Lung function trajectories from birth to school age in African children, and their early life determinants

Lung diseases are a major cause of ill health and premature death globally, with a particularly large burden in Africa. Asthma and chronic obstructive pulmonary disease (COPD) are very common, and COPD is the third biggest killer in Africa. African patients develop more severe asthma and COPD, and at a younger age, compared to the rest of the world.

Low level of lung function in young adult age is an important risk factor for the development of COPD. Furthermore, low lung function increases the likelihood of early death from all causes as early as the third decade of life. Studies from high-income countries have shown that lung function tracks from school age to old age, and that lung function in early childhood is an important determinant of COPD in adulthood. Childhood asthma and lower respiratory tract infections in early life reduce lung function through childhood. The burden and the type of respiratory infections and asthma, as well as environmental factors which adversely affect development of lung function (such as cigarette smoke, biomass exposure, allergens or psychosocial stressors), are markedly different in Africa compared to the high-income countries. However, despite the high frequency and severity of childhood asthma, high incidence of respiratory infections, and many harmful environmental exposures, to date there are no data on early-life factors associated with poor lung function and its trajectory in Africa.

We have shown that there is a scope to intervene in early childhood to improve lung function, and reduce long-term consequences of low lung function in childhood. In order to develop interventions to reduce the risk of low lung function in the needy population in Africa, we have to identify childhood lung function trajectories, and discover their early life environmental determinants, which are specific to this part of the world. This information is crucial to develop novel preventative strategies in this part of the world, which will impact on COPD, and the other adverse consequences of diminished lung function.

Our overall aim is to investigate lung function trajectories in African children from birth to 8 years of age, and to identify early-life risk factors associated with low lung function trajectory. We will focus on early-life exposures and respiratory outcomes during childhood, as the trajectory of long-term lung health is established in early life. To achieve this, we will build on the unique South African birth cohort of 1000 mother-child pairs, with detailed measures of infectious diseases and non-infectious exposures through pregnancy and childhood, extensive biobank of samples, and longitudinal measurements of lung function and respiratory diseases from birth to age 5 years. In the course of this project, we will measure lung function and the progression or severity of clinical symptoms through to age 8 years, with ongoing collection of environmental exposures. This will extend the number of time points at which clinical symptoms and lung function have been measured in an identical way, and lay foundations for longitudinal analyses, thereby creating a unique resource unparalleled anywhere in low-income and middle-income countries.

We will bring together leading UK and South African experts, to investigate lung function trajectories in South African children from birth through age 8 years, and determine early life exposures which lead to the low lung function. We will build African research capacity through collaborations and training between South African and UK expert groups. Our overall vision is to inform the development of intervention strategies to reduce the risk of low lung function trajectories during the growth phase, and prevent multi-organ morbidity and premature death in African populations, an area of critical need.

Early-life factors are crucial for lung function growth, and subsequent COPD pathogenesis. Childhood asthma and early-life LRTIs reduce lung function through childhood, leading to diminished lung function at the physiological plateau in the third decade of life. The burden and pattern of LRTIs and asthma in Africa, as well as environmental factors which affect developmental trajectories of lung function, are markedly different than in high-income countries. However, despite the high prevalence and severity of childhood asthma, high incidence of LRTIs, and many harmful environmental exposures, to date there is no data on early-life factors associated with diminished lung function in Africa.

We propose to extend our work in the Drakenstein Child Health Study (DCHS), a birth cohort of 1000 South African children who have been followed from antenatal period through early childhood, to address early-life determinants of lung function in African population. Unique aspect of the study is that lung function measurements have been taken longitudinally from age 6 weeks. We collected detailed information on LRTI (including aetiology) and environmental exposures. We will bring it together with the expertise in data mapping and analytical approaches in the UK STELAR consortium. We will extend the follow-up in DCHS through age 8 years, and carry out detailed measurement of lung function. This will extend the number of time points at which clinical outcomes and lung function have been measured in an identical way, and lay foundations for longitudinal analyses, thereby creating a unique resource unparalleled anywhere in LMICs. We will identify trajectories of lung function in African children from birth through age 8 years, and determine risk factors for low lung function trajectory, to inform the development of intervention strategies to reduce the risk of low lung function and prevent multi-organ morbidity and premature death in Africa.

Who might benefit from this research?

The proposed project will multiply the effects of previous investments, thereby having an overall scientific impact much greater than its level of requested funding. We will provide an infrastructure for large scale interdisciplinary collaborations to conduct cutting edge science, using existing and newly collected data resources, to produce health benefit for the African population, and broader. Respiratory diseases pose a particularly large burden in Africa. African patients develop more severe asthma and COPD, and at a younger age, compared to the rest of the world. The African population therefore represents an invaluable resource to identify early life factors associated with poor respiratory outcomes. A recent Editorial in the Lancet Global Health emphasised that "health-care policy makers in Africa need to take notice of the silently growing epidemic of COPD and start taking measures to both prevent and treat COPD effectively, before it gets out of hand" (PMID: 25539971). The results of this project are intended to lead to the development of methods for prevention of chronic respiratory diseases, early mortality and premature death, which could be generalisable to other populations.

Our results will identify risk factors and mechanisms that influence the onset and progression of diminished lung function trajectories, and subsequent respiratory disease, thereby identifying pathways that may provide information for targeted interventions to reduce the impact of childhood asthma and adult COPD in African populations. The discovery of risk factors for diminished lung function in Africa will form the basis for identification of novel interventions, as well as biomarkers which are predictive of health or disease, and is intended to allow life-style choices to be made to prevent long-term adverse health outcomes. This will be of great value to patients, society, health-care professionals and industry.

How might they benefit from this research?

The ability to access shared analysis resources in South Africa and the UK will be of great value for training and development of researchers, and the ability to access example analyses and expert advice will reduce their learning curve. Enabling the networking of datasets, expertise and methods for data preparation and analysis can help drive greater value from existing investments. Building South African capacity in statistical methodologies applied to longitudinal measures, and in novel analytical methods including latent class analysis and machine learning approaches, will ensure knowledge and skills transfer to clinicians and researchers in South Africa.

STELAR investigators will have access to a unique collection of well characterised birth cohorts with fundamentally different environmental exposures, and capitalise on the heterogeneity of the collected data to gain insights into pathophysiology of respiratory diseases. To further replicate our findings, we have established a collaboration with the US CREW consortium of 12 US cohorts, funded through the NIH ECHO Paediatric Cohorts initiative. CREW uses STELAR eLab to harmonise and integrate their data, which we have provided using the same open-source model which we propose for DCHS. This knowledge management platform will be further developed in a collaborative manner across all study sites at different continents, providing a global platform to investigate respiratory diseases.

Our findings will represent potentially valuable intellectual property, which we will seek to commercialise in collaboration with companies invested in diagnostics and/or therapeutics. Participating universities have mechanisms and structures in place for exploring industrial applications. Partnerships such as the one described in this application help to make the UK an attractive location to retain research activities, and help expose academics to the process of translating science into products.