{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:30:58Z","timestamp":1792794658317,"version":"4.5.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01HL089897"],"award-info":[{"award-number":["U01HL089897"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL137995"],"award-info":[{"award-number":["R01HL137995"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL166231"],"award-info":[{"award-number":["R01HL166231"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Respir Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Blood eosinophil count is an accepted biomarker for type 2 inflammation in COPD. However, the majority of COPD patients are characterized by non-type 2 inflammation. We aimed to test readily obtainable immune cell ratios as biomarkers for clinical phenotypes in the broad COPD population and to determine pathways represented by these ratios using multi-omics data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using complete blood counts with differential collected at the Phase 2 (5-year) visit in the COPDGene Study, we calculated three immune cell ratios previously described in COPD and other diseases: the neutrophil\u2013lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), and the Systemic Immune-Inflammation Index (SII\u2009=\u2009NLR*platelets). We tested for associations with COPD outcomes, including lung function, chest CT scan phenotypes, and exacerbations. Blood RNA-sequencing and proteomics data were used to identify genes, proteins and pathways associated with the ratios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In univariate analyses, the three biomarkers were associated with COPD severity measures. In zero inflated Poisson regression models, all three were associated with increased odds of having an exacerbation but were not associated with exacerbation counts. Conversely, the three biomarkers were generally associated with prospective exacerbation counts, but not the zero-inflation term. In logistic regression models, the three biomarkers were significantly associated with having two or more exacerbations in the prior year; however, receiver operating characteristic analyses did not lead to clear cutoff values. Complement and PI3K signaling pathways were enriched across more than one ratio in both the RNA-sequencing and proteomics results. Other inflammatory pathways relevant in COPD appeared in different enrichment sets in either omics data type.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Higher levels of three easily obtained blood cell ratios were associated with COPD severity and exacerbations outcomes; however, there are not clear thresholds which would be required for clinical application. Blood RNA-sequencing and proteomics identified inflammatory pathways associated with the three biomarkers, including targets for COPD therapies currently in human trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12931-026-03632-3","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:17:57Z","timestamp":1773825477000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Blood cell ratio biomarkers of systemic inflammation in chronic obstructive pulmonary disease"],"prefix":"10.1186","volume":"27","author":[{"given":"Kaman","family":"So","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aabida","family":"Saferali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-8295","authenticated-orcid":false,"given":"Jeong H.","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3071-7363","authenticated-orcid":false,"given":"Min Hyung","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3954-8620","authenticated-orcid":false,"given":"Enrico","family":"Schiavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Castaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3800-511X","authenticated-orcid":false,"given":"Lisa","family":"Ruvuna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4651-363X","authenticated-orcid":false,"given":"Russell P.","family":"Bowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5191-4847","authenticated-orcid":false,"given":"Jeffrey L.","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1342-4334","authenticated-orcid":false,"given":"Craig P.","family":"Hersh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"issue":"13","key":"3632_CR1","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1042\/CS20160487","volume":"131","author":"PJ Barnes","year":"2017","unstructured":"Barnes PJ. Cellular and molecular mechanisms of asthma and COPD. Clin Sci. 2017;131(13):1541\u201358.","journal-title":"Clin Sci"},{"issue":"178","key":"3632_CR2","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0110-2025","volume":"34","author":"CE Brightling","year":"2025","unstructured":"Brightling CE, Bafadhel M, Han MK, Papon JF, Rabe KF, Rogliani P, et al. A translational view of airway epithelial dysfunction in COPD. Eur Respir Rev Off J Eur Respir Soc. 2025;34(178):250110.","journal-title":"Eur Respir Rev Off J Eur Respir Soc"},{"issue":"7","key":"3632_CR3","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1164\/rccm.202301-0106PP","volume":"207","author":"A Agusti","year":"2023","unstructured":"Agusti A, Celli BR, Criner GJ, Halpin D, Anzueto A, Barnes P, et al. Global initiative for chronic obstructive lung disease 2023 report: GOLD executive summary. Am J Respir Crit Care Med. 2023;207(7):819\u201337.","journal-title":"Am J Respir Crit Care Med"},{"issue":"6","key":"3632_CR4","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1016\/j.jaci.2018.04.010","volume":"141","author":"JH Yun","year":"2018","unstructured":"Yun JH, Lamb A, Chase R, Singh D, Parker MM, Saferali A, et al. Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2018;141(6):2037-2047 e10.","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"3632_CR5","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S2213-2600(18)30006-7","volume":"6","author":"M Bafadhel","year":"2018","unstructured":"Bafadhel M, Peterson S, De Blas MA, Calverley PM, Rennard SI, Richter K, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018;6(2):117\u201326.","journal-title":"Lancet Respir Med"},{"issue":"17","key":"3632_CR6","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1056\/NEJMoa2413181","volume":"392","author":"FC Sciurba","year":"2025","unstructured":"Sciurba FC, Criner GJ, Christenson SA, Martinez FJ, Papi A, Roche N, et al. Mepolizumab to prevent exacerbations of COPD with an eosinophilic phenotype. N Engl J Med. 2025;392(17):1710\u201320.","journal-title":"N Engl J Med"},{"issue":"3","key":"3632_CR7","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1056\/NEJMoa2303951","volume":"389","author":"SP Bhatt","year":"2023","unstructured":"Bhatt SP, Rabe KF, Hanania NA, Vogelmeier CF, Cole J, Bafadhel M, et al. Dupilumab for COPD with Type 2 inflammation indicated by eosinophil counts. N Engl J Med. 2023;389(3):205\u201314.","journal-title":"N Engl J Med"},{"issue":"1","key":"3632_CR8","first-page":"1","volume":"7","author":"CP Hersh","year":"2020","unstructured":"Hersh CP, Zacharia S, Prakash Arivu Chelvan R, Hayden LP, Mirtar A, Zarei S, et al. Immunoglobulin E as a biomarker for the overlap of atopic asthma and chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis. 2020;7(1):1\u201312.","journal-title":"Chronic Obstr Pulm Dis."},{"issue":"8","key":"3632_CR9","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082670","volume":"9","author":"K Oishi","year":"2020","unstructured":"Oishi K, Matsunaga K, Shirai T, Hirai K, Gon Y. Role of Type2 inflammatory biomarkers in chronic obstructive pulmonary disease. J Clin Med. 2020;9(8):2670.","journal-title":"J Clin Med"},{"issue":"4","key":"3632_CR10","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1165\/rcmb.2017-0373OC","volume":"58","author":"E Halper-Stromberg","year":"2018","unstructured":"Halper-Stromberg E, Yun JH, Parker MM, Singer RT, Gaggar A, Silverman EK, et al. Systemic markers of adaptive and innate immunity are associated with chronic obstructive pulmonary disease severity and spirometric disease progression. Am J Respir Cell Mol Biol. 2018;58(4):500\u20139.","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"1","key":"3632_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-018-0717-z","volume":"19","author":"A Fawzy","year":"2018","unstructured":"Fawzy A, Putcha N, Paulin LM, Aaron CP, Labaki WW, Han MK, et al. Association of thrombocytosis with COPD morbidity: the SPIROMICS and COPDGene cohorts. Respir Res. 2018;19(1):20.","journal-title":"Respir Res"},{"key":"3632_CR12","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0095-2022","author":"A Zinellu","year":"2022","unstructured":"Zinellu A, Zinellu E, Mangoni AA, Pau MC, Carru C, Pirina P, et al. Clinical significance of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in acute exacerbations of COPD: present and future. Eur Respir Rev. 2022. https:\/\/doi.org\/10.1183\/16000617.0095-2022.","journal-title":"Eur Respir Rev"},{"issue":"1","key":"3632_CR13","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-025-03677-y","volume":"25","author":"L Fang","year":"2025","unstructured":"Fang L, Zhu J, Fu D. Predictive value of neutrophil-lymphocyte ratio for all-cause mortality in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. BMC Pulm Med. 2025;25(1):206.","journal-title":"BMC Pulm Med"},{"issue":"1","key":"3632_CR14","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1080\/17476348.2019.1675517","volume":"14","author":"AG El-Gazzar","year":"2020","unstructured":"El-Gazzar AG, Kamel MH, Elbahnasy OKM, El-Naggar MES. Prognostic value of platelet and neutrophil to lymphocyte ratio in COPD patients. Expert Rev Respir Med. 2020;14(1):111\u20136.","journal-title":"Expert Rev Respir Med"},{"key":"3632_CR15","doi-asserted-by":"publisher","first-page":"987","DOI":"10.2147\/COPD.S510118","volume":"20","author":"Y Fu","year":"2025","unstructured":"Fu Y, Wang Y, Wang Y, Mou T, He X, Wang J, et al. Biomarkers (NLR, PLR, SII) for frequent COPD exacerbations: diagnostic and clinical management implications in a retrospective study. Int J Chron Obstruct Pulmon Dis. 2025;20:987\u201398.","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"issue":"1","key":"3632_CR16","doi-asserted-by":"publisher","first-page":"32","DOI":"10.3109\/15412550903499522","volume":"7","author":"EA Regan","year":"2010","unstructured":"Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, et al. Genetic epidemiology of COPD (COPDGene) study design. COPD: J Chron Obstruct Pulmon Dis. 2010;7(1):32\u201343.","journal-title":"COPD: J Chron Obstruct Pulmon Dis"},{"issue":"5","key":"3632_CR17","doi-asserted-by":"publisher","first-page":"466","DOI":"10.3109\/15412555.2012.690010","volume":"9","author":"JI Stewart","year":"2012","unstructured":"Stewart JI, Moyle S, Criner GJ, Wilson C, Tanner R, Bowler RP, et al. Automated telecommunication to obtain longitudinal follow-up in a multicenter cross-sectional COPD study. COPD. 2012;9(5):466\u201372.","journal-title":"COPD"},{"issue":"3","key":"3632_CR18","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1164\/rccm.202301-0085OC","volume":"208","author":"MH Ryu","year":"2023","unstructured":"Ryu MH, Yun JH, Morrow JD, Saferali A, Castaldi P, Chase R, et al. Blood gene expression and immune cell subtypes associated with chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2023;208(3):247\u201355.","journal-title":"Am J Respir Crit Care Med"},{"key":"3632_CR19","doi-asserted-by":"publisher","first-page":"104262","DOI":"10.1016\/j.ebiom.2022.104262","volume":"84","author":"KA Serban","year":"2022","unstructured":"Serban KA, Pratte KA, Strange C, Sandhaus RA, Turner AM, Beiko T, et al. Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease. eBioMedicine. 2022;84:104262.","journal-title":"eBioMedicine"},{"issue":"7845","key":"3632_CR20","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/s41586-021-03205-y","volume":"590","author":"D Taliun","year":"2021","unstructured":"Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590(7845):290\u20139.","journal-title":"Nature"},{"issue":"1","key":"3632_CR21","doi-asserted-by":"publisher","first-page":"e1000360","DOI":"10.1371\/journal.pgen.1000360","volume":"5","author":"D Reich","year":"2009","unstructured":"Reich D, Nalls MA, Kao WHL, Akylbekova EL, Tandon A, Patterson N, et al. Reduced neutrophil count in people of african descent is due to a regulatory variant in the duffy antigen receptor for chemokines gene. Visscher PM, editor. PLoS Genet. 2009;5(1):e1000360.","journal-title":"PLoS Genet"},{"issue":"23","key":"3632_CR22","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1001\/jama.2023.7467","volume":"329","author":"LE Merz","year":"2023","unstructured":"Merz LE, Osei MA, Story CM, Freedman RY, Smeland-Wagman R, Kaufman RM, et al. Development of Duffy Null\u2013specific absolute neutrophil count reference ranges. JAMA. 2023;329(23):2088\u20139.","journal-title":"JAMA"},{"issue":"12","key":"3632_CR23","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","volume":"27","author":"A Liberzon","year":"2011","unstructured":"Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27(12):1739\u201340.","journal-title":"Bioinformatics"},{"issue":"1","key":"3632_CR24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27\u201330.","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"3632_CR25","first-page":"25","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium Nat Genet. 2000;25(1):25\u20139.","journal-title":"The Gene Ontology Consortium Nat Genet"},{"issue":"Database issue","key":"3632_CR26","doi-asserted-by":"publisher","first-page":"D691","DOI":"10.1093\/nar\/gkq1018","volume":"39","author":"D Croft","year":"2011","unstructured":"Croft D, O\u2019Kelly G, Wu G, Haw R, Gillespie M, Matthews L, et al. Reactome: a database of reactions, pathways and biological processes. Nucleic Acids Res. 2011;39(Database issue):D691-7.","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"3632_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-014-0089-y","volume":"15","author":"ES Wan","year":"2014","unstructured":"Wan ES, Castaldi PJ, Cho MH, Hokanson JE, Regan EA, Make BJ, et al. Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene. Respir Res. 2014;15(1):89.","journal-title":"Respir Res"},{"issue":"4","key":"3632_CR28","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1080\/14728214.2023.2296088","volume":"28","author":"J De Soyza","year":"2023","unstructured":"De Soyza J, Pye A, Turner AM. Are clinical trials into emerging drugs for the treatment of alpha-1 antitrypsin deficiency providing promising results? Expert Opin Emerg Drugs. 2023;28(4):227\u201331.","journal-title":"Expert Opin Emerg Drugs"},{"issue":"5","key":"3632_CR29","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/S2213-2600(21)00556-7","volume":"10","author":"AJ Yousuf","year":"2022","unstructured":"Yousuf AJ, Mohammed S, Carr L, Yavari Ramsheh M, Micieli C, Mistry V, et al. Astegolimab, an anti-ST2, in chronic obstructive pulmonary disease (COPD-ST2OP): a phase 2a, placebo-controlled trial. Lancet Respir Med. 2022;10(5):469\u201377.","journal-title":"Lancet Respir Med"},{"key":"3632_CR30","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0113-2017","author":"P Paliogiannis","year":"2018","unstructured":"Paliogiannis P, Fois AG, Sotgia S, Mangoni AA, Zinellu E, Pirina P, et al. Neutrophil to lymphocyte ratio and clinical outcomes in COPD: recent evidence and future perspectives. Eur Respir Rev. 2018. https:\/\/doi.org\/10.1183\/16000617.0113-2017.","journal-title":"Eur Respir Rev"},{"issue":"2","key":"3632_CR31","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1080\/15412555.2021.1898578","volume":"18","author":"A Zinellu","year":"2021","unstructured":"Zinellu A, Paliogiannis P, Sotgiu E, Mellino S, Fois AG, Carru C, et al. Platelet count and platelet indices in patients with stable and acute exacerbation of chronic obstructive pulmonary disease: a systematic review and meta-analysis. COPD: J Chron Obstruct Pulmon Dis. 2021;18(2):231\u201345.","journal-title":"COPD: J Chron Obstruct Pulmon Dis"},{"issue":"4","key":"3632_CR32","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1378\/chest.13-2946","volume":"146","author":"RP Bowler","year":"2014","unstructured":"Bowler RP, Kim V, Regan E, Williams A, Santorico SA, Make BJ, et al. Prediction of acute respiratory disease in current and former smokers with and without COPD. Chest. 2014;146(4):941\u201350.","journal-title":"Chest"},{"key":"3632_CR33","unstructured":"Hoesterey DT, Dang H, Markovic D, Buhr RG, Tashkin DP, Barr RG, et al. Neutrophil-to-Lymphocyte Ratio (NLR) as a Biomarker in clinically stable chronic obstructive pulmonary disease: SPIROMICS cohort. Ann Am Thorac Soc. 2025;[online ahead of print]."},{"issue":"2","key":"3632_CR34","first-page":"266","volume":"95","author":"RD Miller","year":"1980","unstructured":"Miller RD, Kueppers F, Offord KP. Serum concentrations of C3 and C4 of the complement system in patients with chronic obstructive pulmonary disease. J Lab Clin Med. 1980;95(2):266\u201371.","journal-title":"J Lab Clin Med"},{"issue":"1","key":"3632_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-32216-0","volume":"13","author":"KM DiLillo","year":"2023","unstructured":"DiLillo KM, Norman KC, Freeman CM, Christenson SA, Alexis NE, Anderson WH, et al. A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD. Sci Rep. 2023;13(1):8228.","journal-title":"Sci Rep"},{"issue":"10","key":"3632_CR36","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1164\/rccm.202311-2059LE","volume":"210","author":"KM DiLillo","year":"2024","unstructured":"DiLillo KM, Ruvuna L, Pratte KA, Serban KA, Labaki WW, Han MK, et al. Validation of systemic complement signatures in the progression of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2024;210(10):1269\u201372.","journal-title":"Am J Respir Crit Care Med"},{"issue":"4","key":"3632_CR37","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00027-2016","volume":"2","author":"JP Westwood","year":"2016","unstructured":"Westwood JP, Mackay AJ, Donaldson G, Machin SJ, Wedzicha JA, Scully M. The role of complement activation in COPD exacerbation recovery. ERJ Open Res. 2016;2(4):00027\u20132016.","journal-title":"ERJ Open Res"},{"issue":"9","key":"3632_CR38","doi-asserted-by":"publisher","first-page":"3222","DOI":"10.1016\/j.jaip.2020.05.031","volume":"8","author":"C David","year":"2020","unstructured":"David C, Jachiet M, Pineton De Chambrun M, Gamez AS, Mehdaoui A, Zenone T, et al. Chronic obstructive pulmonary disease associated with hypocomplementemic urticarial vasculitis. J Allergy Clin Immunol Pract. 2020;8(9):3222-3224.e1.","journal-title":"J Allergy Clin Immunol Pract"},{"key":"3632_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1619835","volume":"16","author":"AB Alarabi","year":"2025","unstructured":"Alarabi AB, Alshbool FZ, Khasawneh FT. Impact of smoking on the complement system: a narrative review. Front Immunol. 2025;16:1619835.","journal-title":"Front Immunol"},{"issue":"3","key":"3632_CR40","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s00204-023-03440-4","volume":"97","author":"M Yu","year":"2023","unstructured":"Yu M, Chen J, Xu Z, Yang B, He Q, Luo P, et al. Development and safety of PI3K inhibitors in cancer. Arch Toxicol. 2023;97(3):635\u201350.","journal-title":"Arch Toxicol"},{"key":"3632_CR41","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1238782","author":"Y Liu","year":"2023","unstructured":"Liu Y, Kong H, Cai H, Chen G, Chen H, Ruan W. Progression of the PI3K\/Akt signaling pathway in chronic obstructive pulmonary disease. Front Pharmacol. 2023. https:\/\/doi.org\/10.3389\/fphar.2023.1238782.","journal-title":"Front Pharmacol"},{"key":"3632_CR42","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/978-3-031-06566-8_19","volume-title":"PI3K and AKT Isoforms in Immunity : Mechanisms and Therapeutic Opportunities","author":"E Fagone","year":"2022","unstructured":"Fagone E, Fruciano M, Gili E, Sambataro G, Vancheri C. Developing PI3K Inhibitors for Respiratory Diseases. In: Dominguez-Villar M, editor. PI3K and AKT Isoforms in Immunity\u202f: Mechanisms and Therapeutic Opportunities. Cham: Springer International Publishing; 2022. p. 437\u201366."},{"issue":"4","key":"3632_CR43","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.clinthera.2024.02.008","volume":"46","author":"H Yang","year":"2024","unstructured":"Yang H, He S, Liang L, Pan J. Efficacy of nemiralisib in chronic obstructive pulmonary disease: a systematic review. Clin Ther. 2024;46(4):360\u20137.","journal-title":"Clin Ther"}],"container-title":["Respiratory Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12931-026-03632-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-026-03632-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-026-03632-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T20:23:47Z","timestamp":1781641427000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12931-026-03632-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,18]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3632"],"URL":"https:\/\/doi.org\/10.1186\/s12931-026-03632-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-8585567\/v1","asserted-by":"object"}]},"ISSN":["1465-993X"],"issn-type":[{"value":"1465-993X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,18]]},"assertion":[{"value":"12 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"COPDGene was approved by the Institutional Review Board at Mass General Brigham and all participating centers. The research was conducted in accordance with the Belmont Report.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"JHY reports consulting fees from Bridge BioTherapeutics and serving on an Advisory Board for Genentech. PJC reports grants from Sanofi and Bayer, and consulting fees from Verona Pharma and Genentech. JLC reports grants from the COPD Foundation, consulting fees from AstraZeneca and participation on Data Safety Monitoring Board or Advisory Board for Novartis and Genetech. CPH reports grants from the Alpha-1 Foundation and Bayer, and consulting fees from Apogee Therapeutics, AstraZeneca, Chiesi, Genentech, Ono Pharma, Sanofi, Takeda, and Verona Pharma. None of the other authors report any conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"184"}}