Review
Beyond the COPD-tobacco binomium: New opportunities for the prevention and early treatment of the diseaseMás alla del binomio EPOC-tabaco: nuevas oportunidades para la prevención y tratamiento precoz de la enfermedad

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Abstract

Chronic Obstructive Pulmonary Disease (COPD) has been traditionally understood as a self-inflicted disease cause by tobacco smoking occurring in individuals older than 50–60 years. This traditional paradigm has changed over the last decade because new scientific evidence showed that there are many genetic (G) and environmental (E) factors associated with reduced lung function, that vary, accumulate, and interact over time (T), even before birth (GxExT). This new perspective opens novel windows of opportunity for the prevention, early diagnosis, and personalized treatment of COPD. This review presents the evidence that supports this proposal, as well as its practical implications, with particular emphasis on the need that clinical histories in patients with suspected COPD should investigate early life events and that spirometry should be used much more widely as a global health marker.

Resumen

La enfermedad pulmonar obstructiva crónica (EPOC) ha sido tradicionalmente entendida como una enfermedad auto infringida por el hábito tabáquico que ocurre en adultos de más de 50–60 años. Este paradigma tradicional ha cambiado en los últimos diez años por la aparición de nueva evidencia científica que muestra que existen otros muchos factores genéticos (G) y del entorno (E) asociados a baja función pulmonar, que varían, se acumulan e interaccionan con el tiempo (T), incluso desde antes del nacimiento (GxExT). Esta nueva perspectiva abre nuevas ventanas de oportunidad temporal para la prevención, diagnóstico temprano y terapéutica personalizada de la EPOC. Esta revisión presenta esta nueva evidencia científica y discute las implicaciones prácticas que comporta, con especial énfasis en la importancia de una historia clínica que recoja posibles eventos tempranos en la vida y el uso de la espirometría forzada como marcador de salud global.

Introduction

Chronic obstructive pulmonary disease (COPD) is a major public health problem worldwide due to its high prevalence (it affects 11.8% of the general Spanish population over the age of 40),1 its increasing incidence (particularly in relation to population aging), its associated morbidity and mortality (COPD is currently the third leading cause of death worldwide), and its social and economic costs (around 38,000 million euros/year in the European Union).2

This disease has traditionally been considered a self-inflicted condition caused by smoking, characterized by progressive airflow limitation and primarily affecting men over the age of 60.3, 4 This understanding of COPD, closely linked to aging, has resulted in a significant underdiagnosis of the disease (74.7% in Spain)1 and, therefore, an important undertreatment of the condition. However, both epidemiological and clinical data contradicting this traditional paradigm have begun to emerge in the last decade. Firstly, recent data show that 20%–40% of COPD patients have never smoked,5 which inevitably results in the need to identify other underlying causes of COPD beyond tobacco consumption. However, in no case should this finding involve reducing efforts in the fight against smoking (still the primary environmental risk factor for the onset of COPD). Instead, it should open new windows of opportunity for the early prevention and diagnosis of this disease based on the identification of new potential risk factors.6

In addition, several studies have discovered different lung function trajectories (that is, trajectomes [a term proposed by the authors of this paper]) throughout a patient’s lifetime (Fig. 1). Thus, the lungs of a healthy child are not yet fully developed at birth. These organs grow and mature through childhood and adolescence, reaching their functional peak at around 20–25 years of age (earlier in women)7 (Fig. 1). Following a brief plateau, the normal lung function trajectory is characterized by a gradual functional decline with age (20–30 mL/year), in such a way that a healthy individual never reaches a level of lung function that limits their exercise capacity. Nevertheless, this normal trajectory can be altered by genetic and/or environmental factors present during any of these stages. This results in the existence of a set of lung function trajectories (trajectomes) throughout a person’s lifetime, which might fall either below or above the normal trajectory (Fig. 1). As stated by Fletcher and Peto in a publication dated 1977, the then so-called “susceptible smokers” could experience an accelerated lung function loss over time4 (Fig. 1). In fact, this observation was considered the focal point of the pathogenesis of COPD for the next 40 years, owing to which all treatments were aimed at attempting to halt such acceleration. However, much more recently, in 2015, a study carried out with three independent cohorts (Framingham Offspring Cohort, Copenhagen City Heart Study, and Lovelance Smokers Cohort) demonstrated that 50% of COPD patients diagnosed at the age of 60 had developed the disease transiting a different trajectory, which was characterized by a reduced lung function peak at the age of 25 years, followed by a normal lung function decline with age.8 This fundamental article radically changed the understanding of the disease and opened the door to the completion of several studies aimed at analyzing the factors determining such trajectories in early life stages.9, 10 The importance of this new perspective was reinforced by the finding that subjects who did not reach a normal peak lung function had a higher prevalence and incidence of cardiovascular and metabolic comorbidities (diabetes), as well as early mortality11 (Fig. 2). Therefore, although tobacco smoking continues to be the most important environmental risk factor for the onset of COPD, the COPD-tobacco pairing must be overcome in order to identify and prevent new risk factors for the disease, as well as to diagnose and treat it much earlier with the ambitious, albeit possible, goal of “eradicating” COPD.12 Thus, in this paper we review the genetic and environmental factors associated with the early-life roots of COPD, and discuss the potential consequences and practical opportunities of this new approach to COPD beyond tobacco consumption.

Section snippets

Early origins of chronic obstructive pulmonary disease

All human diseases, COPD not being an exception, are the result of interactions between a person’s genetic makeup (G) and environmental factors (E), based on what is known as G × E interactions. A recent study performed on the general population recruited a total of 11,423 residents of the metropolitan area of Vienna (Austria), aged 6–82 years, and proved that, in addition to smoking, there are many environmental and host factors linked to reduced lung function, that these factors change and

Maternal smoking

Fetal exposure to maternal smoking during pregnancy alters normal lung development, possibly making the lung less resilient to other future environmental exposures and doubling the risk of symptoms of wheezing and “asthma” in the mother’s offspring.14 However, as we will discuss below, the specific epigenetic mechanism underlying the relationship between maternal smoking and “asthma” has not been identified.15

Environmental pollution

Outdoor air pollution is mainly caused by industrial and motor vehicle emissions, and

Genetic determinants

Alpha-1 antitrypsin deficiency is a well-established genetic cause of COPD,48 but nearly a hundred genetic variants associated with the risk of developing COPD, in addition to lung function and other pulmonary and non-pulmonary features of the disease, have now been described (thus helping explain the disease’s clinical heterogeneity), although the greatest contribution to the phenotype is known to arise from the combined effect of many common variants with a small individual effect.49 In this

Practical implications

Considering that COPD (and other diseases frequently associated with this condition, such as cardiovascular disease and/or diabetes) may originate in early life stages and that it is actually caused by an accumulation of several G × E interactions over time (G × E × T) has several important practical implications, including preventive, diagnostic, and therapeutic aspects.

Conclusions

Chronic obstructive pulmonary disease goes beyond smoking (which remains a key environmental risk factor) and is related to numerous risk factors present in early life stages that interact with a person’s genetic makeup through epigenetic changes induced throughout their lifetime. This new perspective on COPD (G × E × T) can also be applied to many other human diseases that are traditionally considered to be linked to aging. Spirometry is a useful, inexpensive, non-invasive, and reproducible

Conflicts of interest

The authors of this paper declare that they have no competing financial interests nor known personal relationships that may have influenced the research described in this paper.

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    Please cite this article as: Vila M, Faner R, Agustí A. Más alla del binomio EPOC-tabaco: nuevas oportunidades para la prevención y tratamiento precoz de la enfermedad. Med Clin (Barc). 2022;159:33–39.

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