Understanding the host-environmental interactions across the lifespan determining lung function trajectories and COPD

Chronic Obstructive Pulmonary Disease (COPD) is a major public health problem because of its high prevalence (>10% of adults), associated morbidity, raising incidence and cost (circa 38 billion annually in the EU only). COPD has been traditionally understood as a self-inflicted disease caused by tobacco smoking occurring in old individuals. As a result, its prevention has been limited to smoking avoidance, and available treatments are palliative. Over the past few years, however, our group and others have proposed that the pathogenesis of COPD goes well beyond smoking and that there is a range of lung function trajectories through life (trajectome; Lancet Resp Med 2022), some of them with roots in early life, that lead to COPD. Our group also showed that lung function trajectories below the normal range are associated with cardiovascular and metabolic morbidity, and premature death. Collectively, these observations indicate that lung function in general, and the trajectome in particular, are global health markers.
In this setting, however, several potentially relevant aspects have not been investigated yet, including: 
(1) the mechanisms driving abnormal peak lung function, development of COPD and multimorbidity; and (2) how other lung function parameters (FVC, FEV1/FVC)), host features (i.e. gender, BMI) and multimorbidity (type and severity) associate with the trajectome.

The complexity of COPD
COPD is defined by airflow limitation (FEV1/FVC <0.7) in an individual exposed to damaging particles and gases. Yet, because COPD can start early in life, and takes a long time to manifest clinically the concepts of Pre-COPD and EarlyCOPD have been recently proposed. Pre-COPD, is defined as the presence of structural and/or functional lung abnormalities in the absence of airflow limitation, whereas EarlyCOPD is considered in smokers younger than 50 years with airflow limitation (FEV1/FVC<0.7), and/or with accelerated lung function decline and/or emphysema. Note that PreCOPD, EarlyCOPD and COPD can include patients following different trajectories. COPD is often associated with extra-pulmonary multimorbidity. Yet, the nature of this association is controversial, as it can be due to shared molecular pathways or risk factors or driven by the ‘spill-over’ of mediators from the lung into the systemic circulation. Here we propose that it is in fact a combination of genetic and molecular determinants, exposome, and spill over mediators starting from detrimental interactions early in life.