{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:33:09Z","timestamp":1790623989242,"version":"4.1.0"},"reference-count":223,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Respirology"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The natural history of COPD is complex, and the disease is best understood as a syndrome resulting from numerous interacting factors throughout the life cycle with smoking being the strongest inciting feature. Unfortunately, diagnosis is often delayed with several longitudinal cohort studies shedding light on the long \u2018preclinical\u2019 period of COPD. It is now accepted that individuals presenting with different COPD phenotypes may experience varying natural history of their disease. This includes its inception, early stages and progression to established disease. Several scenarios regarding lung function course are possible, but it may conceptually be helpful to distinguish between individuals with normal maximally attained lung function in their early adulthood who thereafter experience faster than normal FEV\n                    <jats:sub>1<\/jats:sub>\n                    decline, and those who may achieve a lower than normal maximally attained lung function. This may be the main mechanism behind COPD in the latter group, as the decline in FEV\n                    <jats:sub>1<\/jats:sub>\n                    during their adult life may be normal or only slightly faster than normal. Regardless of the FEV\n                    <jats:sub>1<\/jats:sub>\n                    trajectory, continuous smoking is strongly associated with disease progression, development of structural lung disease and poor prognosis. In developing countries, factors such as exposure to biomass and sequelae after tuberculosis may lead to a more airway\u2010centred COPD phenotype than seen in smokers. Mechanistically, COPD is characterized by a combination of structural and inflammatory changes. It is unlikely that all patients share the same individual or combined mechanisms given the heterogeneity of resultant phenotypes. Lung explants, bronchial biopsies and other tissue studies have revealed important features. At the small airway level, progression of COPD is clinically imperceptible, and the pathological course of the disease is poorly described. Asthmatic features can further add confusion. However, the small airway epithelium is likely to represent a key focus of the disease, combining impaired subepithelial crosstalk and structural\/inflammatory changes. Insufficient resolution of inflammatory processes may facilitate these changes. Pathologically, epithelial metaplasia, inversion of the goblet to ciliated cell ratio, enlargement of the submucosal glands and neutrophil and CD8\u2010T\u2010cell infiltration can be detected. Evidence of type 2 inflammation is gaining interest in the light of new therapeutic agents. Alarmin biology is a promising area that may permit control of inflammation and partial reversal of structural changes in COPD. Here, we review the latest work describing the development and progression of COPD with a focus on lung function trajectories, exacerbations and survival. We also review mechanisms focusing on epithelial changes associated with COPD and lack of resolution characterizing the underlying inflammatory processes.\n                  <\/jats:p>","DOI":"10.1111\/resp.14007","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T17:04:47Z","timestamp":1611853487000},"page":"298-321","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Natural history and mechanisms of\n                    <scp>COPD<\/scp>"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0401-0081","authenticated-orcid":false,"given":"Peter","family":"Lange","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Section of Respiratory Medicine Copenhagen University Hospital \u2010 Herlev  Herlev Denmark"},{"name":"Department of Public Health, Section of Epidemiology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Engi","family":"Ahmed","sequence":"additional","affiliation":[{"name":"IRMB University of Montpellier, INSERM, CHU Montpellier  Montpellier France"},{"name":"Department of Respiratory Diseases University of Montpellier, CHU Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zakaria Mohamed","family":"Lahmar","sequence":"additional","affiliation":[{"name":"Department of Respiratory Diseases University of Montpellier, CHU Montpellier, INSERM  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando J.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine Weill Cornell Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4645-5209","authenticated-orcid":false,"given":"Arnaud","family":"Bourdin","sequence":"additional","affiliation":[{"name":"Department of Respiratory Diseases University of Montpellier, CHU Montpellier, INSERM  Montpellier France"},{"name":"PhyMedExp University of Montpellier, INSERM U1046, CNRS UMR 9214  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201701-0218PP"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200912-1843CC"},{"key":"e_1_2_7_4_1","first-page":"1185","article-title":"Respiratory insufficiency","volume":"268","author":"Dornhorst AC","year":"1955","journal-title":"Lancet"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02058-2018"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201801-0051LE"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201703-0451PP"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/resp.12642"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201710-2028PP"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(14)70008-6"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60990-2"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/crj.12010"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2019.07.003"},{"key":"e_1_2_7_14_1","first-page":"103","article-title":"Identifying patients with undiagnosed COPD in primary care settings: insight from screening tools and epidemiologic studies","volume":"2","author":"Han MK","year":"2015","journal-title":"Chronic Obstr. 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