- Article
- Source: Campus Sanofi
- 15 May 2024
Role of type 2 Inflammation
Type 2 Inflammation may increase the risk of exacerbations and lung function impairment in COPD23,24
COPD is characterized by mucus production, airway obstruction, and coughing13
Inflammation manifests systemically and locally
- Chronic inflammation causes structural changes, including narrowing of the airways and decreased lung elasticity13
- Studies have identified a relationship between inflammation and mucus hypersecretion in respiratory conditions such as COPD25
Listen to Prof Nicola Hanania : “We no longer look at it as a one-size-fits-all disease”
1:36 minutes
Nicola Hanania is Professor of Medicine, Section Chief of Pulmonary Critical Care and Sleep Medicine at the Ben Taub Hospital in Houston, Texas, and Director of the Airways Clinical Research Center, ACRC, at the Bear College of Medicine.
Listen to the whole episode of the podcast on the EMJ website
Sponsored by Sanofi and Regeneron, in partnership with EMJ.
I think our approach to this all disease has changed, knowing that it has multiple what we call phenotypes, but also not only that, but we have identified multiple mechanism of the disease, so we no longer look at it as a one-size-fits-all disease. And so therefore it's very important for clinician to do some really digging deep into history to identify these phenotypes, whether it's a frequent exacerbative phenotype, whether it's a chronic bronchitic phenotype, whether it's an emphysema mainly phenotype, but now we use biomarkers like blood eosinophils and maybe more to come, including radiology biomarkers in the future, may help us subdivide this group of patients so that we can do a more personalized approach. And I think it's very exciting time for COPD, so we have moved from this blue-bloater pink puffer type approach to now having multiple, as I mentioned, subtypes or phenotypes, and including the identifying more mechanism so that we have more targeted approach to this disease. And hopefully that will help improve outcomes in the future, obviously. That's the main goal is to move that increased risk of mortality that we have seen in COPD, while we have seen so much achievement with other diseases in COPD. Unfortunately, we haven't moved that envelope a lot, so I think we're hoping with new approaches we may improve outcomes.
Look for elevated blood eosinophils (>300 Cells/Lμ) - A Biomarker of Type 2 Inflammation in COPD13
Elevated eosinophils in COPD are a treatable trait and marker of type 2 inflammation13
The 2024 GOLD Report recognizes elevated blood EOS as a clinically used biomarker in identifying COPD with type 2 inflammation
Type 2 inflammation in COPD can involve multiple pathways, cytokines, and inflammatory cells28-33
IL-4, IL-13, an IL-5 are type 2 cytokines involved in COPD
.webp)
.webp)
aBased on findings from 5 studies in COPD patients without asthma. Eosinophil levels used to define type 2 inflammation ranged from ≥300 cells/μL to ≥340 cells/μL (blood), ≥2% in induced sputum or 3% in peripheral blood. Percentages of patients with type 2 inflammation ranged from 12.3% to ~40%23,24
bA severe exacerbation was defined as a hospitalization due to COPD. Exacerbations had to be a minimum of 4 weeks apart to be considered separate exacerbations.27
cIn a cohort of patients with EOS >200 cells/μL.26
dReproduced with permission of the American Thoracic Society. Fritzsching B et al. Am J Respir Crit Care Med. 2015;191(8):902-91325
eAlcian blue PAS staining of mucus in airway epithelial cells.25
fResults from an observational study of 1553 patients with GOLD spirometry grade 2-4 COPD (postbronchodilator FEV1/FVC ratio <0.7, with FEV, >80% predicted)23
gResults from a 1-year observational study of 479 patients with COPD, 173 of whom had blood eosinophil levels ≥200 cells/μL and/or ≥2% of the total white blood cell count.24
COPD, chronic obstructive pulmonary disease; EOS, eosinophils; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IFN-y, interferon-gamma; ILC2, innate lymphoid type-2 cells; MUC5AC, mucin 5AC; PAS, periodic acid-Schiff; TNF-a, tumor necrosis factor alpha; TSLP, thymic stromal lymphopoietin.
References
1. Halpin DMG, Dransfield MT, Han MK, et al. The effect of exacerbation history on outcomes in the IMPACT trial. Eur Respir J. 2020;55:1901921. doi:10.1183/13993003.01921-2019
2. Suissa S, Dell’Anniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012;67(11):957-963.
3. Halpin DMG, Decramer M, Celli BR, Mueller A, Metzdorf N, Tashkin DP. Effect of a single exacerbation on decline in lung function in COPD. Respir Med. 2017;128:85-91.
4. Cosio Piqueras MG, Cosio MG. Disease of the airways in chronic obstructive pulmonary disease. Eur Respir J. 2001;18(suppl 34):41s-49s.
5. Tajti G, Gesztelyi R, Pak K, et al. Positive correlation of airway resistance and serum asymmetric dimethylarginine level in COPD patients with systemic markers of low-grade inflammation. Int J Chron Obstruct Pulmon Dis. 2017;12:873-884.
6. Higham A, Quinn AM, Cançado JED, Singh D. The pathology of small airways disease in COPD: historical aspects and future directions. Respir Res. 2019;20(1):49. doi:10.1186/s12931-019-1017-y
7. O’Donnell DE, Parker CM. COPD exacerbations. 3: Pathophysiology. Thorax. 200661(4):354-361.
8. Calverley PMA. Respiratory failure in chronic obstructive pulmonary disease. Eur Respir J. 2003;22:26s-30s.
9. Roussos C, Koutsoukou A. Respiratory failure. Eur Respir J. 2003;22(suppl 47):3s-14s.
10. Aghapour M, Raee P, Moghaddam SJ, Hiemstra PS, Heijink IH. Airway epithelial barrier dysfunction in chronic obstructive pulmonary disease: role of cigarette smoke exposure. Am J Respir Cell Mol Biol. 2018;58(2):157-169.
11. Brightling CE, Saha S, Hollins F. Interleukin-13: prospects for new treatment. Clin Exp Allergy. 2010;40(1):42-49.
12. Barberà JA, Peinado VI, Santos S. Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J. 2003;21(5):892-905.
13. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2024 report). Accessed [February 9, 2024]. https://goldcopd.org/2024-gold-report-2/
14. Jones PW. St George’s Respiratory Questionnaire: MCID. COPD. 2005 Mar;2(1):75-79.
15. Jones P. St George’s Respiratory Questionnaire Manual. [Version 2.4, March 2022]. Accessed [February 9, 2024]. https://www.sgul.ac.uk/research/research-operations/research-administration/st-georges-respiratory-questionnaire/docs/SGRQ-Manual-March-2022.pdf
16. Evidera website. EXACT and E-RS:COPD content. Accessed [February 9, 2024]. https://www.evidera.com/what-we-do/patient-centered-research/coa-instrument-management-services/exact-program/ exact-content/
17. Leidy NK, Bushnell DM, Thach C, Hache C, Gutzwiller FS. Interpreting Evaluating Respiratory Symptoms in COPD diary scores in clinical trials: terminology, methods, and recommendations. Chronic Obstr Pulm Dis. 2022;9(4):576-590.
18. Oshagbemi OA, Franssen FME, van Kraaij S, et al. Blood eosinophil counts, withdrawal of inhaled corticosteroids and risk of COPD exacerbations and mortality in the clinical practice research datalink (CPRD). COPD. 2019;16(2):152-159.
19. Casanova C, Celli BR, de-Torres JP, et al. Prevalence of persistent blood eosinophilia: relation to outcomes in patients with COPD. Eur Respir J. 2017;50:1701162. doi:10.1183/13993003.01162-2017
20. Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-Singer R; ECLIPSE investigators. Eosinophilic inflammation in COPD: prevalence and clinical characteristics. Eur Respir J. 2014;44(6):1697-1700.
21. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662-671.
22. Oshagbemi OA, Burden AM, Braeken DCW, et al. Stability of blood eosinophils in patients with chronic obstructive pulmonary disease and in control subjects, and the impact of sex, age, smoking, and baseline counts. Am J Respir Crit Care Med. 2017;195(10):1402-1404.
23. Yun JH, Lamb A, Chase R, et al; COPDGene and ECLIPSE Investigators. Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2018;141(6):2037-2047.e10. doi:10.1016/j.jaci.2018.04.010
24. Bélanger M, Couillard S, Courteau J, et al. Eosinophil counts in first COPD hospitalizations: a comparison of health service utilization. Int J Chron Obstruct Pulmon Dis. 2018;13:3045-3054.
25. Fritzsching B, Zhou-Suckow Z, Trojanek JB, et al. Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis lung disease. Am J Respir Crit Care Med. 2015;191(8):902-913.
26. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease. The Copenhagen General Population Study. Am J Respir Crit Care Med. 2016;193(9):965-974.
27. George L, Taylor AR, Esteve- Codina A, et al; U-BIOPRED and the EvA study teams. Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma. Allergy. 2020;75(2):370-380.
28. Yousuf A, Ibrahim W, Greening NJ, Brightling CE. T2 biologics for chronic obstructive pulmonary disease. J Allergy Clin Immunol Pract. 2019;7(5):1406-1416.
29. Barnes PJ. Inflammatory endotypes in COPD. Allergy. 2019;74(7):1249-1256.
30. Oishi K, Matsunaga K, Shirai T, Hirai K, Gon Y. Role of type 2 inflammatory biomarkers in chronic obstructive pulmonary disease. J Clin Med. 2020;9(8):2670. doi:10.3390/jcm9082670
31. Gabryelska A, Kuna P, Antczak A, Białasiewicz P, Panek M. IL-33 mediated inflammation in chronic respiratory diseases—understanding the role of the member of IL-1 superfamily. Front Immunol. 2019;10:692. doi:10.3389/fimmu.2019.00692
32. Allinne J, Scott G, Lim WK, et al. IL-33 blockade affects mediators of persistence and exacerbation in a model of chronic airway inflammation. J Allergy Clin Immunol. 2019;144(6):1624-1637.e10.
33. Calderon AA, Dimond C, Choy DF, et al. Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD. Eur Respir Rev. 2023;32(167):220144. doi:10.1183/16000617.0144-2022
34. Gandhi NA, Bennett BL, Graham NMH, Pirozzi G, Stahl N, Yancopoulos D. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35-50.
35. Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol. 2007;119(6):1303-1310.
36. Doyle AD, Mukherjee M, LeSuer WE, et al. Eosinophil-derived IL-13 promotes emphysema. Eur Respir J. 2019;53(5):1801291. doi:10.1183/13993003.01291-2018
37. Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(1):16-27.
38. Defrance T, Carayon P, Billian G, et al. Interleukin 13 is a B cell stimulating factor. J Exp Med. 1994;179(1):135-143.
39. Yanagihara Y, Ikizawa K, Kajiwara K, Koshio T, Basaki Y, Akiyama K. Functional significance of IL-4 receptor on B cells in IL-4– induced human IgE production. J Allergy Clin Immunol. 1995;96(6 pt 2):1145-1151.
40. Gandhi NA, Pirozzi G, Graham NMH. Commonality of the IL-4/IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13(5):425-437.
41. Kaur D, Hollins F, Woodman L, et al. Mast cells express IL-13Rα1: IL-13 promotes human lung mast cell proliferation and FcεRI expression. Allergy. 2006;61(9):1047-1053.
42. Saatian B, Rezaee F, Desando S, et al. Interleukin-4 and interleukin-13 cause barrier dysfunction in human epithelial cells. Tissue Barriers. 2013;1(2):e24333. doi:10.4161/tisb.24333
43. Zheng T, Zhu Z, Wang Z, et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase– and cathepsin-dependent emphysema. J Clin Invest. 2000;106(9):1081-1093.
44. Garudadri S, Woodruff PG. Targeting chronic obstructive pulmonary disease phenotypes, endotypes, and biomarkers. Ann Am Thorac Soc. 2018;15(suppl 4):S234-S238.
45. Alevy YG, Patel AC, Romero AG, et al. IL-13–induced airway mucus production is attenuated by MAPK13 inhibition. J Clin Invest. 2012;122(12):4555-4568.
46. Singanayagam A, Footitt J, Marczynski M, et al. Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease. J Clin Invest. 2022;132(8):e12901. doi:10.1172/JCI120901
47. Zhu Z, Homer RJ, Wang Z, et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999;103(6):779-788.
48. Cooper PR, Poll CT, Barnes PJ, Sturton RG. Involvement of IL-13 in tobacco smoke-induced changes in the structure and function of rat intrapulmonary airways. Am J Respir Cell Mol Biol. 2010;43(2):220-226.
49. Arora S, Dev K, Agarwal B, Das P, Syed MA. Macrophages: their role, activation, and polarization in pulmonary diseases. Immunobiology. 2018;223(4-5):383-396.
50. He S, Xie L, Lu J, Sun S. Characteristics and potential role of M2 macrophages in COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:3029-3039.
51. Wang X, Xu C, Ji J, et al. IL-4/IL-13 upregulates Sonic hedgehog expression to induce allergic airway epithelial remodeling. Am J Physiol Lung Cell Mol Physiol. 2020;318(5):L888-L899.
52. Linden D, Guo-Parke H, Coyle PV, et al. Respiratory viral infection: a potential “missing link” in the pathogenesis of COPD. Eur Respir Rev. 2019;28(151):180063. doi:10.1183/16000617.0063-2018
53. Wang Z, Bafadhel M, Haldar K, et al. Lung microbiome dynamics in COPD exacerbations. Eur Respir J. 2016;47(4):1082-1092.
MAT-BH-2400291/V1/May/2024