Understanding COPD Etiology, Pathophysiology, and Definition

Abstract

COPD, one of the leading worldwide health problems, currently lacks truly disease-modifying medical therapies applicable to most patients. Developing such novel therapies has been hampered by the marked heterogeneity of phenotypes between individuals with COPD. Such heterogeneity suggests that, rather than a single cause (particularly just direct inhalation of tobacco products), development and progression of COPD likely involve both complex gene-by-environment interactions to multiple inhalational exposures and a variety of molecular pathways. However, there has been considerable recent progress toward understanding how specific pathological processes can lead to discrete COPD phenotypes, particularly that of small airways disease. Advances in imaging techniques that correlate to specific types of histological damage, and in the immunological mechanisms of lung damage in COPD, hold promise for development of personalized therapies. At the same time, there is growing recognition that the current diagnostic criteria for COPD, based solely on spirometry, exclude large numbers of individuals with very similar disease manifestations. This concise review summarizes current understanding of the etiology and pathophysiology of COPD and provides background explaining the increasing calls to expand the diagnostic criteria used to diagnose COPD and some challenges in doing so.

Keywords: COPD; nosology; pathophysiology; small airways disease.

Fig. 1.

Epigenetic changes induced by smoking lead to progressive small airway damage and inflammation in early COPD. (A and C) Normal small airways; (B and D) small airways in early COPD. A: Normal distal epithelium contains self-renewing basal cells, which differentiate into ciliated, mucus-producing goblet, and secretory (club) cells, joined by tight junctions that form an impermeable barrier. Mucus is separated from the epithelial surface by a robust aqueous periciliary layer. B: Smoking induces hyperplasia of basal and goblet cells, squamous metaplasia, loss of club and ciliated cells, decrease in the periciliary layer and ciliary damage and crowding, and junctional barrier loss. C: In normal small airways, dimeric immunoglobulin A (IgA) (structure shown in inset) is transcytosed by the polymeric immunoglobulin receptor (pIgR) into the mucosal lumen. pIgR cleavage at the luminal surface liberates secretory IgA, which prevents bacterial invasion. D: Smoking reduces pIgR expression, leading to localized secretory IgA deficiency in small airways, allowing bacteria to invade and induce sustained airway inflammation. Illustration by Patricia Ferrer Beals. From Reference , with permission. NF-KB = nuclear factor kappa B; pIgR = polymeric immunoglobulin receptor; IgA = immunoglobulin A.

Fig. 2.

Illustration of changes in parametric response mapping (PRM) metrics in a representative male patient with COPD. (A, B) Representative coronal computed tomography sections of the same individual at baseline (left) and after 5-y follow-up (right). A: All PRM metric values are depicted as normal lung parenchyma (green), functional small airway disease (fSAD, yellow) and emphysema (red). B: Only those individual voxels that were classified as fSAD at baseline (yellow) and which became emphysematous are shown. From Reference , with permission. PRM = parametric response mapping; fSAD = functional small airway disease; emph = emphysema.

Fig. 3.

Distribution of spirometry in the COPDGene cohort, which led to description of the preserved ratio but impaired spirometry (PRISm) phenotype. FEV₁% predicted is plotted on the x axis while FEV₁/FVC is plotted on the y axis. Dashed lines represent fixed-threshold criteria used to delineate PRISm individuals (highlighted in blue upper-left quadrant), individuals with normal lung function (upper-right quadrant), those with mild (lower-right quadrant), and moderate to severe COPD (lower-left quadrant). From Reference , with permission.

Fig. 4.

Features used to define COPD in the COPD Genetic Epidemiology Study (COPDGene). Exposure in the COPDGene study includes individuals with a total of ≥ 10 pack-years smoking. Computed tomography (CT) imaging includes individuals with quantitative assessment showing ≥ 5% emphysema, a square root of airway wall area for a standardized airway of 10 mm internal diameter ≥ 2.5 mm, or ≥ 15% gas trapping. Symptoms include individuals with a Modified Medical Research Council dyspnea scale ≥ 2 or chronic bronchitis. Spirometry includes individuals with FEV₁ < 80% predicted or FEV₁/FVC < 0.7. From Reference , with permission. CT = computed tomography.

Fig. 5.

Logistic regression and Cox regression models for FEV1 progression and all-cause mortality, respectively, with the proposed COPDGene 2019 classification of categories. (A) Change in FEV₁ assessment was done on n = 4,925 participants who returned for phase 2 clinical follow-up. Adjusted for age at first visit, sex, race, pack-years, and current smoking. Bolded numbers indicate categories where the 95% CI did not include 1.0. Symbols as in Figure 4. From Reference , with permission.