Clinical and pathogenetic features of the combination of asthma-COPD overlap and type 2 diabetes mellitus

The absence of clear diagnostic criteria, specific biomarkers, and the heterogeneity of asthma-COPD overlap (ACO) pose challenges in studying both the epidemiology and molecular mechanisms of ACO. This leads clinicians to resort to trial and error methods in finding the optimal treatment for ACO patients.

Objective: to investigate the clinical and laboratory characteristics in patients with a combined course of ACO and type 2 diabetes mellitus (T2DM).

Object and research methods. A total of 120 patients were examined, comprising 22 patients with chronic obstructive pulmonary disease (COPD) (group 1), 21 with asthma (group 2), 24 with ACO (group 3), 31 with ACO+T2DM (group 4), 22 with T2DM (group 5), and 20 healthy individuals (HI) (group 6). The study assessed indicators of pulmonary function test, body mass index, and visceral fat level. Glucose, 8-isoprostane, insulin, sCD14, C-reactive protein, fibrinogen, cholesterol, triglycerides, high-density lipoproteins, low-density lipoproteins, HOMA-IR, QUICKI, TYG indices were examined. Simultaneously, neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio, and systemic immune inflammation index (SIII) were determined.

Results. In patients with ACO+T2DM, more pronounced breathlessness on the mMRC scale, increased exacerbation frequency, higher body mass index, visceral fat, and BODE index were observed with the lowest forced expiratory volume in 1st second. Simultaneously, this group of patients exhibited more pronounced dyslipidemia, characterized by higher levels of total cholesterol and triglycerides, along with lower levels of high-density lipoproteins. It was established that the NLR in patients with COPD, asthma and ACO was significantly higher than in patients with T2DM and HI (p<0.05). The median NLR in ACO+T2DM was likely higher compared to the 1st and 2nd groups by 1.32 and 1.38 times, respectively (p<0.05), but did not differ from the 3rd group (p>0.05). Monocyte-lymphocyte ratio allowed differentiation of patients with ACO and ACO+T2DM from the 5th and 6th groups (p<0.05). In all patient groups, the SIII was higher than in HI, and in patients with ACO+T2DM, this index was higher than in COPD by 26% (p<0.05) and in T2DM by 25% (p<0.05). The level of 8-isoprostane was highest in ACO+T2DM patients, with a statistically significant difference from all groups, particularly by 62.5; 60 and 41.1% compared to COPD, asthma and ACO, respectively (p<0.05). The level of C-reactive protein was noticeably higher in the main group, with a significant difference between the 5th and 6th groups (p<0.05) and a tendency to higher levels than in asthma. The fibrinogen level in ACO+T2DM patients was 29% higher than in patients with asthma and ACO. In patients with ACO and ACO+T2DM, the sCD14 level was 2.5 times higher than in HI and patients with T2DM (p<0.05), higher than in COPD but slightly lower than in asthma (p>0.05). There was no statistically significant difference between T2DM and HI (p>0.05).

References

1. Mattila T., Vasankari T., Kauppi P. (2022) Mortality of asthma, COPD, and asthma-COPD overlap during an 18-year follow up. Resp. Med., 207: 107–112. DOI: 10.1016/j.rmed.2022.107112.
2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022. Available from ginasthma.org. Accessed: March 15, 2023.
3. Global Initiative for Asthma (GINA) Diagnosis and initial treatment of asthma,COPD, and asthma-COPD overlap: A joint project of GINA and GOLD updated April 2017. ginasthma.org/wp-content/uploads/2019/11/GINA-GOLD-2017-overlap-pocket-guide-wms-2017-ACO.pdf. Accessed: March 15, 2023.
4. Soriano J.B., Kendrick P.J., Paulson K.R. et al. (2020) Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir. Med., 8: 585–596. doi: 10.1016/s2213-2600(20)30105-3.
5. Lim J.U., Kim D.K., Lee M.G. et al. (2020) Clinical Characteristics and Changes of Clinical Features in Patients with Asthma- COPD Overlap in Korea according to Different Diagnostic Criteria. Tuberc. Respir. Dis. (Seoul), 83(Suppl. 1): 34–45. doi: 10.4046/trd.2020.0031.
6. Hua Y. et al. (2023) Monocyte-to-lymphocyte ratio predicts mortality and cardiovascular mortality in the general population International. Int. J. Cardiol., 379: 118–126. doi: 10.1016/j.ijcard.2023.03.016.
7. Furman D., Campisi J., Verdin E. et al. (2019) Chronic inflammation in the etiology of disease across the life span. Nat. Med., 25: 1822–1832. doi: 10.1038/s41591-019-0675-0.
8. Poredos P., Poredos A.V., Gregoric I. (2021) Endothelial Dysfunction and Its Clinical Implications Angiology, 72: 604–615. doi: 10.1177/0003319720987752.
9. Marzoog B.A. (2022) Recent advances in molecular biology of metabolic syndrome pathophysiology: endothelial dysfunction as a potential therapeutic target. J. Diabetes Metab. Disord., 21: 1903–1911. doi: 10.1007/s40200-022-01088-y.
10. Mekov E., Nuñez A., Sin D.D. et al. (2021) Update on Asthma-COPD Overlap (ACO): A Narrative Review. Int. J. Chron. Obstruct. Pulmon. Dis., 16: 1783–1799. doi: 10.2147/COPD.S312560.
11. Gibson P.G., Simpson J.L. (2009) The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax, 64(8): 728–735. doi: 10.1136/thx.2008.108027.
12. Peltola L., Pätsi H., Harju T. (2020) COPD Comorbidities Predict High Mortality — Asthma-COPD-Overlap Has Better Prognosis. COPD, 17(4): 366–372. doi: 10.1080/15412555.2020.1783647.
13. Gayle A.V., Minelli C., Quint J.K. (2022) Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis. BMC Pulm. Med., 22: 28. DOI: 10.1186/s12890-022-01823-4.
14. Romem A., Rokach A., Bohadana A. et al. (2020) Identification of Asthma-COPD Overlap, Asthma, and Chronic Obstructive Pulmonary Disease Phenotypes in Patients with Airway Obstruction: Influence on Treatment Approach. Respiration, 99(1): 35–42. DOI: 10.1159/000503328.
15. Akmatov K., Ermakova T., Holstiege J. et al.(2020) Comorbidity profile of patients with concurrent diagnoses of asthma and COPD in Germany. Sci. Rep., 10: 17945. DOI: 10.1038/s41598-020-74966-1.
16. Zhang R.H., Zhou J.B., Cai Y.H. et al. (2020) Non-linear association between diabetes mellitus and pulmonary function: a population-based study. Respir Res., 21(1): 292. doi: 10.1186/s12931-020-01538-2.
17. Ghosh N., Choudhury P., Kaushik S.R. et al. (2020) Metabolomic fingerprinting and systemic inflammatory profiling of asthma COPD overlap (ACO). Respir. Res., 21(1): 126. doi: 10.1186/s12931-020-01390-4.
18. Li M., Yang T., He R. et al. (2020) The Value of Inflammatory Biomarkers in Differentiating Asthma-COPD Overlap from COPD. Int. J. Chron. Obstruct. Pulmon. Dis., 15: 3025–3037. doi: 10.2147/COPD.S273422.
19. Fu J.J., McDonald V.M., Gibson P.G., Simpson J.L. (2014) Systemic Inflammation in Older Adults With Asthma-COPD Overlap Syndrome. Allergy Asthma Immunol. Res., 6(4): 316–324. doi: 10.4168/aair.2014.6.4.316.
20. Hlapčić I., Dugac A.V., Popović-Grle S. (2020) Influence of disease severity, smoking status and therapy regimes on leukocyte subsets and their ratios in stable chronic obstructive pulmonary disease. Arch. Med. Sci., 18(3): 672–681. doi: 10.5114/aoms.2020.100720.
21. Ke J., Qiu F., Fan W., Wei S. (2023) Associations of complete blood cell count-derived inflammatory biomarkers with asthma and mortality in adults: a population-based study. Front. Immunol., 14: 1205687. doi: 10.3389/fimmu.2023.1205687.
22. Adamstein N.H., MacFadyen J.G., Rose L.M. et al. (2021) The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur. Heart J., 42(9): 896–903. doi: 10.1093/eurheartj/ehaa1034.
23. Huang W.J., Huang G.T., Zhan Q.M. et al.(2020) The neutrophil to lymphocyte ratio as a novel predictor of asthma and its exacerbation: a systematic review and meta-analysis. Eur. Rev. Med. Pharmacol. Sci., 24(22): 11719–11728. doi: 10.26355/eurrev_202011_23819.
24. Paliogiannis P., Fois A.G., Sotgia S. et al. (2018) The neutrophil‐to‐ lymphocyte ratio as a marker of chronic obstructive pulmonary disease and its exacerbations: a systematic review and meta‐analysis. Eur. J. Clin. Invest., 48: e12984. doi: 10.1111/eci.12984.
25. Ma H., Yang L., Liu L. et al. (2022) Using inflammatory index to distinguish asthma, asthma-COPD overlap and COPD: A retrospective observational study. Front. Med. (Lausanne), 9: 1045503. doi: 10.3389/fmed.2022.1045503.
26. Zeig-Owens R., Singh A., Aldrich T.K. et al. (2018) Blood Leukocyte Concentrations, FEV1 Decline, and Airflow Limitation. A 15-Year Longitudinal Study of World Trade Center-exposed Firefighters. Ann. Am. Thorac. Soc., 15(2): 173–183. doi: 10.1513/AnnalsATS.201703-276OC.
27. Wu X., Wang C., Li H. et al. (2021) Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis. Ann. Med., 53(1): 1118–1128. doi: 10.1080/07853890.2021.1948603.
28. Zhenghao W., Zhenxiong Zh., Zehua L. et al. (2019) CD14: Biology and role in the pathogenesis of disease. Cytokine Growth Factor Rev., 48: 24–31. doi: 10.1016/j.cytogfr.2019.06.003.
29. Ribes I., Reus S., Asensio S. et al. (2021). Inflammatory Biomarkers in the Pathogenesis of Respiratory Dysfunction in People Living with HIV. Curr. HIV Res., 19(5): 384–390. doi: 10.2174/1570162X19666210607103157.
30. Chen J., Han Y.-S., Yi W.-J. et al. (2020) Serum sCD14, PGLYRP2 and FGA as potential biomarkers for multidrug-resistant tuberculosis based on data-independent acquisition and targeted proteomics. J. Cell Mol. Med., 24: 12537–12549. doi: 10.1016/j.cytogfr.2019.06.003.
31. Zingaropoli M.A., Nijhawan P., Carraro A. et al. (2021) Increased sCD163 and sCD14 Plasmatic Levels and Depletion of Peripheral Blood Pro-Inflammatory Monocytes, Myeloid and Plasmacytoid Dendritic Cells in Patients With Severe COVID-19 Pneumonia. Front. Immunol., 12: 627548. doi: 10.3389/fimmu.2021.627548.
32. Cao V.T., Carter M.C., Brenchley J.M. et al. (2023) sCD14 and Intestinal Fatty Acid Binding Protein Are Elevated in the Serum of Patients With Idiopathic Anaphylaxis. J. Allergy Clin. Immunol. Pract., 11(7): 2080–2086.e5. doi: 10.1016/j.jaip.2023.03.037.
33. Palipane M., Snyder J.D., LeMessurier K.S. et al. (2019) Macrophage CD14 impacts immune defenses against influenza virus in allergic hosts. Microb. Pathog., 127: 212–219. doi: 10.1016/j.micpath.2018.12.008.
34. Hua M.C., Su H.M., Kuo M.L. et al. (2019) Association of maternal allergy with human milk soluble CD14 and fatty acids, and early childhood atopic dermatitis. Pediatr. Allergy Immunol., 30(2): 204–213. doi: 10.1111/pai.13011.
35. Sanjurjo L., Castelblanco E., Julve J. et al. (2023) Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14. Antioxidants, 12: 1083. doi: 10.3390/antiox12051083.
36. Muendlein H.I., Connolly W.M., Cameron J. et al. (2022) Neutrophils and macrophages drive TNF-induced lethality via TRIF/CD14-mediated responses. Sci. Immunol., 7(78): eadd0665. doi: 10.1126/sciimmunol.add0665.
37. Laugerette F., Vors C., Alligier M. et al. (2020) Postprandial Endotoxin Transporters LBP and sCD14 Differ in Obese vs. Overweight and Normal Weight Men during Fat-Rich Meal Digestion. Nutrients, 12(6): 1820. doi: 10.3390/nu12061820.
38. Bahijri S.M., Ajabnoor G.M., Hegazy G.A. et al. (2020) Diet influences levels of plasma lipopolysaccharide (LPS) and its soluble receptor (sCD14) in Saudis. J. Pak. Med. Assoc., 70(11): 1956–1961. doi: 10.5455/JPMA.28279.
39. Wang C., Jiang S., Zhang S. et al. (2021) Research Progress of Metabolomics in Asthma. Metabolites, 11: 567. doi: 10.3390/metabo11090567.
40. Nieto-Fontarigo J.J., Salgado F.J., San-José M.E. et al. (2018) The CD14 (-159 C/T) SNP is associated with sCD14 levels and allergic asthma, but not with CD14 expression on monocytes. Sci. Rep., 8(1): 4147. doi: 10.1038/s41598-018-20483-1.
41. LeVan T.D., Smith L.M., Heires A.J. et al. (2017) Interaction of CD14 haplotypes and soluble CD14 on pulmonary function in agricultural workers. Respir. Res., 18(1): 49. doi: 10.1186/s12931-017-0532-y.
42. Chen D., Wang H. (2020) The clinical and immune features of CD14 in colorectal cancer identified via large-scale analysis. Int. Immunopharmacol., 88: 106966. doi: 10.1016/j.intimp.2020.106966.
43. Beers D.R., Zhao W., Neal D.W. et al. (2020) Elevated acute phase proteins reflect peripheral inflammation and disease severity in patients with amyotrophic lateral sclerosis. Sci. Rep., 10(1): 15295. doi: 10.1038/s41598-020-72247-5.
44. Stadlbauer V., Engertsberger L., Komarova I. et al. (2020) Dysbiosis, gut barrier dysfunction and inflammation in dementia: a pilot study. BMC Geriatr., 20(1): 248. doi: 10.1186/s12877-020-01644-2.
45. Looby S.E., Kantor A., Burdo T.H. et al. (2022) Factors Associated With Systemic Immune Activation Indices in a Global Primary Cardiovascular Disease Prevention Cohort of People With Human Immunodeficiency Virus on Antiretroviral Therapy. Clin. Infect. Dis., 75(8): 1324–1333. doi: 10.1093/cid/ciac166.
46. Stanislawski M.A., Lange L.A., Raffield L.M. et al.(2021) Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants. Arterioscler. Thromb. Vasc. Biol., 41(6): e369–e378. doi: 10.1161/ATVBAHA.121.316035.
47. Olson N.C., Koh I., Reiner A.P. et al. (2020) Soluble CD14, Ischemic Stroke, and Coronary Heart Disease Risk in a Prospective Study: The REGARDS Cohort. J. Am. Heart Assoc., 9(6): e014241. doi: 10.1161/JAHA.119.014241.
48. Reiner A.P., Lange E.M., Jenny N.S. et al. (2013) Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. Arterioscler. Thromb. Vasc. Biol., 33(1): 158–164. doi: 10.1161/ATVBAHA.112.300421.
49. Zhou T., Huang X., Ma J. et al. (2019) Association of plasma soluble CD14 level with asthma severity in adults: a case control study in China. Respir. Res., 20(1): 19. doi: 10.1186/s12931-019-0987-0.
50. Shitole S.G., Biggs M.L., Reiner A.P. et al. (2019) Soluble CD14 and CD14 Variants, Other Inflammatory Markers, and Glucose Dysregulation in Older Adults: The Cardiovascular Health Study. Diabetes Care, 42(11): 2075–2082. doi: 10.2337/dc19-0723.
51. Aune S.K., Byrkjeland R., Solheim S. et al. (2021) Gut related inflammation and cardiorespiratory fitness in patients with CAD and type 2 diabetes: a sub-study of a randomized controlled trial on exercise training. Diabetol. Metab. Syndr., 13(1): 36. doi: 10.1186/s13098-021-00655-2.
52. Vaez H., Najafi M., Toutounchi N.S. et al. (2016) Metformin Alleviates Lipopolysaccharide-induced Acute Lung Injury through Suppressing Toll-like Receptor 4 Signaling. Iran J. Allergy Asthma Immunol., 15(6): 498–507.
53. de Courten B., Moreno-Navarrete J.M., Lyons J. et al. (2016) Contrasting association of circulating sCD14 with insulin sensitivity in non-obese and morbidly obese subjects. Mol. Nutr. Food Res., 60(1): 103–109. doi: 10.1002/mnfr.201500102.

Clinical and pathogenetic features of the combination of asthma-COPD overlap and type 2 diabetes mellitus

References

Clinical and pathogenetic features of the combination of asthma-COPD overlap and type 2 diabetes mellitus