Comorbidities of COPD: Mechanisms and Treatment. Update 2023
Main Article Content
Abstract
Chronic obstructive pulmonary disease (COPD) is chronic disease that affects mostly the lungs but there is growing evidence that it is also a systemic condition associated with a number of accompanying diseases known as comorbidities. Chronic inflammation and oxidative stress are the highlight pathogenic processes that interrelate COPD and comorbidities with additional disease specific risk factors and mechanisms. Through complex interactions COPD increases the risk for certain comorbidities and they in turn have negative impact on health status and contribute to mortality in COPD patients. Treatment of comorbidities in terms of coexistence with COPD may require more specific personalized therapeutic approach. Here we review the pathogenic mechanisms which define COPD as a systemic disease; the most common comorbidities of COPD: cardiovascular disease, diabetes and metabolic syndrome, cachexia, osteoporosis, depression/anxiety and obstructive sleep apnea; the pathways which connect these diseases with COPD and the latest treatment approaches.
Keywords:
COPD, Comorbidities of COPD:
Article Details
How to Cite
STRATEV, Velin; FJELDSTAD, Odd-Magne.
Comorbidities of COPD: Mechanisms and Treatment. Update 2023.
Medical Research Archives, [S.l.], v. 11, n. 6, june 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3949>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i6.3949.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Accessed December 2022. https://goldcopd.org/ (2022).
2. World Health Organization (WHO). Accessed January 2023. https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd) (2023)
3. Kim-Dorner, SJ., Schmidt, T., Kuhlmann, A. et al. Age- and gender-based comorbidity categories in general practitioner and pulmonology patients with COPD. npj Prim. Care Respir. Med. 2022; 32:17.
4. Agusti A, Calverley P, Celli B, et al. Characterization of COPD heterogeneity in the ECLIPSE cohort. Respiratory Research 2010; 11: 122.
5. McGarvey LP, John M, Anderson JA, et al. Ascertainment of cause-specific mortality in COPD, operations of the TORCH Clinical Endpoint Committee. Thorax 2007; 62: 411-5.
6. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350: 2645-53.
7. Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet 2011; 378:1015-26.
8. Van Pottelberge GR, Bracke KR, Joos GF, et al. The role of dendritic cells in the pathogenesis of COPD: liaison officers in the front line. COPD 2009; 6:284-90.
9. Van Eeden SF, Sin DD. Chronic obstructive pulmonary disease: a chronic systemic inflammatory disease. Respiration 2008; 75:224-38.
10. Thomsen M, Dahl M, Lange P, et al. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 982-8.
11. Fogarty AW, Jones S, Britton JR, et al. Systemic inflammation and decline in lung function in a general population: a prospective study. Thorax 2007; 62:515-20.
12. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007; 29:527-34.
13. Bozinovski S, Hutchinson A, Thompson M, et al. Serum amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177:269-78.
14. Bowler RP, Barnes PJ, Crapo JD. The role of oxidative stress in chronic obstructive pulmonary disease. J COPD 2004; 2:255-77.
15. MacNee W. Oxidants. In: Chronic obstructive pulmonary disease. Edited by Robert Stockley et al. 2007 Blackwell Publishing Ltd.
16. Stratev V, Petev J, Galcheva S, Peneva M. Increasing oxidative stress and inflammation in patients with exacerbated chronic obstructive pulmonary disease (COPD) and their association with lung function. Eur Respir J 2012; vol. 40: Suppl. 56:P4595.
17. Morrison D, Rahman I, Lannan S, et al. Epithelial permeability, inflammation and oxidant stress in the airspaces of smokers. Am J Respir Crit Care Med 1999; 159:473-9.
18. Tuder RM, Zhen L, Cho CY et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 2003; 29:88-97.
19. Terashima T, Klut ME, English D et al. Cigarette smoking causes sequestration of polymorphonuclear leukocytes released from the bone marrow in lung micro-vessels. Am J Respir Cell Mol Biol 1999; 20:171-7.
20. Tsukagoshi H, Kawata T, Shimizu Y, et al. 4-Hydroxy-2-nonenal enhances fibronectin production by IMR-90 human lung fibroblast party via activation of epidermal growth factor receptor-linked extracellular signal-regulated kinase p44 =42 pathway. Toxicol Appl Pharmacol 2002; 184:127-35.
21. Agusti AG, Sauleda J, Miralles C, et al. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:485-9.
22. Stratev V, Dimitrova V, Petkova D. COPD and Comorbidities: Relating Mechanisms and Treatment. Curr Resp Med Rev 2019; 15:90-101(12)
23. Drakopoulou M, Toutouzas K, Michelongona A, et al. Vulnerable plaque and inflammation: potential clinical strategies. Curr Pharm Des. 2011; 17:4190–209.
24. Linden F, Domschke G, Erbel C, et al. Inflammatory therapeutic targets in coronary atherosclerosis-from molecular biology to clinical application. Front Physiol. 2014; 5:455.
25. Libby, P. Inflammation in atherosclerosis. Nature. 2002; 420:868–74.
26. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013; 62:263–71.
27. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol. 2010; 7:77–86.
28. Li X-F, Wan C-Q and Mao Y-M (2022) Analysis of pathogenesis and drug treatment of chronic obstructive pulmonary disease complicated with cardiovascular disease. Front. Med. 9:979959. doi: 10.3389/fmed.2022.979959.
29. Chan SMH, Selemidis S, Bozinovski S, et al. Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies. Pharmacol Ther. 2019; 198:160–88.
30. Karnati S, Seimetz M, Kleefeldt F, et al. Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target. Front. Cardiovasc. Med. 2021; 8:649512.
31. Harris B, Klein R, Jerosch-Herold M, Hoffman EA, Ahmed FS, Jacobs DR, et al. The association of systemic microvascular changes with lung function and lung density: a cross-sectional study. PLoS ONE. (2012) 7:e50224.
32. Kyomoto Y, Kanazawa H, Tochino Y, Watanabe T, Asai K, Kawaguchi T. Possible role of airway microvascular permeability on airway obstruction in patients with chronic obstructive pulmonary disease. Respir Med. 2019; 146:137–41.
33. Heijink IH, Noordhoek JA, Timens W et al. Abnormalities in airway epithelial junction formation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 189:1439–42.
34. Kim BG, Lee PH, Lee SH, Baek AR, Park JS, Lee J, et al. Impact of the endothelial tight junction protein claudin-5 on clinical profiles of patients with COPD. Allergy, Immunol Res. 2018; 10:533-542.
35. Bernardi E, Merlo C, Cogo A. Endothelial function in COPD is in an intermediate position between healthy subjects and coronary artery disease patients and is related to physical activity. Lung. 2018; 196:669–72.
36. Arunachalam G, Sundar IK, Hwang JW, Yao H, Rahman I. Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD. J Inflamm. 2010; 7:34.
37. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart. 2016; 37:2129–200.
38. Jabbour A, Macdonald PS, Keogh AM, Kotlyar E, Mellemkjaer S, Coleman CF, et al. Differences between beta-blockers in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized crossover trial. J Am Coll Cardiol. 2010; 55:1780–7.
39. Kubota Y, Tay WT, Teng TK, Asai K, Noda T, Kusano K, et al. Impact of beta-blocker use on the long-term outcomes of heart failure patients with chronic obstructive pulmonary disease. ESC Heart Fail. 2021; 8:3791–9.
40. Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL. Association of b-blocker use with survival and pulmonary function in patients with chronic obstructive pulmonary and cardiovascular disease: a systematic review and metaanalysis. Eur Heart J. 2020; 41:4415–22.
41. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMGCoA reductase. Science. 2001; 292:1160–4.
42. Tousoulis D, Psarros C, Demosthenous M, Patel R, Antoniades C, Stefanadis C. Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins. J Am Coll Cardiol. 2014; 63:2491–502.
43. Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev. 2009; 18:222–32.
44. Schenk P, Spiel AO, Hüttinger F, Gmeiner M, Fugger J, Pichler M, et al. Can simvastatin reduce COPD exacerbations? A randomised double-blind controlled study. Eur Respir J. 2021; 58:2001798.
45. Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014; 370:2201–10.
46. Kim J-H, Choi HG, Kwon MJ, Kim JH, Park J-Y, Hwang YI, Jang SH and Jung K-S (2022) The Influence of Prior Statin Use on the Prevalence and Exacerbation of Chronic Obstructive Pulmonary Disease in an Adult Population. Front. Med. 9:842948. doi: 10.3389/fmed.2022.842948.
47. Wu WT, Chen C-Y. Protective effect of statins on pulmonary hypertension in chronic obstructive pulmonary disease patients: a nationwide retrospective, matched cohort study. Sci Rep. 2020; 10:3104.
48. Parikh MA, Aaron CP, Hoffman EA, Schwartz JE, Madrigano J, Austin JHM, et al. Angiotensin-converting inhibitors and angiotensin II receptor blockers and longitudinal change in percent emphysema on computed tomography. The MultiEthnic Study of Atherosclerosis lung study. Ann Am Thorac Soc. 2017; 14:649–58.
49. Chandy D, Aronow WS, Banach M. Current perspectives on treatment of hypertensive patients with chronic obstructive pulmonary disease. Integr Blood Press Control. 2013; 6:101–9.
50. Lai CC, Wang YH, Wang CY, Wang HC, Yu CJ, Chen L. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2018; 13:867–74.
51. Cazzola, M.; Bettoncelli, G.; Sessa, E.; Cricelli, C.; Biscione, G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration 2010; 80:112–119.
52. Ho, T.W.; Huang, C.T.; Ruan, S.Y.; Tsai, Y.J.; Lai, F.; Yu, C.J. Diabetes mellitus in patients with chronic obstructive pulmonary disease-The impact on mortality. PLoS ONE 2017; 12, e0175794.
53. Rana, J.S.; Mittleman, M.A.; Sheikh, J.; Hu, F.B.; Manson, J.E.; Colditz, G.A.; Speizer, F.E.; Barr, R.G.; Camargo, C.A., Jr. Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care 2004; 27:2478–2484.
54. Park, S.S.; Perez Perez, J.L.; Perez Gandara, B.; Agudelo, C.W.; Rodriguez Ortega, R.; Ahmed, H.; Garcia-Arcos, I.; McCarthy, C.; Geraghty, P. Mechanisms Linking COPD to Type 1 and 2 Diabetes Mellitus: Is There a Relationship between Diabetes and COPD? Medicina 2022; 58:1030.
55. Van den Borst, B.; Gosker, H.R.; Koster, A.; Yu, B.; Kritchevsky, S.B.; Liu, Y.; Meibohm, B.; Rice, T.B.; Shlipak, M.; Yende, S.; et al. The influence of abdominal visceral fat on inflammatory pathways and mortality risk in obstructive lung disease. Am. J. Clin. Nutr. 2012; 96:516–526.
56. Vozoris, N.T.; O’Donnell, D.E. Prevalence, risk factors, activity limitation and health care utilization of an obese, population-based sample with chronic obstructive pulmonary disease. Can. Respir. J. 2012; 19:732618.
57. Van den Borst, B.; Gosker, H.R.; Wesseling, G.; de Jager, W.; Hellwig, V.A.; Snepvangers, F.J.; Schols, A.M. Low-grade adipose tissue inflammation in patients with mild-to-moderate chronic obstructive pulmonary disease. Am. J. Clin. Nutr. 2011; 94:1504–1512.
58. Yoon, H.I.; Li, Y.; Man, S.F.P.; Tashkin, D.; Wise, R.A.; Connett, J.E.; Anthonisen, N.A.; Churg, A.; Wright, J.L.; Sin, D.D. The complex relationship of serum adiponectin to COPD outcomes COPD and adiponectin. Chest 2012; 142:893–899.
59. Rains, J.L.; Jain, S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med. 2011; 50:567–575.
60. 125. Evans, J.L.; Goldfine, I.D.; Maddux, B.A.; Grodsky, G.M. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003; 52:1–8.
61. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006 23: 469-480.
62. Wei W, Kim Y, Boudreau N. Association of smoking with serum and dietary levels of antioxidants in adults: NHANES III, 1988-1994. Am J Public Health, 2001; 91:258-264.
63. Lam, K.B.; Jordan, R.E.; Jiang, C.Q.; Thomas, G.N.; Miller, M.R.; Zhang, W.S.; Lam, T.H.; Cheng, K.K.; Adab, P. Airflow obstruction and metabolic syndrome: The Guangzhou Biobank Cohort Study. Eur. Respir. J. 2010; 35:317–323.
64. 30. Watz, H.; Waschki, B.; Kirsten, A.; Müller, K.C.; Kretschmar, G.; Meyer, T.; Holz, O.; Magnussen, H. The metabolic syndrome in patients with chronic bronchitis and COPD: Frequency and associated consequences for systemic inflammation and physical inactivity. Chest 2009; 136:1039–1046.
65. Vujic, T.; Nagorni, O.; Maric, G.; Popovic, L.; Jankovic, J. Metabolic syndrome in patients with chronic obstructive pulmonary disease: Frequency and relationship with systemic inflammation. Hippokratia 2016; 20:110–114.
66. Breyer, M.K.; Spruit, M.A.; Hanson, C.K.; Franssen, F.M.; Vanfleteren, L.E.; Groenen, M.T.; Bruijnzeel, P.L.; Wouters, E.F.; Rutten, E.P. Prevalence of metabolic syndrome in COPD patients and its consequences. PLoS ONE 2014; 9, e98013.
67. Piazzolla, G.; Castrovilli, A.; Liotino, V.; Vulpi, M.R.; Fanelli, M.; Mazzocca, A.; Candigliota, M.; Berardi, E.; Resta, O.; Sabbà, C.; et al. Metabolic syndrome and Chronic Obstructive Pulmonary Disease (COPD): The interplay among smoking, insulin resistance and vitamin D. PLoS ONE 2017; 12, e0186708.
68. Maruthur, N.M.; Tseng, E.; Hutfless, S.; Wilson, L.M.; Suarez-Cuervo, C.; Berger, Z.; Chu, Y.; Iyoha, E.; Segal, J.B.; Bolen, S. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann. Intern. Med. 2016; 164:740–751.
69. Zhu, A.; Teng, Y.; Ge, D.; Zhang, X.; Hu, M.; Yao, X. Role of metformin in treatment of patients with chronic obstructive pulmonary disease: A systematic review. J. Thorac. Dis. 2019; 11:4371–4378.
70. Sexton, P.; Metcalf, P.; Kolbe, J. Respiratory effects of insulin sensitisation with metformin: A prospective observational study. COPD 2014; 11:133–142.
71. Yen, F.S.; Wei, J.C.; Yang, Y.C.; Hsu, C.C.; Hwu, C.M. Respiratory outcomes of metformin use in patients with type 2 diabetes and chronic obstructive pulmonary disease. Sci. Rep. 2020; 10:10298.
72. Polverino, F.; Wu, T.D.; Rojas-Quintero, J.; Wang, X.; Mayo, J.; Tomchaney, M.; Tram, J.; Packard, S.; Zhang, D.; Cleveland, K.H.; et al. Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment. Am. J. Respir. Crit. Care Med. 2021; 204:651–666.
73. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis. 1989; 139(6):1435–1438.
74. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr. 2005; 82(1):53–59.
75. McDonald MN, Wouters EFM, Rutten E, et al. It’s more than low BMI: prevalence of cachexia and associated mortality in COPD. Respir Res.2019; 20(1):100.
76. Kwan HY, Maddocks M, Nolan CM, et al. The prognostic significance of weight loss in chronic obstructive pulmonary disease-related cachexia: a prospective cohort study. J Cachexia Sarcopenia Muscle. 2019; 10(6):1330–1338.
77. Puig-Vilanova E, Rodriguez DA, Lloreta J, et al. Oxidative stress, redox signaling pathways, and autophagy in cachectic muscles of male patients with advanced COPD and lung cancer. Free Radic Biol Med. 2015; 79:91–108.
78. Sanders KJC, Kneppers AEM, van de Bool C, Langen RCJ, Schols AM. Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective. J Cachexia Sarcopenia Muscle. 2016; 7(1):5–22.
79. Brusik M, Ukropec J, Joppa P, et al. Circulatory and adipose tissue leptin and adiponectin in relationship to resting energy expenditure in patients with chronic obstructive pulmonary disease. Physiol Res. 2012; 61(5):469–480.
80. Mokari-Yamchi A, Sharifi A, Kheirouri S. Increased serum levels of S100A1, ZAG, and adiponectin in cachectic patients with COPD. Int J Chron Obstruct Pulmon Dis. 2018; 13:3157–3163.
81. Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012; 12:CD000998.
82. van Beers M, Rutten-van Mölken M, van de Bool C, et al. Clinical outcome and cost-effectiveness of a 1-year nutritional intervention programme in COPD patients with low muscle mass: the randomized controlled NUTRAIN trial. Clin Nutr. 2020; 39:405–413.
83. van Wetering CR, Hoogendoorn M, Broekhuizen R, et al. Efficacy and costs of nutritional rehabilitation in muscle-wasted patients with chronic obstructive pulmonary disease in a community-based setting: a prespecified subgroup analysis of the INTERCOM trial. J Am Med Dir Assoc. 2010; 11:179–187.
84. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013; 188:e13–64.
85. Kneppers AEM, Haast RAM, Langen RCJ, et al. Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis. J Cachexia Sarcopenia Muscle. 2019; 10:311–322.
86. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 189:e15–e62.
87. Garcia JM, Boccia RV, Graham CD, et al. Anamorelin for patients with cancer cachexia: an integrated analysis of two Phase 2, randomised, placebo-controlled, double-blind trials. Lancet Oncol. 2015; 16:108–116.
88. 173. Currow DC, Abernethy AP. Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. Future Oncol. 2014; 10:789–802.
89. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 189:e15–e62.
90. Weisberg J, Wanger J, Olson J, et al. Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest. 2002; 121:1070–1078.
91. Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and osteoporosis. Chest. 2011; 139:648-657.
92. Sözen T, Özıs¸ık L, Bas¸aran N. An overview and management of osteoporosis. Eur J Rheumatol. 2017;4(1):46-56. Chen Y, Ramsook A, Coxson H, Bon J, Reid W. Prevalence and risk factors for osteoporosis in individuals with COPD: a systematic review and meta-analysis. Chest. 2019; 156:1092-1110.
93. Law M, Hackshaw A. A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ (Clin Res Ed). 1997; 315:841-846.
94. Marinucci L, Balloni S, Fettucciari K, Bodo M, Talesa VN, Antognelli C. Nicotine induces apoptosis in human osteoblasts via a novel mechanism driven by H(2)O(2) and entailing glyoxalase 1-dependent MG-H1 accumulation leading to TG2-mediated NF-kB desensitization: implication for smokersrelated osteoporosis. Free Radic Biol Med. 2018; 117:6-17.
95. Papakitsou E, Margioris A, Dretakis K, et al. Body mass index (BMI) and parameters of bone formation and resorption in postmenopausal women. Maturitas. 2004; 47:185-193.
96. Santos L, Elliott-Sale KJ, Sale C. Exercise and bone health across the lifespan. Biogerontology. 2017; 18:931-946.
97. Yuan Y, Chen X, Zhang L, et al. The roles of exercise in bone remodeling and in prevention and treatment of osteoporosis. Prog Biophys Mol Biol. 2016; 122:122-130.
98. Lee SH, Kwon HY. Prevalence of osteoporosis in Korean patients with chronic obstructive pulmonary disease and their health-related quality of life according to the Korea National Health and Nutrition Examination Survey 2008-2011. J Bone Metab. 2017; 24:241-248.
99. Kim SW, Lee JM, Ha JH, et al. Association between vitamin D receptor polymorphisms and osteoporosis in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015; 10:1809-1817.
100. Lin CW, Chen YY, Chen YJ, Liang CY, Lin MS, Chen W. Prevalence, risk factors, and health-related quality of life of osteoporosis in patients with COPD at a community hospital in Taiwan. Int J Chron Obstruct Pulmon Dis. 2015; 10:1493-1500.
101. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet (London, England). 2007; 370:797-799.
102. Xiong Z, Leme AS, Ray P, Shapiro SD, Lee JS. CX3CR1+ lung mononuclear phagocytes spatially confined to the interstitium produce TNF-α and IL-6 and promote cigarette smoke-induced emphysema. J Immunol (Baltimore, Md: 1950). 2011; 186: 3206-3214.
103. Chen K, Pociask DA, McAleer JP, et al. IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke. PLoS ONE. 2011; 6: e20333.
104. Liang B, Feng Y. The association of low bone mineral density with systemic inflammation in clinically stable COPD. Endocrine. 2012; 42:190-195.
105. Vitenberga Z, Pilmane M, Babjoniševa A. The evaluation of inflammatory, anti-inflammatory and regulatory factors contributing to the pathogenesis of COPD in airways. Pathol Res Pract. 2019; 215:97-105.
106. Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018; 61:7-16.
107. Amiche MA, Albaum JM, Tadrous M, et al. Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials. Osteoporos Int. 2016; 27:1709-1718.
108. Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 2011; 66: 699-708.
109. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:1911-1930.
110. Janssens W, Bouillon R, Claes B, et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax. 2010; 65:215-220.
111. Kokturk N, Baha A, Oh YM, Young Ju J, Jones PW. Vitamin D deficiency: what does it mean for chronic obstructive pulmonary disease (COPD)? A comprehensive review for pulmonologists. Clin Respir J. 2018; 12:382-397.
112. Graat-Verboom L, Smeenk FW, van den Borne BE, et al. Progression of osteoporosis in patients with COPD: a 3-year follow up study. Respir Med. 2012; 106:861-870.
113. International Osteoporosis Foundation (IOF). Exercise Recommendations of Bone Health. Available online: https://www.osteoporosis.foundation/healthprofessionals/prevention/exercise (accessed on 10 April 2023).
114. Thorpe, O.; Kumar, S.; Johnston, K. Barriers to and enablers of physical activity in patients with COPD following a hospital admission: A qualitative study. Int. J. Chronic Obstr. Pulm. Dis. 2014; 9: 115.
115. Walawska-Hrycek, A.; Galus, W.; Hrycek, E.; Kaczmarczyk, A.; Krzystanek, E. The impact of vitamin D low doses on its serum level and cytokine profile in multiple sclerosis patients. J. Clin. Med. 2021; 10: 2781.
116. Dawson-Hughes, B.; Mithal, A.; Bonjour, J.P.; Boonen, S.; Burckhardt, P.; Fuleihan, G.E.; Josse, R.G.; Lips, P.; Morales-Torres, J.; Yoshimura, N. IOF position statement: Vitamin D recommendations for older adults. Osteoporos. Int. 2010; 21:1151–1154.
117. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for prevention of falls and their consequences. J. Am. Geriatr. Soc. 2014; 62:147–152.
118. Rafiq, R.; Prins, H.J.; Boersma, W.G.; Daniels, J.M.; den Heijer, M.; Lips, P.; de Jongh, R.T. Effects of daily vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients: A pilot trial. Int. J. Chronic Obstr. Pulm. Dis. 2017; 12:2583–2592.
119. Calafiore, D.; Fortunato, L.; Migliario, M. Vitamin D for clinical diseases in women: An indispensable factor in medicine and dentistry. J. Clin. Med. 2022; 11:3104.
120. Fujieda, Y.; Horita, T.; Nishimoto, N.; Tanimura, K.; Amasaki, Y.; Kasahara, H.; Furukawa, S.; Takeda, T.; Fukaya, S.; Matsui, K.; et al. Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial. Mod. Rheumatol. 2021; 31:593–599.
121. Invernizzi, M.; Cisari, C.; Carda, S. The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment. Aging Clin. Exp. Res. 2015; 27:107–113.
122. Inoue, D.; Watanabe, R.; Okazaki, R. COPD and osteoporosis: Links, risks, and treatment challenges. Int. J. Chronic Obstr. Pulm. Dis. 2016; 11:637–648.
123. Nuti, R.; Brandi, M.L.; Checchia, G.; Di Munno, O.; Dominguez, L.; Falaschi, P.; Fiore, C.E.; Iolascon, G.; Maggi, S.; Michieli, R.; et al. Guidelines for the management of osteoporosis and fragility fractures. Intern. Emerg. Med. 2019; 14:85–102.
124. Yohannes AM and and George S Alexopoulos. Depression and anxiety in patients with COPD. Eur Respir Rev. 2014 September; 23: 345-349.
125. Pumar, M.I.; Gray, C.R.; Walsh, J.R.; Yang, I.A.; Rolls, T.A.; Ward, D.L. Anxiety and depression-Important psychological comorbidities of COPD. J. Thorac. Dis. 2014; 6:1615–1631.
126. Van Manen, J.G.; Bindels, P.J.; Dekker, F.W.; CJ, I.J.; van der Zee, J.S.; Schadé, E. Risk of depression in patients with chronic obstructive pulmonary disease and its determinants. Thorax 2002; 57:412–416.
127. Van Manen, J.G.; Bindels, P.J.; Dekker, F.W.; CJ, I.J.; van der Zee, J.S.; Schadé, E. Risk of depression in patients with chronic obstructive pulmonary disease and its determinants. Thorax 2002; 57:412–416.
128. Norwood R. Prevalence and impact of depression in chronic obstructive pulmonary disease patients. Curr Opin Pulm Med 2006; 12: 113-117.
129. Yohannes, A.M.; Kaplan, A.; Hanania, N.A. Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management. Cleve. Clin. J. Med. 2018; 85 (Suppl. S1), S11–S18.
130. National Institute for Health and Clinical Excellence. CG91 Depression with a Chronic Physical Health Problem: NICE Guideline. London, UK: National Collaborating Centre for Mental Health; 2009. Available from: https://www.nice.org.uk/guidance/cg91. [accessed 2023 March 20].
131. Kunik, M.E.; Braun, U.; Stanley, M.A.; Wristers, K.; Molinari, V.; Stoebner, D.; Orengo, C.A. One session cognitive behavioural therapy for elderly patients with chronic obstructive pulmonary disease. Psychol. Med. 2001; 31:717–723.
132. Ma, R.C.; Yin, Y.Y.; Wang, Y.Q.; Liu, X.; Xie, J. Effectiveness of cognitive behavioural therapy for chronic obstructive pulmonary disease patients: A systematic review and meta-analysis. Complement. Ther. Clin. Pract. 2020; 38:101071.
133. Pollok, J.; van Agteren, J.E.; Carson-Chahhoud, K.V. Pharmacological interventions for the treatment of depression in chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2018; 12, Cd012346.
134. Tselebis А, Pachi А, Ilias I, et al. Strategies to improve anxiety and depression in patients with COPD: A mental health perspective. Neuropsychiatr Dis Treat 2016; 12:297-328.
135. Fritzsche, A.; Clamor, A.; von Leupoldt, A. Effects of medical and psychological treatment of depression in patients with COPD—A review. Respir. Med. 2011; 105:1422–1433.
136. Vozoris, N.T.; Wang, X.; Austin, P.C.; Stephenson, A.L.; O’Donnell, D.E.; Gershon, A.S.; Gill, S.S.; Rochon, P.A. Serotonergic antidepressant use and morbidity and mortality among older adults with COPD. Eur. Respir. J. 2018; 52, 1800475.
137. Edwards, B.A.; Eckert, D.J.; Jordan, A.S. Obstructive sleep apnoea pathogenesis from mild to severe: Is it all the same? Respirology 2017; 22:33–42.
138. Lyons, M.M.; Bhatt, N.Y.; Pack, A.I.; Magalang, U.J. Global burden of sleep-disordered breathing and its implications. Respirology 2020; 25:690–702.
139. Malhotra, A.; Schwartz, A.R.; Schneider, H.; Owens, R.L.; Deyoung, P.; Han, M.K.; Wedzicha, J.A.; Hansel, N.N.; Zeidler, M.R.; Wilson, K.C.; et al. Research Priorities in Pathophysiology for Sleep-disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Research Statement. Am. J. Respir. Crit. Care Med. 2018; 197:289–299.
140. McNicholas WT. COPD-OSA Overlap Syndrome: Evolving Evidence Regarding Epidemiology, Clinical Consequences, and Management. Chest. 2017 Dec; 152(6):1318-1326.
141. Owens RL, Macrea M and Teodorescu M. The overlaps of asthma or COPD with OSA: A focused review. Respirology 2017; 22: 1073-1083.
142. Krachman, S.L.; Tiwari, R.; Vega, M.E.; Yu, D.; Soler, X.; Jaffe, F.; Kim, V.; Swift, I.; D’Alonzo, G.E.; Criner, G.J. Effect of Emphysema Severity on the Apnea–Hypopnea Index in Smokers with Obstructive Sleep Apnea. Ann. Am. Thorac. Soc. 2016; 13:1129–1135.
143. Adler, D.; Bailly, S.; Benmerad, M.; Joyeux-Faure, M.; Jullian-Desayes, I.; Soccal, P.M.; Janssens, J.P.; Sapène, M.; Grillet, Y.; Stach, B.; et al. Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 2020, 15, e0235331.
144. Kendzerska, T.; Leung, R.S.; Aaron, S.D.; Ayas, N.; Sandoz, J.S.; Gershon, A.S. Cardiovascular Outcomes and All-Cause Mortality in Patients with Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease (Overlap Syndrome). Ann. Am. Thorac. Soc. 2019; 16:71–81.
145. Ganga, H.V.; Nair, S.U.; Puppala, V.K.; Miller, W.L. Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: A retrospective cohort study. J. Geriatr. Cardiol. 2013; 10:129–134.
146. Toraldo, D.M.; De Nuccio, F.; Nicolardi, G. Fixed-pressure nCPAP in patients with obstructive sleep apnea (OSA) syndrome and chronic obstructive pulmonary disease (COPD): A 24-month follow-up study. Sleep Breath. 2010; 14:115–123.
147. Stanchina, M.L.; Welicky, L.M.; Donat, W.; Lee, D.; Corrao, W.; Malhotra, A. Impact of CPAP Use and Age on Mortality in Patients with Combined COPD and Obstructive Sleep Apnea: The Overlap Syndrome. J. Clin. Sleep Med. 2013; 9:767–772.
148. Zheng, M.Y.; Yee, M.B.J.; Wong, M.K.; Grunstein, M.R.; Piper, B.A. A pilot randomized trial comparing CPAP vs bilevel PAP spontaneous mode in the treatment of hypoventilation disorder in patients with obesity and obstructive airway disease. J. Clin. Sleep Med. 2022; 18: 99–107.
149. Tavares LP, Galvão I, Ferrero MR. Novel Immunomodulatory Therapies for Respiratory Pathologies. Comprehensive Pharmacology. 2022:554–94. doi: 10.1016/B978-0-12-820472-6.00073-6. Epub 2022 Jun 9. PMCID: PMC8238403.
2. World Health Organization (WHO). Accessed January 2023. https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd) (2023)
3. Kim-Dorner, SJ., Schmidt, T., Kuhlmann, A. et al. Age- and gender-based comorbidity categories in general practitioner and pulmonology patients with COPD. npj Prim. Care Respir. Med. 2022; 32:17.
4. Agusti A, Calverley P, Celli B, et al. Characterization of COPD heterogeneity in the ECLIPSE cohort. Respiratory Research 2010; 11: 122.
5. McGarvey LP, John M, Anderson JA, et al. Ascertainment of cause-specific mortality in COPD, operations of the TORCH Clinical Endpoint Committee. Thorax 2007; 62: 411-5.
6. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004; 350: 2645-53.
7. Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet 2011; 378:1015-26.
8. Van Pottelberge GR, Bracke KR, Joos GF, et al. The role of dendritic cells in the pathogenesis of COPD: liaison officers in the front line. COPD 2009; 6:284-90.
9. Van Eeden SF, Sin DD. Chronic obstructive pulmonary disease: a chronic systemic inflammatory disease. Respiration 2008; 75:224-38.
10. Thomsen M, Dahl M, Lange P, et al. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 982-8.
11. Fogarty AW, Jones S, Britton JR, et al. Systemic inflammation and decline in lung function in a general population: a prospective study. Thorax 2007; 62:515-20.
12. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007; 29:527-34.
13. Bozinovski S, Hutchinson A, Thompson M, et al. Serum amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177:269-78.
14. Bowler RP, Barnes PJ, Crapo JD. The role of oxidative stress in chronic obstructive pulmonary disease. J COPD 2004; 2:255-77.
15. MacNee W. Oxidants. In: Chronic obstructive pulmonary disease. Edited by Robert Stockley et al. 2007 Blackwell Publishing Ltd.
16. Stratev V, Petev J, Galcheva S, Peneva M. Increasing oxidative stress and inflammation in patients with exacerbated chronic obstructive pulmonary disease (COPD) and their association with lung function. Eur Respir J 2012; vol. 40: Suppl. 56:P4595.
17. Morrison D, Rahman I, Lannan S, et al. Epithelial permeability, inflammation and oxidant stress in the airspaces of smokers. Am J Respir Crit Care Med 1999; 159:473-9.
18. Tuder RM, Zhen L, Cho CY et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am J Respir Cell Mol Biol 2003; 29:88-97.
19. Terashima T, Klut ME, English D et al. Cigarette smoking causes sequestration of polymorphonuclear leukocytes released from the bone marrow in lung micro-vessels. Am J Respir Cell Mol Biol 1999; 20:171-7.
20. Tsukagoshi H, Kawata T, Shimizu Y, et al. 4-Hydroxy-2-nonenal enhances fibronectin production by IMR-90 human lung fibroblast party via activation of epidermal growth factor receptor-linked extracellular signal-regulated kinase p44 =42 pathway. Toxicol Appl Pharmacol 2002; 184:127-35.
21. Agusti AG, Sauleda J, Miralles C, et al. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 166:485-9.
22. Stratev V, Dimitrova V, Petkova D. COPD and Comorbidities: Relating Mechanisms and Treatment. Curr Resp Med Rev 2019; 15:90-101(12)
23. Drakopoulou M, Toutouzas K, Michelongona A, et al. Vulnerable plaque and inflammation: potential clinical strategies. Curr Pharm Des. 2011; 17:4190–209.
24. Linden F, Domschke G, Erbel C, et al. Inflammatory therapeutic targets in coronary atherosclerosis-from molecular biology to clinical application. Front Physiol. 2014; 5:455.
25. Libby, P. Inflammation in atherosclerosis. Nature. 2002; 420:868–74.
26. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013; 62:263–71.
27. Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol. 2010; 7:77–86.
28. Li X-F, Wan C-Q and Mao Y-M (2022) Analysis of pathogenesis and drug treatment of chronic obstructive pulmonary disease complicated with cardiovascular disease. Front. Med. 9:979959. doi: 10.3389/fmed.2022.979959.
29. Chan SMH, Selemidis S, Bozinovski S, et al. Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies. Pharmacol Ther. 2019; 198:160–88.
30. Karnati S, Seimetz M, Kleefeldt F, et al. Chronic Obstructive Pulmonary Disease and the Cardiovascular System: Vascular Repair and Regeneration as a Therapeutic Target. Front. Cardiovasc. Med. 2021; 8:649512.
31. Harris B, Klein R, Jerosch-Herold M, Hoffman EA, Ahmed FS, Jacobs DR, et al. The association of systemic microvascular changes with lung function and lung density: a cross-sectional study. PLoS ONE. (2012) 7:e50224.
32. Kyomoto Y, Kanazawa H, Tochino Y, Watanabe T, Asai K, Kawaguchi T. Possible role of airway microvascular permeability on airway obstruction in patients with chronic obstructive pulmonary disease. Respir Med. 2019; 146:137–41.
33. Heijink IH, Noordhoek JA, Timens W et al. Abnormalities in airway epithelial junction formation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 189:1439–42.
34. Kim BG, Lee PH, Lee SH, Baek AR, Park JS, Lee J, et al. Impact of the endothelial tight junction protein claudin-5 on clinical profiles of patients with COPD. Allergy, Immunol Res. 2018; 10:533-542.
35. Bernardi E, Merlo C, Cogo A. Endothelial function in COPD is in an intermediate position between healthy subjects and coronary artery disease patients and is related to physical activity. Lung. 2018; 196:669–72.
36. Arunachalam G, Sundar IK, Hwang JW, Yao H, Rahman I. Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD. J Inflamm. 2010; 7:34.
37. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart. 2016; 37:2129–200.
38. Jabbour A, Macdonald PS, Keogh AM, Kotlyar E, Mellemkjaer S, Coleman CF, et al. Differences between beta-blockers in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized crossover trial. J Am Coll Cardiol. 2010; 55:1780–7.
39. Kubota Y, Tay WT, Teng TK, Asai K, Noda T, Kusano K, et al. Impact of beta-blocker use on the long-term outcomes of heart failure patients with chronic obstructive pulmonary disease. ESC Heart Fail. 2021; 8:3791–9.
40. Yang YL, Xiang ZJ, Yang JH, Wang WJ, Xu ZC, Xiang RL. Association of b-blocker use with survival and pulmonary function in patients with chronic obstructive pulmonary and cardiovascular disease: a systematic review and metaanalysis. Eur Heart J. 2020; 41:4415–22.
41. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMGCoA reductase. Science. 2001; 292:1160–4.
42. Tousoulis D, Psarros C, Demosthenous M, Patel R, Antoniades C, Stefanadis C. Innate and adaptive inflammation as a therapeutic target in vascular disease: the emerging role of statins. J Am Coll Cardiol. 2014; 63:2491–502.
43. Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev. 2009; 18:222–32.
44. Schenk P, Spiel AO, Hüttinger F, Gmeiner M, Fugger J, Pichler M, et al. Can simvastatin reduce COPD exacerbations? A randomised double-blind controlled study. Eur Respir J. 2021; 58:2001798.
45. Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014; 370:2201–10.
46. Kim J-H, Choi HG, Kwon MJ, Kim JH, Park J-Y, Hwang YI, Jang SH and Jung K-S (2022) The Influence of Prior Statin Use on the Prevalence and Exacerbation of Chronic Obstructive Pulmonary Disease in an Adult Population. Front. Med. 9:842948. doi: 10.3389/fmed.2022.842948.
47. Wu WT, Chen C-Y. Protective effect of statins on pulmonary hypertension in chronic obstructive pulmonary disease patients: a nationwide retrospective, matched cohort study. Sci Rep. 2020; 10:3104.
48. Parikh MA, Aaron CP, Hoffman EA, Schwartz JE, Madrigano J, Austin JHM, et al. Angiotensin-converting inhibitors and angiotensin II receptor blockers and longitudinal change in percent emphysema on computed tomography. The MultiEthnic Study of Atherosclerosis lung study. Ann Am Thorac Soc. 2017; 14:649–58.
49. Chandy D, Aronow WS, Banach M. Current perspectives on treatment of hypertensive patients with chronic obstructive pulmonary disease. Integr Blood Press Control. 2013; 6:101–9.
50. Lai CC, Wang YH, Wang CY, Wang HC, Yu CJ, Chen L. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2018; 13:867–74.
51. Cazzola, M.; Bettoncelli, G.; Sessa, E.; Cricelli, C.; Biscione, G. Prevalence of comorbidities in patients with chronic obstructive pulmonary disease. Respiration 2010; 80:112–119.
52. Ho, T.W.; Huang, C.T.; Ruan, S.Y.; Tsai, Y.J.; Lai, F.; Yu, C.J. Diabetes mellitus in patients with chronic obstructive pulmonary disease-The impact on mortality. PLoS ONE 2017; 12, e0175794.
53. Rana, J.S.; Mittleman, M.A.; Sheikh, J.; Hu, F.B.; Manson, J.E.; Colditz, G.A.; Speizer, F.E.; Barr, R.G.; Camargo, C.A., Jr. Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care 2004; 27:2478–2484.
54. Park, S.S.; Perez Perez, J.L.; Perez Gandara, B.; Agudelo, C.W.; Rodriguez Ortega, R.; Ahmed, H.; Garcia-Arcos, I.; McCarthy, C.; Geraghty, P. Mechanisms Linking COPD to Type 1 and 2 Diabetes Mellitus: Is There a Relationship between Diabetes and COPD? Medicina 2022; 58:1030.
55. Van den Borst, B.; Gosker, H.R.; Koster, A.; Yu, B.; Kritchevsky, S.B.; Liu, Y.; Meibohm, B.; Rice, T.B.; Shlipak, M.; Yende, S.; et al. The influence of abdominal visceral fat on inflammatory pathways and mortality risk in obstructive lung disease. Am. J. Clin. Nutr. 2012; 96:516–526.
56. Vozoris, N.T.; O’Donnell, D.E. Prevalence, risk factors, activity limitation and health care utilization of an obese, population-based sample with chronic obstructive pulmonary disease. Can. Respir. J. 2012; 19:732618.
57. Van den Borst, B.; Gosker, H.R.; Wesseling, G.; de Jager, W.; Hellwig, V.A.; Snepvangers, F.J.; Schols, A.M. Low-grade adipose tissue inflammation in patients with mild-to-moderate chronic obstructive pulmonary disease. Am. J. Clin. Nutr. 2011; 94:1504–1512.
58. Yoon, H.I.; Li, Y.; Man, S.F.P.; Tashkin, D.; Wise, R.A.; Connett, J.E.; Anthonisen, N.A.; Churg, A.; Wright, J.L.; Sin, D.D. The complex relationship of serum adiponectin to COPD outcomes COPD and adiponectin. Chest 2012; 142:893–899.
59. Rains, J.L.; Jain, S.K. Oxidative stress, insulin signaling, and diabetes. Free Radic. Biol. Med. 2011; 50:567–575.
60. 125. Evans, J.L.; Goldfine, I.D.; Maddux, B.A.; Grodsky, G.M. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003; 52:1–8.
61. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006 23: 469-480.
62. Wei W, Kim Y, Boudreau N. Association of smoking with serum and dietary levels of antioxidants in adults: NHANES III, 1988-1994. Am J Public Health, 2001; 91:258-264.
63. Lam, K.B.; Jordan, R.E.; Jiang, C.Q.; Thomas, G.N.; Miller, M.R.; Zhang, W.S.; Lam, T.H.; Cheng, K.K.; Adab, P. Airflow obstruction and metabolic syndrome: The Guangzhou Biobank Cohort Study. Eur. Respir. J. 2010; 35:317–323.
64. 30. Watz, H.; Waschki, B.; Kirsten, A.; Müller, K.C.; Kretschmar, G.; Meyer, T.; Holz, O.; Magnussen, H. The metabolic syndrome in patients with chronic bronchitis and COPD: Frequency and associated consequences for systemic inflammation and physical inactivity. Chest 2009; 136:1039–1046.
65. Vujic, T.; Nagorni, O.; Maric, G.; Popovic, L.; Jankovic, J. Metabolic syndrome in patients with chronic obstructive pulmonary disease: Frequency and relationship with systemic inflammation. Hippokratia 2016; 20:110–114.
66. Breyer, M.K.; Spruit, M.A.; Hanson, C.K.; Franssen, F.M.; Vanfleteren, L.E.; Groenen, M.T.; Bruijnzeel, P.L.; Wouters, E.F.; Rutten, E.P. Prevalence of metabolic syndrome in COPD patients and its consequences. PLoS ONE 2014; 9, e98013.
67. Piazzolla, G.; Castrovilli, A.; Liotino, V.; Vulpi, M.R.; Fanelli, M.; Mazzocca, A.; Candigliota, M.; Berardi, E.; Resta, O.; Sabbà, C.; et al. Metabolic syndrome and Chronic Obstructive Pulmonary Disease (COPD): The interplay among smoking, insulin resistance and vitamin D. PLoS ONE 2017; 12, e0186708.
68. Maruthur, N.M.; Tseng, E.; Hutfless, S.; Wilson, L.M.; Suarez-Cuervo, C.; Berger, Z.; Chu, Y.; Iyoha, E.; Segal, J.B.; Bolen, S. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Ann. Intern. Med. 2016; 164:740–751.
69. Zhu, A.; Teng, Y.; Ge, D.; Zhang, X.; Hu, M.; Yao, X. Role of metformin in treatment of patients with chronic obstructive pulmonary disease: A systematic review. J. Thorac. Dis. 2019; 11:4371–4378.
70. Sexton, P.; Metcalf, P.; Kolbe, J. Respiratory effects of insulin sensitisation with metformin: A prospective observational study. COPD 2014; 11:133–142.
71. Yen, F.S.; Wei, J.C.; Yang, Y.C.; Hsu, C.C.; Hwu, C.M. Respiratory outcomes of metformin use in patients with type 2 diabetes and chronic obstructive pulmonary disease. Sci. Rep. 2020; 10:10298.
72. Polverino, F.; Wu, T.D.; Rojas-Quintero, J.; Wang, X.; Mayo, J.; Tomchaney, M.; Tram, J.; Packard, S.; Zhang, D.; Cleveland, K.H.; et al. Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment. Am. J. Respir. Crit. Care Med. 2021; 204:651–666.
73. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis. 1989; 139(6):1435–1438.
74. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr. 2005; 82(1):53–59.
75. McDonald MN, Wouters EFM, Rutten E, et al. It’s more than low BMI: prevalence of cachexia and associated mortality in COPD. Respir Res.2019; 20(1):100.
76. Kwan HY, Maddocks M, Nolan CM, et al. The prognostic significance of weight loss in chronic obstructive pulmonary disease-related cachexia: a prospective cohort study. J Cachexia Sarcopenia Muscle. 2019; 10(6):1330–1338.
77. Puig-Vilanova E, Rodriguez DA, Lloreta J, et al. Oxidative stress, redox signaling pathways, and autophagy in cachectic muscles of male patients with advanced COPD and lung cancer. Free Radic Biol Med. 2015; 79:91–108.
78. Sanders KJC, Kneppers AEM, van de Bool C, Langen RCJ, Schols AM. Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective. J Cachexia Sarcopenia Muscle. 2016; 7(1):5–22.
79. Brusik M, Ukropec J, Joppa P, et al. Circulatory and adipose tissue leptin and adiponectin in relationship to resting energy expenditure in patients with chronic obstructive pulmonary disease. Physiol Res. 2012; 61(5):469–480.
80. Mokari-Yamchi A, Sharifi A, Kheirouri S. Increased serum levels of S100A1, ZAG, and adiponectin in cachectic patients with COPD. Int J Chron Obstruct Pulmon Dis. 2018; 13:3157–3163.
81. Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012; 12:CD000998.
82. van Beers M, Rutten-van Mölken M, van de Bool C, et al. Clinical outcome and cost-effectiveness of a 1-year nutritional intervention programme in COPD patients with low muscle mass: the randomized controlled NUTRAIN trial. Clin Nutr. 2020; 39:405–413.
83. van Wetering CR, Hoogendoorn M, Broekhuizen R, et al. Efficacy and costs of nutritional rehabilitation in muscle-wasted patients with chronic obstructive pulmonary disease in a community-based setting: a prespecified subgroup analysis of the INTERCOM trial. J Am Med Dir Assoc. 2010; 11:179–187.
84. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013; 188:e13–64.
85. Kneppers AEM, Haast RAM, Langen RCJ, et al. Distinct skeletal muscle molecular responses to pulmonary rehabilitation in chronic obstructive pulmonary disease: a cluster analysis. J Cachexia Sarcopenia Muscle. 2019; 10:311–322.
86. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 189:e15–e62.
87. Garcia JM, Boccia RV, Graham CD, et al. Anamorelin for patients with cancer cachexia: an integrated analysis of two Phase 2, randomised, placebo-controlled, double-blind trials. Lancet Oncol. 2015; 16:108–116.
88. 173. Currow DC, Abernethy AP. Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. Future Oncol. 2014; 10:789–802.
89. Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 189:e15–e62.
90. Weisberg J, Wanger J, Olson J, et al. Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest. 2002; 121:1070–1078.
91. Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and osteoporosis. Chest. 2011; 139:648-657.
92. Sözen T, Özıs¸ık L, Bas¸aran N. An overview and management of osteoporosis. Eur J Rheumatol. 2017;4(1):46-56. Chen Y, Ramsook A, Coxson H, Bon J, Reid W. Prevalence and risk factors for osteoporosis in individuals with COPD: a systematic review and meta-analysis. Chest. 2019; 156:1092-1110.
93. Law M, Hackshaw A. A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ (Clin Res Ed). 1997; 315:841-846.
94. Marinucci L, Balloni S, Fettucciari K, Bodo M, Talesa VN, Antognelli C. Nicotine induces apoptosis in human osteoblasts via a novel mechanism driven by H(2)O(2) and entailing glyoxalase 1-dependent MG-H1 accumulation leading to TG2-mediated NF-kB desensitization: implication for smokersrelated osteoporosis. Free Radic Biol Med. 2018; 117:6-17.
95. Papakitsou E, Margioris A, Dretakis K, et al. Body mass index (BMI) and parameters of bone formation and resorption in postmenopausal women. Maturitas. 2004; 47:185-193.
96. Santos L, Elliott-Sale KJ, Sale C. Exercise and bone health across the lifespan. Biogerontology. 2017; 18:931-946.
97. Yuan Y, Chen X, Zhang L, et al. The roles of exercise in bone remodeling and in prevention and treatment of osteoporosis. Prog Biophys Mol Biol. 2016; 122:122-130.
98. Lee SH, Kwon HY. Prevalence of osteoporosis in Korean patients with chronic obstructive pulmonary disease and their health-related quality of life according to the Korea National Health and Nutrition Examination Survey 2008-2011. J Bone Metab. 2017; 24:241-248.
99. Kim SW, Lee JM, Ha JH, et al. Association between vitamin D receptor polymorphisms and osteoporosis in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015; 10:1809-1817.
100. Lin CW, Chen YY, Chen YJ, Liang CY, Lin MS, Chen W. Prevalence, risk factors, and health-related quality of life of osteoporosis in patients with COPD at a community hospital in Taiwan. Int J Chron Obstruct Pulmon Dis. 2015; 10:1493-1500.
101. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet (London, England). 2007; 370:797-799.
102. Xiong Z, Leme AS, Ray P, Shapiro SD, Lee JS. CX3CR1+ lung mononuclear phagocytes spatially confined to the interstitium produce TNF-α and IL-6 and promote cigarette smoke-induced emphysema. J Immunol (Baltimore, Md: 1950). 2011; 186: 3206-3214.
103. Chen K, Pociask DA, McAleer JP, et al. IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke. PLoS ONE. 2011; 6: e20333.
104. Liang B, Feng Y. The association of low bone mineral density with systemic inflammation in clinically stable COPD. Endocrine. 2012; 42:190-195.
105. Vitenberga Z, Pilmane M, Babjoniševa A. The evaluation of inflammatory, anti-inflammatory and regulatory factors contributing to the pathogenesis of COPD in airways. Pathol Res Pract. 2019; 215:97-105.
106. Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine. 2018; 61:7-16.
107. Amiche MA, Albaum JM, Tadrous M, et al. Fracture risk in oral glucocorticoid users: a Bayesian meta-regression leveraging control arms of osteoporosis clinical trials. Osteoporos Int. 2016; 27:1709-1718.
108. Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 2011; 66: 699-708.
109. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96:1911-1930.
110. Janssens W, Bouillon R, Claes B, et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax. 2010; 65:215-220.
111. Kokturk N, Baha A, Oh YM, Young Ju J, Jones PW. Vitamin D deficiency: what does it mean for chronic obstructive pulmonary disease (COPD)? A comprehensive review for pulmonologists. Clin Respir J. 2018; 12:382-397.
112. Graat-Verboom L, Smeenk FW, van den Borne BE, et al. Progression of osteoporosis in patients with COPD: a 3-year follow up study. Respir Med. 2012; 106:861-870.
113. International Osteoporosis Foundation (IOF). Exercise Recommendations of Bone Health. Available online: https://www.osteoporosis.foundation/healthprofessionals/prevention/exercise (accessed on 10 April 2023).
114. Thorpe, O.; Kumar, S.; Johnston, K. Barriers to and enablers of physical activity in patients with COPD following a hospital admission: A qualitative study. Int. J. Chronic Obstr. Pulm. Dis. 2014; 9: 115.
115. Walawska-Hrycek, A.; Galus, W.; Hrycek, E.; Kaczmarczyk, A.; Krzystanek, E. The impact of vitamin D low doses on its serum level and cytokine profile in multiple sclerosis patients. J. Clin. Med. 2021; 10: 2781.
116. Dawson-Hughes, B.; Mithal, A.; Bonjour, J.P.; Boonen, S.; Burckhardt, P.; Fuleihan, G.E.; Josse, R.G.; Lips, P.; Morales-Torres, J.; Yoshimura, N. IOF position statement: Vitamin D recommendations for older adults. Osteoporos. Int. 2010; 21:1151–1154.
117. American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for prevention of falls and their consequences. J. Am. Geriatr. Soc. 2014; 62:147–152.
118. Rafiq, R.; Prins, H.J.; Boersma, W.G.; Daniels, J.M.; den Heijer, M.; Lips, P.; de Jongh, R.T. Effects of daily vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients: A pilot trial. Int. J. Chronic Obstr. Pulm. Dis. 2017; 12:2583–2592.
119. Calafiore, D.; Fortunato, L.; Migliario, M. Vitamin D for clinical diseases in women: An indispensable factor in medicine and dentistry. J. Clin. Med. 2022; 11:3104.
120. Fujieda, Y.; Horita, T.; Nishimoto, N.; Tanimura, K.; Amasaki, Y.; Kasahara, H.; Furukawa, S.; Takeda, T.; Fukaya, S.; Matsui, K.; et al. Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial. Mod. Rheumatol. 2021; 31:593–599.
121. Invernizzi, M.; Cisari, C.; Carda, S. The potential impact of new effervescent alendronate formulation on compliance and persistence in osteoporosis treatment. Aging Clin. Exp. Res. 2015; 27:107–113.
122. Inoue, D.; Watanabe, R.; Okazaki, R. COPD and osteoporosis: Links, risks, and treatment challenges. Int. J. Chronic Obstr. Pulm. Dis. 2016; 11:637–648.
123. Nuti, R.; Brandi, M.L.; Checchia, G.; Di Munno, O.; Dominguez, L.; Falaschi, P.; Fiore, C.E.; Iolascon, G.; Maggi, S.; Michieli, R.; et al. Guidelines for the management of osteoporosis and fragility fractures. Intern. Emerg. Med. 2019; 14:85–102.
124. Yohannes AM and and George S Alexopoulos. Depression and anxiety in patients with COPD. Eur Respir Rev. 2014 September; 23: 345-349.
125. Pumar, M.I.; Gray, C.R.; Walsh, J.R.; Yang, I.A.; Rolls, T.A.; Ward, D.L. Anxiety and depression-Important psychological comorbidities of COPD. J. Thorac. Dis. 2014; 6:1615–1631.
126. Van Manen, J.G.; Bindels, P.J.; Dekker, F.W.; CJ, I.J.; van der Zee, J.S.; Schadé, E. Risk of depression in patients with chronic obstructive pulmonary disease and its determinants. Thorax 2002; 57:412–416.
127. Van Manen, J.G.; Bindels, P.J.; Dekker, F.W.; CJ, I.J.; van der Zee, J.S.; Schadé, E. Risk of depression in patients with chronic obstructive pulmonary disease and its determinants. Thorax 2002; 57:412–416.
128. Norwood R. Prevalence and impact of depression in chronic obstructive pulmonary disease patients. Curr Opin Pulm Med 2006; 12: 113-117.
129. Yohannes, A.M.; Kaplan, A.; Hanania, N.A. Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management. Cleve. Clin. J. Med. 2018; 85 (Suppl. S1), S11–S18.
130. National Institute for Health and Clinical Excellence. CG91 Depression with a Chronic Physical Health Problem: NICE Guideline. London, UK: National Collaborating Centre for Mental Health; 2009. Available from: https://www.nice.org.uk/guidance/cg91. [accessed 2023 March 20].
131. Kunik, M.E.; Braun, U.; Stanley, M.A.; Wristers, K.; Molinari, V.; Stoebner, D.; Orengo, C.A. One session cognitive behavioural therapy for elderly patients with chronic obstructive pulmonary disease. Psychol. Med. 2001; 31:717–723.
132. Ma, R.C.; Yin, Y.Y.; Wang, Y.Q.; Liu, X.; Xie, J. Effectiveness of cognitive behavioural therapy for chronic obstructive pulmonary disease patients: A systematic review and meta-analysis. Complement. Ther. Clin. Pract. 2020; 38:101071.
133. Pollok, J.; van Agteren, J.E.; Carson-Chahhoud, K.V. Pharmacological interventions for the treatment of depression in chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2018; 12, Cd012346.
134. Tselebis А, Pachi А, Ilias I, et al. Strategies to improve anxiety and depression in patients with COPD: A mental health perspective. Neuropsychiatr Dis Treat 2016; 12:297-328.
135. Fritzsche, A.; Clamor, A.; von Leupoldt, A. Effects of medical and psychological treatment of depression in patients with COPD—A review. Respir. Med. 2011; 105:1422–1433.
136. Vozoris, N.T.; Wang, X.; Austin, P.C.; Stephenson, A.L.; O’Donnell, D.E.; Gershon, A.S.; Gill, S.S.; Rochon, P.A. Serotonergic antidepressant use and morbidity and mortality among older adults with COPD. Eur. Respir. J. 2018; 52, 1800475.
137. Edwards, B.A.; Eckert, D.J.; Jordan, A.S. Obstructive sleep apnoea pathogenesis from mild to severe: Is it all the same? Respirology 2017; 22:33–42.
138. Lyons, M.M.; Bhatt, N.Y.; Pack, A.I.; Magalang, U.J. Global burden of sleep-disordered breathing and its implications. Respirology 2020; 25:690–702.
139. Malhotra, A.; Schwartz, A.R.; Schneider, H.; Owens, R.L.; Deyoung, P.; Han, M.K.; Wedzicha, J.A.; Hansel, N.N.; Zeidler, M.R.; Wilson, K.C.; et al. Research Priorities in Pathophysiology for Sleep-disordered Breathing in Patients with Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Research Statement. Am. J. Respir. Crit. Care Med. 2018; 197:289–299.
140. McNicholas WT. COPD-OSA Overlap Syndrome: Evolving Evidence Regarding Epidemiology, Clinical Consequences, and Management. Chest. 2017 Dec; 152(6):1318-1326.
141. Owens RL, Macrea M and Teodorescu M. The overlaps of asthma or COPD with OSA: A focused review. Respirology 2017; 22: 1073-1083.
142. Krachman, S.L.; Tiwari, R.; Vega, M.E.; Yu, D.; Soler, X.; Jaffe, F.; Kim, V.; Swift, I.; D’Alonzo, G.E.; Criner, G.J. Effect of Emphysema Severity on the Apnea–Hypopnea Index in Smokers with Obstructive Sleep Apnea. Ann. Am. Thorac. Soc. 2016; 13:1129–1135.
143. Adler, D.; Bailly, S.; Benmerad, M.; Joyeux-Faure, M.; Jullian-Desayes, I.; Soccal, P.M.; Janssens, J.P.; Sapène, M.; Grillet, Y.; Stach, B.; et al. Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 2020, 15, e0235331.
144. Kendzerska, T.; Leung, R.S.; Aaron, S.D.; Ayas, N.; Sandoz, J.S.; Gershon, A.S. Cardiovascular Outcomes and All-Cause Mortality in Patients with Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease (Overlap Syndrome). Ann. Am. Thorac. Soc. 2019; 16:71–81.
145. Ganga, H.V.; Nair, S.U.; Puppala, V.K.; Miller, W.L. Risk of new-onset atrial fibrillation in elderly patients with the overlap syndrome: A retrospective cohort study. J. Geriatr. Cardiol. 2013; 10:129–134.
146. Toraldo, D.M.; De Nuccio, F.; Nicolardi, G. Fixed-pressure nCPAP in patients with obstructive sleep apnea (OSA) syndrome and chronic obstructive pulmonary disease (COPD): A 24-month follow-up study. Sleep Breath. 2010; 14:115–123.
147. Stanchina, M.L.; Welicky, L.M.; Donat, W.; Lee, D.; Corrao, W.; Malhotra, A. Impact of CPAP Use and Age on Mortality in Patients with Combined COPD and Obstructive Sleep Apnea: The Overlap Syndrome. J. Clin. Sleep Med. 2013; 9:767–772.
148. Zheng, M.Y.; Yee, M.B.J.; Wong, M.K.; Grunstein, M.R.; Piper, B.A. A pilot randomized trial comparing CPAP vs bilevel PAP spontaneous mode in the treatment of hypoventilation disorder in patients with obesity and obstructive airway disease. J. Clin. Sleep Med. 2022; 18: 99–107.
149. Tavares LP, Galvão I, Ferrero MR. Novel Immunomodulatory Therapies for Respiratory Pathologies. Comprehensive Pharmacology. 2022:554–94. doi: 10.1016/B978-0-12-820472-6.00073-6. Epub 2022 Jun 9. PMCID: PMC8238403.