{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:00:19Z","timestamp":1792184419310,"version":"4.4.0"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Universities and Research","award":["B53D23003760006\/G53D23000700001"],"award-info":[{"award-number":["B53D23003760006\/G53D23000700001"]}]},{"award":["B53D23003760006\/G53D23000700001"],"award-info":[{"award-number":["B53D23003760006\/G53D23000700001"]}],"id":[{"id":"https:\/\/ror.org\/0341vw408","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Cigarette smoking promotes persistent systemic alterations in COPD, yet the interplay among genetic susceptibility, oxidative stress, immune dysregulation, impaired control of persistent viral replication, and long-term outcomes remains incompletely understood. Methods: We conducted an observational study in 102 patients aged \u226570 years with severe-to-very-severe COPD undergoing pulmonary rehabilitation. Current smokers (n = 38) were compared with never\/former smokers (n = 64). Analyses included Chr15q25 genotyping (rs16969968), oxidative stress biomarkers (tail intensity, 8-OHdG, MDA, and bilirubin), hematological and immunological parameters, \u03b17nAChR expression, TTV load as a surrogate marker of immune competence, latent virus prevalence, and five-year survival assessed by multivariable Cox regression. Results: Current smokers exhibited significantly higher DNA damage (tail intensity, p = 0.001; 8-OHdG, p = 0.002), lower bilirubin levels (p = 0.031), increased neutrophil and CD4+ T-cell counts (p = 0.031 and p = 0.028, respectively), altered \u03b17nAChR expression on CD4+ T cells (p = 0.030), and higher TTV load (p = 0.002) than never\/former smokers. The rs16969968 AA genotype was more frequent among current smokers. In survival analyses, an elevated WBC count was independently associated with increased mortality risk (HR 1.12, 95% CI 1.01\u20131.23; p = 0.035), whereas higher bilirubin levels showed a protective association. TTV load, smoking status, and FEV1 were not independently associated with mortality. Conclusions: In severe-to-very-severe COPD, smoking is associated with a distinct biological profile characterized by enhanced oxidative DNA damage, systemic inflammation, immune remodeling, reduced antioxidant defenses, and impaired control of persistent viral replication. WBC and bilirubin emerged as the biomarkers most consistently associated with long-term outcomes. These findings support integrated biological profiling as a tool for risk stratification and precision-guided rehabilitation in advanced COPD.<\/jats:p>","DOI":"10.3390\/biom16071009","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:16:28Z","timestamp":1783689388000},"page":"1009","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effects of Cigarette Smoking on Oxidative Stress, DNA Damage, Immunological Profile, Viral Susceptibility, and Survival in Patients with Chronic Obstructive Pulmonary Disease"],"prefix":"10.3390","volume":"16","author":[{"given":"Antonio","family":"de Iure","sequence":"first","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Laboratory of Experimental Neurophysiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0776-3601","authenticated-orcid":false,"given":"Laura","family":"Vitiello","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Clinical and Molecular Epidemiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Proietti","sequence":"additional","affiliation":[{"name":"AgEA Coordinating Body, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0151-6477","authenticated-orcid":false,"given":"Paola","family":"Fortugno","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Human Functional Genomics Laboratory, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Limongi","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Laboratory of Microbiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8377-0742","authenticated-orcid":false,"given":"Carla","family":"Prezioso","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Laboratory of Microbiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-5271","authenticated-orcid":false,"given":"Fabrizio","family":"Maggi","sequence":"additional","affiliation":[{"name":"National Institute for Infectious Diseases \u201cLazzaro Spallanzani\u201d\u2014INMI IRCCS, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2533-2939","authenticated-orcid":false,"given":"Guido","family":"Antonelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Sapienza University, Viale Porta Tiburtina 28, 00185 Rome, Italy"},{"name":"Microbiology and Virology Unit, Sapienza University Hospital Policlinico Umberto I, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6020-1021","authenticated-orcid":false,"given":"Barbara","family":"Picconi","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Laboratory of Experimental Neurophysiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-2195","authenticated-orcid":false,"given":"Carlo","family":"Tomino","sequence":"additional","affiliation":[{"name":"Scientific Direction, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Felzani","sequence":"additional","affiliation":[{"name":"San Raffaele Sulmona, Viale dell\u2019Agricoltura, 67039 Sulmona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3833-6717","authenticated-orcid":false,"given":"Stefano","family":"Bonassi","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Clinical and Molecular Epidemiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele University, Via di Val Cannuta 247, 00166 Rome, Italy"},{"name":"Clinical and Molecular Epidemiology, IRCCS San Raffaele, Via di Val Cannuta 247, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","unstructured":"GBD 2019 Risk Factors Collaborators (2021). 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