“Another Hole in the Wall”

FOR RELATED ARTICLE, SEE PAGE 327Emphysema was originally defined by histology as “an abnormal permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by the destruction of alveolar walls and without obvious fibrosis.”1Han M.K. Bartholmai B. Liu L.X. et al.Clinical significance of radiologic characterizations in COPD.COPD. 2009; 6: 459-467Crossref PubMed Scopus (78) Google Scholar However later, in the era of chest CT scans, the detection of low-attenuation areas as a surrogate marker of histologic emphysema has been validated as a tool for its identification in daily clinical practice.2Bergin C. Muller N. Nichols D.M. The diagnosis of emphysema: a computer tomographic-pathologic correlation.Am Rev Respir Dis. 1986; 133: 541-546PubMed Google Scholar Three subtypes of emphysema have been defined on the basis of the alteration of the secondary pulmonary lobule: (1) centrilobular emphysema (CLE), which is associated with tobacco smoking and located more frequently in the upper lobes; (2) paraseptal emphysema (PSE), which can also occur in the absence of tobacco exposure and usually is associated with pneumothorax, and (3) panlobular emphysema, which is related to alpha-1 antitrypsin deficiency and preferentially is seen in the lower lung lobes.3Lynch D.A. Austin J.H. Hogg J.C. et al.CT-definable subtypes of chronic obstructive pulmonary disease: a statement of the Fleischner Society.Radiology. 2015; 277: 192-205Crossref PubMed Scopus (342) Google Scholar FOR RELATED ARTICLE, SEE PAGE 327 Presence of emphysema is highly prevalent in patients with COPD and ranges from 30% to 60% depending on the method of detection and type of population studied.4Ezponda A. Casanova C. Divo M. et al.Chest CT-assessed comorbidities and all-cause mortality risk in COPD patients in the BODE cohort.Respirology. 2022; 27: 286-293Crossref PubMed Scopus (4) Google Scholar The recently updated global initiative for chronic obstructive lung disease (GOLD) guidelines mention the importance of the identification and distribution of emphysema in patients with severe obstructive disease (FEV1<45%) with lung hyperinflation to select those who are candidates for surgical or endoscopic lung volume reduction techniques.5GOLD Guidelines Scientific Commitee Summary.https://goldcopd.org/2023-gold-report-2/Date accessed: February 26, 2023Google Scholar This recent update also acknowledged the association of emphysema presence in patients with COPD with an accelerated lung function decline and a higher risk of lung cancer.5GOLD Guidelines Scientific Commitee Summary.https://goldcopd.org/2023-gold-report-2/Date accessed: February 26, 2023Google Scholar In the literature, emphysema presence has also been associated with more respiratory symptoms, worse quality of life, and higher mortality rates.6Martinez C.H. Chen Y.H. Westgate P.M. et al.COPDGene investigatorsRelationship between quantitative CT metrics and health status and BODE in chronic obstructive pulmonary disease.Thorax. 2012; 67: 399-406Crossref PubMed Scopus (101) Google Scholar Information regarding the specific impact of different types of emphysema on the natural course of the disease in COPD is scarce. In this issue of CHEST, the work from Shiraishi et al7Shiraishi Y. Tanabe N. Shimizu K. et al.Stronger associations of centrilobular than paraseptal emphysema with longitudinal changes in diffusing capacity and mortality in COPD.Chest. 2023; 164: 327-338Google Scholar reports that retrospectively analyzed two prospectively recruited Japanese cohorts. The authors determined the prevalence and differential impact of CLE and PSE on longitudinal FEV1 and carbon monoxide transfer coefficient decline, which was measured annually for 5 years. They also explored the differential impact of these types of emphysema on 10-year mortality rates. They concluded that a CT scan finding of moderate or more severe CLE, but not PSE, is associated with an accelerated impairment in diffusing capacity for carbon monoxide in all GOLD stages and higher long-term mortality rates in patients with severe COPD according to the GOLD guidelines. This report is the first study to show that CLE is the emphysema type associated with a higher long-term mortality rate in patients with severely obstructed COPD. Importantly, cardiovascular disease and lung cancer are known to be the most common causes of death in patients with COPD. Unfortunately, the authors of the present work did not analyze the specific causes of death in their cohort, which limits the capacity to relate the emphysema type with a specific cause of death. However, the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) cohort recently described an association between CLE and the presence of bioactive molecules implicated in the pathogenesis of atherosclerosis and coronary artery calcium in those patients.8Bhatt S.P. Nath H.P. Kim Y.I. et al.Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort.Respir Res. 2018; 19: 257Crossref PubMed Scopus (14) Google Scholar In addition, the Pamplona International Early Lung Cancer Action Program (IELCAP) lung cancer screening cohort had also described an association between CLE and a higher lung cancer risk in a population that included a significant proportion of patients with COPD.9González J. Henschke C.I. Yankelevitz D.F. et al.Emphysema phenotypes and lung cancer risk.PLoS One. 2019; 14e0219187Crossref Scopus (14) Google Scholar To our knowledge, Shiraishi et al7Shiraishi Y. Tanabe N. Shimizu K. et al.Stronger associations of centrilobular than paraseptal emphysema with longitudinal changes in diffusing capacity and mortality in COPD.Chest. 2023; 164: 327-338Google Scholar also make the important and novel find that CLE was associated with faster diffusing capacity decline in all GOLD guideline spirometric stages. Unfortunately, the type of study performed and the information reported (mainly clinical, radiologic, and physiologic) does not allow us to determine the reason for this finding. The literature indicates that patients with CLE have higher WBCs counts and a unique protease-antiprotease imbalance that is characterized by a higher expression of matrix metalloproteinase 9 and transforming growth beta 1.10Kukkonen M.K. Tiili E. Vehmas T. Oksa P. Piirilä P. Hirvonen A. Association of genes of protease-antiprotease balance pathway to lung function and emphysema subtypes.BMC Pulm Med. 2013; 13: 36Crossref PubMed Scopus (0) Google Scholar This could cause a greater destruction of the alveolo-capillary membrane with the subsequent alteration of the diffusing capacity, which is an active process that, according to this study findings, could cause a faster decline in the diffusing capacity of those patients with COPD. As the authors acknowledged, their work has some limitations. The most important one is that it was performed in two cohorts of Japanese men, which limits the external validity of their findings. These findings should be replicated in other COPD cohorts with sufficient number of women to perform a robust statistical analysis. The work from Shiraishi et al7Shiraishi Y. Tanabe N. Shimizu K. et al.Stronger associations of centrilobular than paraseptal emphysema with longitudinal changes in diffusing capacity and mortality in COPD.Chest. 2023; 164: 327-338Google Scholar has several clinical messages for the future treatment of patients with COPD. First, it further supports the recommendation to perform a chest CT scan in every patient with COPD, which could help in the identification of CLE. Second, the identification of CLE could become an important radiologic biomarker of disease progression because of its potential impact on diffusing capacity decline, risk of lung cancer, osteoporosis,11Gonzalez J. Rivera-Ortega P. Rodríguez-Fraile M. et al.Exploring the association between emphysema phenotypes and low bone mineral density in smokers with and without COPD.Int J Chron Obstruct Pulmon Dis. 2020; 15: 1823-1829Crossref Scopus (2) Google Scholar cardiovascular disease, and death. Third, the recognition of imaging biomarkers should trigger further investigation of novel molecules in the treatment of patients with COPD, such as the potential use of metformin in the treatment of cigarette-induced emphysema in human beings.12Polverino F. Wu T.D. Rojas-Quintero J. et al.Metformin: experimental and clinical evidence for a potential role in emphysema treatment.Am J Respir Crit Care Med. 2021; 204: 651-666Crossref Scopus (33) Google Scholar More studies like this that will identify the types of holes in the lung walls will help us better define the natural history of the disease. None declared. Stronger Associations of Centrilobular Than Paraseptal Emphysema With Longitudinal Changes in Diffusing Capacity and Mortality in COPDCHESTVol. 164Issue 2PreviewA CT scan finding of moderate or more severe CLE, but not PSE, was associated with a subsequent accelerated impairment in diffusing capacity and higher long-term mortality in severe GOLD stage among patients with COPD. 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