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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38564415
202403-0565ED
10.1164/rccm.202403-0565ED
Editorials
The Evolving Contours of Chronic Obstructive Pulmonary Disease
Roche Nicolas 1 2 3
Han MeiLan K. 4
1 Cochin Hospital
Assistance Publique–Hôpitaux de Paris Centre
Paris, France
2 Institut Cochin
Université Paris Cité
Paris, France
3 Integrative Respiratory Epidemiology
Centre for Research in Epidemiology and Population Health
Villejuif, France
4 University of Michigan
Ann Arbor, Michigan
2 4 2024
1 9 2024
2 4 2024
210 5 535537
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
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pmcThe concept of “pre–chronic obstructive pulmonary disease (pre-COPD)” refers to a heterogeneous group of conditions in which some features of COPD are present, but persistent chronic airflow obstruction, the hallmark defining feature of COPD itself, is lacking (1). These situations comprise functional abnormalities (impaired spirometry, small airway disease, increased airway resistance, impaired diffusion, hyperinflation, respiratory-related impaired exercise capacity), chronic or recurrent respiratory symptoms (cough with or without sputum production, exertional dyspnea, wheezing, recurrent acute respiratory episodes), and imaging features (emphysema, airway wall thickness, air trapping) (2, 3). These characteristics are associated with an increased risk of developing spirometry-confirmed COPD, but many of these subjects will never develop COPD, and some of their pre-COPD features may disappear, especially when exposures to risk factors for COPD are removed.

In this issue of the Journal, Çolak and colleagues (pp. 607–617) describe the occurrence of COPD during follow-up in subjects with no airflow obstruction, defined as FEV1/FVC < 0.70, but with any of the following conditions, which they refer to as a pre-disease state of COPD: 1) symptoms of chronic bronchitis; 2) preserved ratio impaired spirometry (PRISm; FEV1/FVC ⩾ 0.70 and greater than or equal to the lower limit of normal [LLN] but FEV1 and/or FVC < 80% predicted); 3) “early airflow limitation” (FEV1/FVC ⩾ 0.70 but less than the LLN); or 4) asthma (4). They found that an increased risk of incident COPD during follow-up was independently associated with chronic bronchitis, PRISm, FEV1/FVC less than the LLN, active smoking history, and asthma.

The term predisease refers to intermediate situations between health and disease (5), in which some pathobiologic mechanism involved in the disease’s development has been initiated, but the potential to revert back to normal still exists. Following systems biology modeling, predisease corresponds to unstable states in which homeostasis is disrupted, making them more susceptible to perturbations, but the critical transition to disease has not yet been completed. Importantly, both health and disease are more resilient (robust and stable) states compared with predisease. Clinical, functional, biological, or imaging biomarkers can be used to detect predisease states (6) and to assess the risk of evolution to COPD (7).

Chronic bronchitis and PRISm could be viewed as representing such biomarkers, as shown by Çolak and colleagues (4) and others. Twenty years ago, the Global Initiative for Chronic Obstructive Lung Disease document proposed the consideration of a zero category of COPD (8), corresponding to patients with chronic cough and sputum production but no airflow obstruction. In other words, chronic bronchitis was assimilated to an early stage of the disease. However, this category was subsequently abandoned because several studies showed that many patients with chronic bronchitis do not progress to COPD (1), especially after smoking cessation: chronic bronchitis is an unstable feature, which is characteristic of predisease states. The same is true for PRISm, which can persist or transition to normal lung function or chronic airflow obstruction (9, 10).

The choice of an FEV1/FVC threshold to define airflow obstruction, using a fixed ratio (0.70) or the LLN, is a source of endless debates. Although the first is easier to use, it is less physiologically relevant, as FEV1/FVC ratio decreases with age: the fixed ratio can lead to underdiagnosis in younger adults and overdiagnosis in older subjects (11). However, an analysis of cohorts showed that the fixed ratio was more accurate than the LLN to predict future COPD-related hospitalizations and mortality (12). Early airflow obstruction defined by FEV1/FVC > 0.70 but < LLN, another feature studied by Çolak and colleagues (4), occurs mostly in younger adults and may be subject to greater instability (13).

Regarding imaging biomarkers, emphysema without airflow obstruction can remain stable but not disappear. As such, whether it corresponds to the definition of a predisease condition is debatable. Small airway alterations have been shown to be the earliest structural change in the development of COPD (14). Their routine assessment is difficult because they are largely silent until markedly impaired and are best identified using combinations of functional and imaging tests, spirometry alone being insufficiently reliable (15). The natural history of emphysema and small airway disease in patients with no airflow obstruction (i.e., with pre-COPD) is largely unknown (16).

Ultimately, whether features currently covered by the term pre-COPD really correspond to predisease or represent early stages of the disease itself can be questioned, keeping in mind that for now, an irreversible component (responsible for persistent airway obstruction) is currently mandatory to define COPD. Including patients with features currently corresponding to the pre-COPD concept within the COPD spectrum would require changing the very definition of COPD.

Two approaches could be imagined to support such a move. The first approach would be to keep the current definition but broaden the definition of airflow obstruction to include functional abnormalities other than low FEV1/FVC ratio (using spirometry, plethysmography, or forced oscillometry) or imaging (computed tomography [CT] based) markers of small airway disease. The second approach would be to define COPD as a heterogeneous lung condition characterized by chronic respiratory symptoms due to abnormalities of the airways and/or alveoli that can cause persistent, often progressive, airflow obstruction. This second option would explicitly allow early stages of COPD (before fixed airflow obstruction is present) to be reversible and/or curable, which is in complete opposition to how COPD is currently considered. Such a change would preserve the possibility of preventing the occurrence of permanent airway obstruction by intervening sufficiently early in the course of the disease.

This issue of pre-COPD and whether some corresponding features should be included in the definition of COPD is particularly relevant considering the recently identified developmental origins of COPD (17, 18), the natural history of which remains to be fully deciphered.

Irrespective of how they are conceptually considered, one key issue to be solved is how individuals with pre-COPD/early COPD will be detected (19) to facilitate the implementation of preventive measures, encourage research on the natural history of these conditions, and ultimately allow the development of novel disease-modifying therapies. These subjects usually have few symptoms and remain largely ignored. Identifying them requires the implementation of systematic screening or case-finding approaches, relying on four pillars: the identification of risk factors, symptoms, lung function abnormalities, and imaging features. The two first pillars are purely clinical and can rely on any healthcare professional or on the population itself, provided that awareness is raised and that appropriate tools/checklists/questionnaires are made widely available (19, 20). However, although cumulative tobacco smoking is easy to quantify, the assessment of most other risk factors is poorly standardized.

The third pillar requires lung function testing. Spirometry is the lung function test that best combines metrological reliability and accessibility, but it is not the most sensitive to detect airflow obstruction, especially at an early stage. Therefore, other direct or indirect lung function markers suggestive of airflow obstruction should be considered when available, as mentioned earlier. Finally, the fourth pillar (imaging) takes advantage of CT-based lung cancer screening programs and the multidimensional assessment offered by CT. Optimizing the detection of pre-COPD/early COPD in the population would require integrating risk and symptom detection, lung function checks, and systematic reporting of lung cancer screening CT scans in systematic public health programs adapted to the capacity of local healthcare systems and accompanied by information campaigns.

New insights into the etiologies and trajectories of COPD and crisper, clinically implementable definitions of early stages represent an important opportunity to improve our understanding of disease development and develop early intervention strategies.

Originally Published in Press as DOI: 10.1164/rccm.202403-0565ED on April 2, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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