Низкоинтенсивное воспаление в постковидном периоде как стратегическая цель лечения и реабилитации

По состоянию на начало 2023 г. в мире насчитывается более 660 млн реконвалесцентов новой коронавирусной инфекции (НКИ), однако, даже несмотря на успешное лечение острого периода заболевания, такие пациенты имеют высокий риск развития отдалённых осложнений в постковидном периоде, в первую очередь со стороны сердечно-сосудистой системы. Одним из факторов, который серьёзно повышает риск данных осложнений, является состояние низкоинтенсивного системного воспаления (НИВ). НИВ не является клиническим диагнозом, характеризуется уровнем С-реактивного белка в периферической крови в пределах 3–10 мг/л и чаще всего выявляется при рутинном обследовании пациентов, в большинстве случаев не имеющих какой-либо клинической симптоматики. В связи с этим состояние НИВ чаще всего остаётся незамеченным и необоснованно игнорируемым, несмотря на достаточно обширные литературные данные о влиянии НИВ на патогенез многих сердечно-сосудистых заболеваний. Разработка медикаментозной терапии НИВ осложняется полиэтиологичностью данного состояния. Причинами НИВ могут выступать как генетические факторы, практически не поддающиеся коррекции, так и состояния, поддающиеся медикаментозному и немедикаментозному вмешательству, как, например, повышенная кишечная проницаемость к провоспалительным агентам, в том числе к липополисахариду грамотрицательной флоры, наличие очага хронической нелеченой инфекции и эндокринная патология (ожирение и сахарный диабет 2-го типа). В данном обзоре представлены основные имеющиеся на сегодняшний день данные о состоянии НИВ у пациентов, перенёсших НКИ, включая результаты собственных наблюдений пациентов, прошедших курс реабилитационных мероприятий, а также наиболее значимые, по нашему мнению, факторы, предрасполагающие к развитию НИВ у представленной категории пациентов.

1. COVID-19 coronavirus pandemic worldometer. Last updated June 28, 2023, 20:30 GMT. URL: https://www.worldometers.info/coronavirus/ [date of access: 28.06.2023].

2. Evans RA, McAuley H, Harrison EM, Shikotra A, Singapuri A, Sereno M, et al. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): A UK multicentre, prospective cohort study. Lancet Respir Med. 2022; 9(11): 12751287. doi: 10.1016/S2213-2600(21)00383-0

3. Huang L, Yao Q, Gu X, Wang Q, Ren L, Wang Y, et al. 1-year outcomes in hospital survivors with COVID-19: A longitudinal cohort study. Lancet. 2021; 398(10302): 747-758. doi: 10.1016/s0140-6736(21)01755-4

4. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet. 2021; 397(10270): 220-232. doi: 10.1016/s0140-6736(20)32656-8

5. Rifai N, Ridker PM. Population distributions of C-reactive protein in apparently healthy men and women in the United States: Implication for clinical interpretation. Clin Chem. 2003; 49(4): 666669. doi: 10.1373/49.4.666

6. Imhof A, Fröhlich M, Loewel H, Helbecque N, Woodward M, Amouyel P, et al. Distributions of C-reactive protein measured by high-sensitivity assays in apparently healthy men and women from different populations in Europe. Clin Chem. 2003; 49(4): 669672. doi: 10.1373/49.4.669

7. Filbin MR, Mehta A, Schneider AM, Kays KR, Guess JR, Gentili M, et al. Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions. Cell Rep Med. 2021; 2(5): 100287. doi: 10.1016/j.xcrm.2021.100287

8. Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, Liew F, Russell CD, Moore SC, et al. Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021; 6(57): eabg9873. doi: 10.1126/sciimmunol.abg9873

9. Florencio LL, Fernández-de-Las-Peñas C. Long COVID: Systemic inflammation and obesity as therapeutic targets. Lancet Respir Med. 2022; 10(8): 726-727. doi: 10.1016/S2213-2600(22)00159-X

10. PHOSP-COVID Collaborative Group. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: A prospective observational study. Lancet Respir Med. 2022; 10(8): 761-775. doi: 10.1016/S2213-2600(22)00127-8

11. Maamar M, Artime A, Pariente E, Fierro P, Ruiz Y, Gutiérrez S, et al. Post-COVID-19 syndrome, low-grade inflammation and inflammatory markers: A cross-sectional study. Curr Med Res Opin. 2022; 38(6): 901-909. doi: 10.1080/03007995.2022.2042991

12. Beloglazov V, Dudchenko L, Yatskov I, DuBuske L. The impact of post COVID rehabilitation on the level of systemic inflammation in patients with post COVID syndrome. J Allergy Clin Immunol. 2023; 151(2): AB25. doi: 10.1016/j.jaci.2022.12.081

13. Silva Andrade B, Siqueira S, de Assis Soares WR, de Souza Rangel F, Santos NO, Dos Santos Freitas A, et al. Long-COVID and post-COVID health complications: An up-to-date review on clinical conditions and their possible molecular mechanisms. Viruses. 2021; 13(4): 700. doi: 10.3390/v13040700

14. Elseidy SA, Awad AK, Vorla M, Fatima A, Elbadawy MA, Mandal D, et al. Cardiovascular complications in the post-acute COVID-19 syndrome (PACS). Int J Cardiol Heart Vasc. 2022; 40: 101012. doi: 10.1016/j.ijcha.2022.101012

15. Wang W, Wang CY, Wang SI, Wei JC. Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks. E Clinical Medicine. 2022; 53: 101619. doi: 10.1016/j.eclinm.2022.101619

16. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018; 14(10): 576-590. doi: 10.1038/s41574-018-0059-4

17. Ortega-Gómez A, Perretti M, Soehnlein O. Resolution of inflammation: An integrated view. EMBO Mol Med. 2013; 5(5): 661-674. doi: 10.1002/emmm.201202382

18. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008; 8(5): 349-361. doi: 10.1038/nri2294

19. Calder PC, Ahluwalia N, Albers R, Bosco N, BourdetSicard R, Haller D, et al. A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies. Br J Nutr. 2013; 109(1): S1-34. doi: 10.1017/S0007114512005119

20. Hallenbeck JM, Hansson GK, Becker KJ. Immunology of ischemic vascular disease: Plaque to attack. Trends Immunol. 2005; 26(10): 550-556. doi: 10.1016/j.it.2005.08.007

21. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352(16): 1685-1695. doi: 10.1056/NEJMra043430

22. Harford KA, Reynolds CM, McGillicuddy FC, Roche HM. Fats, inflammation and insulin resistance: Insights to the role of macrophage and T-cell accumulation in adipose tissue. Proc Nutr Soc. 2011; 70(4): 408-417. doi: 10.1017/S0029665111000565

23. Collaboration IRGCERF, Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, et al. Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. Lancet. 2012; 379(9822): 1205-1213. doi: 10.1016/s0140-6736(11)61931-4

24. Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. Gut microbiota and extreme longevity. Curr Biol. 2016; 26(11): 1480-1485. doi: 10.1016/j.cub.2016.04.016

25. Wang H, Peng G, Bai J, He B, Huang K, Hu X, et al. Cytomegalovirus infection and relative risk of cardiovascular disease (ischemic heart disease, stroke, and cardiovascular death): A metaanalysis of prospective studies up to 2016. J Am Heart Assoc. 2017; 6(7): e005025. doi: 10.1161/JAHA.116.005025

26. Karczewski J, Śledzińska E, Baturo A, Jończyk I, Maleszko A, Samborski P, et al. Obesity and inflammation. Eur Cytokine Netw. 2018; 29(3): 83-94. doi: 10.1684/ecn.2018.0415

27. Tsounis EP, Triantos C, Konstantakis C, Marangos M, Assimakopoulos SF. Intestinal barrier dysfunction as a key driver of severe COVID-19. World JVirol. 2023; 12(2): 68-90. doi: 10.5501/wjv.v12.i2.68

28. Eleftheriotis G, Tsounis EP, Aggeletopoulou I, Dousdampanis P, Triantos C, Mouzaki A, et al. Alterations in gut immunological barrier in SARS-CoV-2 infection and their prognostic potential. Front Immunol. 2023; 14: 1129190. doi: 10.3389/fimmu.2023.1129190

29. Sun Z, Song ZG, Liu C, Tan S, Lin S, Zhu J, et al. Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients. BMC Med. 2022; 20(1): 24. doi: 10.1186/s12916-021-02212-0

30. Palomino-Kobayashi LA, Ymaña B, Ruiz J, Mayanga-Herrera A, Ugarte-Gil MF, Pons MJ. Zonulin, a marker of gut permeability, is associated with mortality in a cohort of hospitalised Peruvian COVID-19 patients. Front Cell Infect Microbiol. 2022; 12: 1000291. doi: 10.3389/fcimb.2022.1000291

31. Carnevale R, Sciarretta S, Valenti V, di Nonno F, Calvieri C, Nocella C, et al. Low-grade endotoxaemia enhances artery thrombus growth via Toll-like receptor 4: Implication for myocardial infarction. Eur Heart J. 2020; 41(33): 3156-3165. doi: 10.1093/eurheartj/ehz893

32. Zhang T, Ma C, Zhang Z, Zhang H, Hu H. NF-κB signaling in inflammation and cancer. MedComm (2020). 2021; 2(4): 618-653. doi: 10.1002/mco2.104

33. Grylls A, Seidler K, Neil J. Link between microbiota and hypertension: Focus on LPS/TLR4 pathway in endothelial dysfunction and vascular inflammation, and therapeutic implication of probiotics. Biomed Pharmacother. 2021; 137: 111334. doi: 10.1016/j.biopha.2021.111334

34. Carnevale R, Nocella C, Petrozza V, Cammisotto V, Pacini L, Sorrentino V, et al. Localization of lipopolysaccharide from Escherichia coli into human atherosclerotic plaque. Sci Rep. 2018; 8(1): 3598. doi: 10.1038/s41598-018-22076-4

35. Jaw JE, Tsuruta M, Oh Y, Schipilow J, Hirano Y, Ngan DA, et al. Lung exposure to lipopolysaccharide causes atherosclerotic plaque destabilisation. Eur Respir J. 2016; 48(1): 205-215. doi: 10.1183/13993003.00972-2015

36. Violi F, Cammisotto V, Bartimoccia S, Pignatelli P, Carnevale R, Nocella C. Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease. Nat Rev Cardiol. 2023; 20(1): 24-37. doi: 10.1038/s41569-022-00737-2

37. Poburski D, Leovsky C, Boerner JB, Szimmtenings L, Ristow M, Glei M, et al. Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model. Sci Rep. 2016; 6: 37120. doi: 10.1038/srep37120

38. Vieira-Potter VJ. Inflammation and macrophage modulation in adipose tissues. Cell Microbiol. 2014; 16(10): 1484-1492. doi: 10.1111/cmi.12336

39. Gleeson M, McFarlin B, Flynn M. Exercise and Toll-like receptors. Exerc Immunol Rev. 2006; 12: 34-53.

40. Kawanishi N, Mizokami T, Yano H, Suzuki K. Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice. Med Sci Sports Exerc. 2013; 45(9): 1684-1693. doi: 10.1249/MSS.0b013e31828ff9c6

41. Gonzalo-Encabo P, Maldonado G, Valadés D, Ferragut C, Pérez-López A. The role of exercise training on low-grade systemic inflammation in adults with overweight and obesity: A systematic review. Int J Environ Res Public Health. 2021; 18(24): 13258. doi: 10.3390/ijerph182413258

42. Custodero C, Mankowski RT, Lee SA, Chen Z, Wu S, Manini TM, et al. Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middleage and older adults: A systematic review and meta-analysis. Ageing Res Rev. 2018; 46: 42-59. doi: 10.1016/j.arr.2018.05.004

43. Takagi H, Mizuno Y, Yamamoto H, Goto SN, Umemoto T. All-Literature Investigation of Cardiovascular Evidence Group. Effects of telmisartan therapy on interleukin-6 and tumor necrosis factor-alpha levels: A meta-analysis of randomized controlled trials. Hypertens Res. 2013; 36(4): 368-373. doi: 10.1038/hr.2012.196

44. Kleiber AC, Zheng H, Sharma NM, Patel KP. Chronic AT1 receptor blockade normalizes NMDA-mediated changes in renal sympathetic nerve activity and NR1 expression within the PVN in rats with heart failure. Am J Physiol Heart Circ Physiol. 2010; 298(5): H1546-1555. doi: 10.1152/ajpheart.01006.2009

45. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016; 23(6): 1060-1065. doi: 10.1016/j.cmet.2016.05.011

46. Hyun B, Shin S, Lee A, Lee S, Song Y, Ha NJ, et al. Metformin down-regulates TNF-α secretion via suppression of scavenger receptors in macrophages. Immune Netw. 2013; 13(4): 123-132. doi: 10.4110/in.2013.13.4.123

47. Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005; 54(5): 1566-1572. doi: 10.2337/diabetes.54.5.1566

48. Lakshminarayanan B, Stanton C, O’Toole PW, Ross RP. Compositional dynamics of the human intestinal microbiota with aging: Implications for health. J Nutr Health Aging. 2014; 18(9): 773-786. doi: 10.1007/s12603-014-0549-6

49. Kim CH, Kim HG, Kim JY, Kim NR, Jung BJ, Jeong JH, et al. Probiotic genomic DNA reduces the production of pro-inflammatory cytokine tumor necrosis factor-alpha. FEMS Microbiol Lett. 2012; 328(1): 13-19. doi: 10.1111/j.1574-6968.2011.02470.x

50. Mazidi M, Rezaie P, Ferns GA, Vatanparast H. Impact of probiotic administration on serum C-reactive protein concentrations: Systematic review and meta-analysis of randomized control trials. Nutrients. 2017; 9(1): 20. doi: 10.3390/nu9010020

51. Moro-García MA, Alonso-Arias R, Baltadjieva M, Fernández Benítez C, Fernández Barrial MA, Díaz Ruisánchez E, et al. Oral supplementation with Lactobacillus delbrueckii subsp. bulgaricus 8481 enhances systemic immunity in elderly subjects. Age (Dordr). 2013; 35(4): 1311-1326. doi: 10.1007/s11357-012-9434-6

52. Samah S, Ramasamy K, Lim SM, Neoh CF. Probiotics for the management of type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2016; 118: 172182. doi: 10.1016/j.diabres.2016.06.014

53. Yao K, Zeng L, He Q, Wang W, Lei J, Zou X. Effect of probiotics on glucose and lipid metabolism in type 2 diabetes mellitus: A meta-analysis of 12 randomized controlled trials. Med Sci Monit. 2017; 23: 3044-3053. doi: 10.12659/msm.902600

54. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta. 2015; 1851(4): 469-484. doi: 10.1016/j.bbalip.2014.08.010

55. Generoso Sde V, Rodrigues NM, Trindade LM, Paiva NC, Cardoso VN, Carneiro CM, et al. Dietary supplementation with omega-3 fatty acid attenuates 5-fluorouracil induced mucositis in mice. Lipids Health Dis. 2015; 14: 54. doi: 10.1186/s12944-015-0052-z

56. Costantini L, Molinari R, Farinon B, Merendino N. Impact of omega-3 fatty acids on the gut microbiota. Int J Mol Sci. 2017; 18(12): 2645. doi 10.3390/ijms18122645

57. Tingö L, Hutchinson AN, Bergh C, Stiefvatter L, Schweinlin A, Jensen MG, et al. Potential modulation of inflammation by probiotic and omega-3 supplementation in elderly with chronic low-grade inflammation – A randomized, placebo-controlled trial. Nutrients. 2022; 14(19): 3998. doi: 10.3390/nu14193998

58. Симаненков В.И., Маев И.В., Ткачева О.Н., Алексеенко С.А., Андреев Д.Н., Бордин Д.С., и др. Синдром повышенной эпителиальной проницаемости в клинической практике. Мультидисциплинарный национальный консенсус. Кардиоваскулярная терапия и профилактика. 2021; 20(1): 121-278. doi: 10.15829/1728-8800-2021-2758

59. Остроумова О.Д., Кочетков А.И. Роль нарушений структуры кишечного барьера в патогенезе сердечнососудистых заболеваний и возможности ребамипида в их коррекции. Фарматека. 2020; 27(13): 30-41. doi: 10.18565/pharmateca.2020.13.30-41

60. Jhun J, Kwon JE, Kim SY, Jeong JH, Na HS, Kim EK, et al. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation. PLoS One. 2017; 12(2): e0171674. doi: 10.1371/journal.pone.0171674

61. Sahebkar A, Serban C, Ursoniu S, Wong ND, Muntner P, Graham IM, et al. Lack of efficacy of resveratrol on C-reactive protein and selected cardiovascular risk factors – Results from a systematic review and meta-analysis of randomized controlled trials. Int J Cardiol. 2015; 189: 47-55. doi: 10.1016/j.ijcard.2015.04.008

62. Ticinesi A, Meschi T, Lauretani F, Felis G, Franchi F, Pedrolli C, et al. Nutrition and inflammation in older individuals: Focus on vitamin D, n-3 polyunsaturated fatty acids and whey proteins. Nutrients. 2016; 8(4): 186. doi: 10.3390/nu8040186

63. Tristan Asensi M, Napoletano A, Sofi F, Dinu M. Low-grade inflammation and ultra-processed foods consumption: A review. Nutrients. 2023; 15(6): 1546. doi: 10.3390/nu15061546

64. Shin PK, Park SJ, Kim MS, Kwon DY, Kim MJ, Kim K, et al. A traditional Korean diet with a low dietary inflammatory index increases anti-inflammatory IL-10 and decreases pro-inflammatory NF-κB in a small dietary intervention study. Nutrients. 2020; 12(8): 2468. doi: 10.3390/nu12082468

65. Bonaccio M, Costanzo S, Di Castelnuovo A, Gialluisi A, Ruggiero E, De Curtis A, et al. Increased adherence to a Mediterranean diet is associated with reduced low-grade inflammation after a 12.7-year period: Results from the Moli-sani Study. J Acad Nutr Diet. 2023; 123(5): 783-795.e7. doi: 10.1016/j.jand.2022.12.005

66. Schwingshackl L, Hoffmann G. Mediterranean dietary pattern, inflammation and endothelial function: A systematic review and meta-analysis of intervention trials. Nutr Metab Cardiovasc Dis. 2014; 24(9): 929-939. doi: 10.1016/j.numecd.2014.03.003

67. Koelman L, Egea Rodrigues C, Aleksandrova K. Effects of dietary patterns on biomarkers of inflammation and immune responses: A systematic review and meta-analysis of randomized controlled trials. Adv Nutr. 2022; 13(1): 101-115. doi: 10.1093/advances/nmab086

68. Lankinen M, Uusitupa M, Schwab U. Nordic diet and inflammation – A review of observational and intervention studies. Nutrients. 2019; 11(6): 1369. doi: 10.3390/nu11061369

69. Ramos-Lopez O, Martinez-Urbistondo D, Vargas-Nuñez JA, Martinez JA. The role of nutrition on meta-inflammation: Insights and potential targets in communicable and chronic disease management. Curr Obes Rep. 2022; 11(4): 305-335. doi: 10.1007/s13679-022-00490-0

70. Costa CS, Del-Ponte B, Assunção MCF, Santos IS. Consumption of ultra-processed foods and body fat during childhood and adolescence: A systematic review. Public Health Nutr. 2018; 21(1): 148-159. doi: 10.1017/S1368980017001331

71. Lopez-Garcia E, Schulze MB, Fung TT, Meigs JB, Rifai N, Manson JE, et al. Major dietary patterns are related to plasma concentrations of markers of inflammation and endothelial dysfunction. Am J Clin Nutr. 2004; 80(4): 1029-1035. doi: 10.1093/ajcn/80.4.1029

72. Tabung FK, Smith-Warner SA, Chavarro JE, Wu K, Fuchs CS, Hu FB, et al. Development and validation of an empirical dietary inflammatory index. J Nutr. 2016; 146(8): 1560-1570. doi: 10.3945/jn.115.228718

73. Marx W, Veronese N, Kelly JT, Smith L, Hockey M, Collins S, et al. The dietary inflammatory index and human health: An umbrella review of meta-analyses of observational studies. Adv Nutr. 2021; 12(5): 1681-1690. doi: 10.1093/advances/nmab037

74. Seidler UE. Gastrointestinal HCO3-transport and epithelial protection in the gut: New techniques, transport pathways and regulatory pathways. Curr Opin Pharmacol. 2013; 13(6): 900908. doi: 10.1016/j.coph.2013.10.001

75. Tarnawski AS, Ahluwalia A, Jones MK. Increased susceptibility of aging gastric mucosa to injury: The mechanisms and clinical implications. World J Gastroenterol. 2014; 20(16): 4467-4482. doi: 10.3748/wjg.v20.i16.4467

76. Said H, Kaunitz JD. Gastrointestinal defense mechanisms. Curr Opin Gastroenterol. 2016; 32(6): 461-466. doi: 10.1097/MOG.0000000000000316

77. Barnich N, Rodrigues M, Sauvanet P, Chevarin C, Denis S, Le Goff O, et al. Beneficial effects of natural mineral waters on intestinal inflammation and the mucosa-associated microbiota. Int J Mol Sci. 2021; 22(9): 4336. doi: 10.3390/ijms22094336

78. Costa-Vieira D, Monteiro R, Martins MJ. Metabolic syndrome features: Is there a modulation role by mineral water consumption? A review. Nutrients. 2019; 11(5): 1141. doi: 10.3390/nu11051141

79. Schnupf P, Gaboriau-Routhiau V, Cerf-Bensussan N. Modulation of the gut microbiota to improve innate resistance. Curr Opin Immunol. 2018; 54: 137-144. doi: 10.1016/j.coi.2018.08.003

80. Al Nabhani Z, Dulauroy S, Marques R, Cousu C, Al Bounny S, Déjardin F, et al. A weaning reaction to microbiota is required for resistance to immunopathologies in the adult. Immunity. 2019; 50(5): 1276-1288.e5. doi: 10.1016/j.immuni.2019.02.014