Defining COPD
COPD is a complex, heterogeneous disorder in both its presentation and prognosis. This is reflected in the non-specific nature of our clinical definition of the disease. Spirometry-based definitions of COPD have been useful for standardization of research studies and clinical care, but clinicians and researchers recognize that current definitions do not adequately describe the variability of COPD. COPDGene expanded the definition of COPD to better incorporate some of this heterogeneity (COPDGene 2019) by classifying individuals with combinations of: symptoms (dyspnea and chronic bronchitis); spirometry that included obstruction (FEV1/FVC <0.70 ) and PRISm (low FEV1pp with a normal FEV1/FVC ratio); CT measures of emphysema, airway and gas trapping; and exposure (1). While this expanded the diagnosis of COPD to include more individuals in earlier stages of the disease, it did not differentiate between subtypes of COPD.
Subtyping COPD
Because COPD is a heterogeneous disease, the identification of subtypes (i.e., subpopulations of subjects with similar disease characteristics or underlying biology) is of interest. Subtypes can increase our understanding of the biologic mechanisms involved in COPD development and progression, lead to more accurate diagnoses in clinical practice, and facilitate the development of more targeted therapeutics. Traditional subtyping methods generally focus on the observable clinical features of COPD patients, with ‘pink puffers’ and ‘blue bloaters’ being the classic example of distinct subtypes. COPD subtype studies are primarily cross-sectional, and there is little understanding of how consistent subtypes are over time and throughout the COPD disease course. In addition, there has been relatively little focus on early stages of the disease prior to clinical diagnosis.
Airway-Predominant and Emphysema-Predominant Subtypes
One proposed approach for understanding disease heterogeneity to allow for more precise subtyping and risk assessment is to construct continuous disease axes that characterize different underlying pathophysiologic disease processes in COPD. These disease axes were built from unsupervised factor analysis of chest CT and pulmonary function variables (2). Two multidimensional factors were related to reduced pulmonary function. One was labeled the emphysema-predominant axis because of its strong correlation with emphysema measures on CT, and the other was labeled the airway-predominant axis because of its correlation with CT measures of airway thickness.
Individuals were further risk-stratifed based on marked increased mortality associated with the highest two deciles of the emphysema-predominant axis (high-risk emphysema), and with the highest two (high-risk airway) and middle three deciles (moderate-risk airway) of the airway-predominant disease axes. This provided an unsupervised COPD subtype classification scheme that incorporates CT morphologic differences with pulmonary function and that identifies subjects with increased risk for mortality (3). In addition, these subtypes have differential disease progression. The emphysema-predominant subtypes progress in the more traditional pathway from GOLD 0->GOLD 1->GOLD 2-4. Airway-predominant subtypes progress in a more recently recognized pathway from GOLD 0->PRISm->GOLD 2-4 (4). These COPD subtypes identify high-risk groups of individuals characterized by the underlying severity of disease processes that may provide targets for distinct interventions to reduce pulmonary function decline and mortality.
Emphysema-Predominant and Non-Emphysema Predominant Disease
In the interest of defining subtypes in a manner amenable to clinical translation, Castaldi et al. extended the subtype definitions originally proposed by Hersh et al (5). that capture airway-predominant and emphysema-predominant subtypes similar to the subtypes described in the previous paragraph (6). Emphysema-predominant (EPD) was defined as GOLD 2–4 COPD with ≥ 10% CT quantified emphysema (%LAA-950, percentage of CT low attenuation area less than −950 HU), while non-emphysema predominant (NEPD) was defined as GOLD 2–4 COPD with < 5% emphysema. Relative to NEPD, EPD was associated with increased pulmonary progression and increased mortality. This definition showed strong correlation with the emphysema-predominant axis above. This indicates that the emphysema-predominant subtype can likely be simplified to a few measures of pulmonary function and CT emphysema for reproducible clinical use.
Incorporating ‘Omic Data into COPD Subtypes
In addition to current COPD subtyping that characterizes observable phenotypes of the disease, molecular subtyping characterizes disease processes through multi-omics such as genomics, transcriptomics, proteomics and metabolomics). Combining these measures with clinical subtypes can yield insight into mechanisms of different pathways of progression, different disease manifestations, and different responses to treatment. Analysis of blood RNA sequencing data in COPDGene identified a blood gene expression signature that is associated with airway wall thickness and respiratory exacerbations and indicates increased Type 1 interferon signaling, suggesting a potential avenue for targeted treatment in COPD (7). Joint analysis of genetic risk variants summarized in a polygenic risk score and blood gene expression allowed for reasonably accurate cross-sectional diagnosis of COPD and was predictive of future loss of lung function (8). These findings demonstrate the value of multi-omic biomarkers for risk stratification and molecular subgroup identification in COPD, pointing the way forward for future studies to further validate these tools for use in clinical trials and ultimately improved patient care.
References
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