhD, head of the Division of Pediatric Respiratory Medicine and Allergology, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland, and Prof. Dr Urs Frey, MD PhD, head of the University of Basel Children's Hospital (UKBB), Basel, Switzerland. Researchers interested in collaborative work or further information are invited to contact Philipp Latzin [[email protected]] and Urs Frey [[email protected]].

BILD study group

Fabienne Decrue, Basel; Bettina Frauchiger, Bern; Urs Frey, Basel; Oliver Fuchs, Bern; Amanda Gisler, Basel; Olga Gorlanova, Basel; Julian Jakob, Bern; Anne-Christianne Kentgens, Bern; Elisabeth Kieninger, Bern; Insa Korten, Bern; Noemi Künstle, Basel; Philipp Latzin, Bern; Loretta Müller, Bern; Marc-Alexander Oestreich, Bern; Romy Rodriguez, Bern; Yasmin Salem, Bern; Pablo Sinues, Basel; Ruth Steinberg, Bern; Carmen Streibel, Bern; Jakob Usemann, Basel; Corin Willers, Bern; Sophie Yammine, Bern

Ethics approval

The study was approved by the Ethics Committee of the Canton of Bern (Switzerland) and the Ethics Committee of the Canton of Basel (Switzerland), and written informed consent was obtained from participants or their caregivers.

Data availability

See Can I get hold of the data? above.

Supplementary data

Supplementary data are available at IJE online.

Author contributions

U.F. and P.L. were involved in the concept and design of the study and acquisition of data, and critically reviewed the manuscript for important intellectual content. S.Y. and Y.S. were involved in acquisition, analysis and interpretation of the data and drafted and reviewed the manuscript. J.J., O.G., R.S., O.F., L.M. and J.U. were involved in acquisition, analysis and interpretation of the data and critically reviewed the manuscript for important intellectual content.

Funding

This work was supported by the Swiss National Science Foundation (grant numbers 182719 to P.L., 179905 to S.Y. and 320030_204717 to U.F.). The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report or decision to submit the article for publication.

Acknowledgements

The authors thank all the study participants for taking part in the study, along with the study nurses and lung function and laboratory technicians from both study centres: Linda Beul, Fabienne Furrer, Monika Graf, Barbara Hofer, Katrin Hug, Sharon Krattinger, Sandra Lüscher, Barbara Stalder, Andrea Stokes, Sybille Thommen, Gisela Wirz (all Pediatric Respiratory Medicine and Allergology, Department of Pediatrics, Inselspital, Bern University Hospital, Switzerland) and Maya Weber, Katrin Gerber-Windisch, Amelia Imolesi, Sandra Marti Pasqual, Isabel Gonzalez, Mana Okada [all University of Basel Children's Hospital (UKBB), Basel, Switzerland] for their help with the measurements. Additionally, we would like to thank Romy Rodriguez for her support with the data management (Pediatric Respiratory Medicine and Allergology, Department of Pediatrics, Inselspital, Bern University Hospital, Switzerland), as well as Fabienne Decrue and Noemi Künstle [both University of Basel Children's Hospital (UKBB), Basel, Switzerland] for their help in completing the tables for the manuscript.

Conflict of interest

None declared.

References