Chronic obstructive pulmonary disease (COPD) has been traditionally considered a self-inflicted disease caused by tobacco smoking. Current available evidence, however, indicates that the pathogenesis of COPD needs to consider the dynamic and cumulative nature of a series of environment (including smoking plus other exposures)-host interactions that eventually determine lung development, maintenance, repair, and aging. By doing so, these factors modulate the trajectory of lung function of the individual through life and the odds of developing COPD through different routes, which likely represent different forms of the disease that require different preventive and therapeutic strategies.
Tobacco smoking is the main, but not the sole risk factor for COPD.
COPD can start early in life. About 4% to 12% of individuals in the general population never achieve normal peak lung function in early adulthood and are at risk for developing COPD (and other concomitant diseases) later in life, and of dying prematurely.
The pathogenesis of COPD involves a series of dynamic, cumulative, environment-host interactions that occur throughout life and determine lung development, repair, and aging, hence the vital trajectory of lung function.
Prevention beyond smoking avoidance/cessation, prompt detection, and early intervention are likely to be important to reduce disease burden and to improve health status and the prognosis of patients.
Chronic obstructive pulmonary disease (COPD) has been traditionally considered a self-inflicted disease induced by tobacco smoking and characterized by an accelerated decline of lung function with aging. Tobacco smoking continues to be the main, environmental and preventable, risk factor of COPD, so every effort needs to be made to prevent smoking initiation and/or to favor early smoking cessation; however, this classical paradigm is changing rapidly and goes well beyond smoking. This new understanding of the pathogenesis of the disease can open novel windows for prevention and early intervention.
The traditional understanding of chronic obstructive pulmonary disease: a self-inflicted disease caused by tobacco smoking (in males)
In 1976, Fletcher and coworkers published the classic book The Natural History of Chronic Bronchitis and Emphysema . It details the results of a study in a stratified, relatively small (n = 792), random sample of men (no females were included in the study) aged 30 to 59 working in West London, who were followed the next 8 years. Results were summarized 1 year later. Fig. 1 here and in that review became, until recently, the holy grail of the understanding of the pathogenesis of COPD. It stated that a proportion of so-called “susceptible smokers” developed chronic airflow obstruction (COPD) caused by an accelerated decline of lung function with age. This understanding implied that tobacco smoking was the cause of COPD, and that COPD was an irremediable progressive disease that always leads to disability and early death. Yet, as discussed next, evidence over the past decade, or so, contradicts this interpretation.
Some observations do not fit this traditional pathogenic paradigm
The following recent epidemiologic and clinical observations do not fit this traditional paradigm and, overall, partially challenge its validity.
Chronic Obstructive Pulmonary Disease in Never Smokers
Between 20% and 40% of patients with COPD around the world are never smokers. This clearly indicates that there must be other environmental and/or biologic factors than smoking that contribute to the pathogenesis of the disease. In this context, it is well established now that other environmental pollutants, such as those derived from biomass exposure and others, can also contribute to a significant proportion of COPD cases.
As originally recognized by Fletcher and Peto, there is an element of individual susceptibility to environmental exposures (smoking and others), likely related to the genetic and/or epigenetic background of the individual. A large epidemiologic study (15,256 cases and 47,936 control subjects, with replication of top results [ P <5 × 10 −6 ] in another 9498 cases and 9748 control subjects) identified 22 genetic loci associated with COPD ( Table 1 ). Yet, the individual effect size (odds ratio) of each of these 22 genes is small (see Table 1 ), clearly indicating the polygenic basis of COPD. More recent research also emphasizes the role of epigenetic changes, thus contributing to a great level of genetic complexity and interaction with the environmental exposures discussed previously.
|rsID||Closest Gene||Risk Allele Frequency Mean||Odds Ratio||95% Confidence Interval||P Value|
|rs1314164||HHIP||0.59||0.52−0.89||1.21||1.16−1.27||9.10 × 10 −41|
|rs17486278||CHRNA5||0.35||0.24−0.44||1.13||1.08−1.18||1.77 × 10 −28|
|rs7733088||HTR4||0.60||0.47−0.69||1.18||1 13−1.23||5.33 × 10 −26|
|rs9399401||ADGRG6||0.72||0.61−0.75||1.17||1.12−1.23||1.81 × 10 −19|
|rs1441358||THSD4||0.33||0.19−0.55||1.12||1.07−1.17||8.22 × 10 −16|
|rs6837671||FAM13A||0.41||0.36−0.58||1.07||1.02−1.11||7.48 × 10 −15|
|rs11727735||GSTCD||0.94||0.93−0.99||1.25||1.14−1.36||3.84 × 10 −14|
|rs754388||RIN3||0.82||0.80−0.86||1.11||1.05−1.17||4.96 × 10 −14|
|rs113897301||ADAM 19||0.17||0.05−0.19||1.13||1.07−1.19||1.58 × 10 −13|
|rs2047409 ∗||TET2||0.62||0.22−0.65||1 14||1.09−1.19||2.46 × 10 −13|
|rs2955083||KLFSEC||0.88||0.85−0.89||1.17||1.09−1.25||4.16 × 10 −13|
|rs7186831 ∗||CFDP1||0.43||0.23−0.47||1.12||1.07−1.17||1.12 × 10 −11|
|rs10429950 ∗||TGFB2||0.73||0.22−0.77||1.10||1.04−1.15||1.66 × 10 −10|
|rs2070600 ∗||AGER||0.95||0.85−0.99||1.21||1.10−1.32||5.94 × 10 −10|
|rs17707300||CCDC101||0.37||0.11−0.43||1.06||1.02−1.11||6.75 × 10 −10|
|rs2806356 ∗||ARMC2||0.18||0.05−0.24||1.12||1.06−1.18||8.34 × 10 −10|
|rsl6825267 ∗||PID1||0.93||0.87−0.94||1.13||1.04−1.22||1.68 × 10 −9|
|rs2076295||DSP||0.55||0.44−0.58||1.06||1.02−1.14||3.97 × 10 −9|
|rs647097 ∗||MTCL1||0.27||0.26−0.40||1.09||1.04−1.11||6.14 × 10− 9|
|rs1529672||RA RH||0.83||0.68−0.86||1.05||0.99−1.11||2.47 × 10 −8|
|rs721917 ∗||SFTPD||0.42||0.39−0.63||1.07||1.02−1.13||2.49 × 10 −8|
|rs12459249 ∗||CYP2A6||0.66||0.62−0.70||1.08||1.03−1.13||3.42 × 10 −8|