Abstract
In press
The COVID-19 pandemic caused by the SARS-CoV-2 virus has become a global challenge. Community-acquired pneumonia associated with COVID-19 is still one of the most challenging medical problems. It is especially important to study the pathogenesis of Community-Acquired Pneumonia (CAP) and its relationship with various inflammatory processes that occur in the setting of coronavirus infection. The aim of this study was to analyze the pathogenesis of CAP that develops against the background of COVID-19, to study the mechanisms of immune response, inflammatory processes and their impact on the patient's body, and to identify possible approaches to the diagnosis and treatment of this disease. The following materials and research methods were used in the study: a review of scientific sources on the pathogenesis of CAP in COVID-19, the peculiarities of the immune response, cytokine storm and endothelial dysfunction in this pathology. The authors of the analyzed studies, in turn, used an analysis of inflammatory markers (C-reactive protein, D-dimer, cytokines). They report that patients with CAP developing against COVID-19 have activation of the neutrophil chain and a significant increase in the level of proinflammatory cytokines such as IL-6, IL-1β, TNF-α. These processes lead to the development of a severe inflammatory reaction in the lungs and diffuse alveolar damage, which in turn leads to the development of acute respiratory failure. It has been noted that excessive D-dimer release is a key indicator of the development of these complications. Prediction of severe forms of the disease based on the level of cytokines and other inflammatory markers can be an important tool for early detection of the risk of complications in patients. Thus, it was found that in order to improve the prognosis of patients, it is necessary to use methods of monitoring the level of inflammatory markers and individualise therapeutic strategies to correct immune system disorders.
Keywords: community-acquired pneumonia, COVID-19, cytokine storm, D-dimer, immune response, thromboembolism.
References
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433. DOI: 10.1016/j.jaut.2020.102433. PMID: 32113704.
Pokhrel S, Chhetri R. A literature review on impact of COVID-19 pandemic on teaching and learning. Higher education for the future. 2021;8(1):133-41. DOI: 10.1177/2347631120983481.
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine. 2020;382(8):727-33. DOI: 10.1056/NEJMoa2001017. PMID: 31978945.
Heinrich F, Mertz KD, Glatzel M, Beer M, Krasemann S. Using autopsies to dissect COVID-19 pathogenesis. Nature Microbiology. 2023;8(11):1986-94. DOI: 10.1038/s41564-023-01488-7. PMID: 37798476.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. New England journal of medicine. 2020;382(18):1708-20. DOI: 10.1056/NEJMoa2002032. PMID: 32109013.
Nowak B, Szymanski P, Pankowski I, Szarowska A, Zycinska K, Rogowski W, et al. Clinical characteristics and short-term outcomes of patients with coronavirus disease 2019: a retrospective single-center experience of a designated hospital in Poland. Pol Arch Intern Med. 2020;130(5):407-11. DOI: 10.20452/pamw.15361.
Dziublyk YA. Community-acquired pneumonia and COVID-19: discussion issues. Ukrainian Pulmonology Journal. 2020;4:12-4. DOI: 10.31215/2306-4927-2020-110-4-12-14. [In Ukrainian].
Avgaitis SS, Sid EV. Activation of the immune-inflammatory response among patients with community-acquired pneumonia associated with coronavirus infection. Actual Problems of the Modern Medicine: Bulletin of Ukrainian Medical Stomatological Academy. 2024;1:4-9. DOI: 10.31718/2077–1096.24.1.4. [In Ukrainian].
Benvenuto D, Giovanetti M, Ciccozzi A, Spoto S, Angeletti S, Ciccozzi M. The 2019‐new coronavirus epidemic: evidence for virus evolution. J Med Virol. 2020;92(4):455-59. DOI: 10.1002/jmv.25688. PMID: 31994738.
Chen G, Wu DI, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. The Journal of clinical investigation. 2020;130(5):2620-9. DOI: 10.1172/JCI137244. PMID: 32217835.
Melnyk VP, Panasiuk ОV, Sadomova-Andrianova ОV, Antoniuk IV, Sliusarchuk IO, Solonynka HY. Pneumonia caused by SARS-CoV-2: diagnosis and treatment in outpatient settings. Zaporozhye Medical Journal. 2021;23(3):395-401. DOI: 10.14739/2310-1210.2021.3.224926. [In Ukrainian].
Fushtey IM, Mochonyi VA, Sid EV, Efimenko NF. The state of the SIRS and endothelial function in hypertensive patients, stage II in the process of ischemic heart disease developing. Zaporozhye Medical Journal. 2015;17(4):40-3. DOI: 10.14739/2310-1210.2015.4.50308. [In Ukrainian].
Rai V, Mathews G, Agrawal DK. Translational and clinical significance of DAMPs, PAMPs, and PRRs in trauma-induced inflammation. Archives of Clinical and Biomedical Research. 2022;6(5):673-85. DOI: 10.26502/acbr.50170279. PMID: 36147548.
Haftcheshmeh SM, Abedi M, Mashayekhi K, Mousavi MJ, Navashenaq JG, Mohammadi A, et al. Berberine as a natural modulator of inflammatory signaling pathways in the immune system: Focus on NF‐κB, JAK/STAT, and MAPK signaling pathways. Phytotherapy Research. 2022;36(3):1216-30. DOI: 10.1002/ptr.7407. PMID: 35142403.
Lu Q, Zhu Z, Tan C, Zhou H, Hu Y, Shen G, et al. Changes of serum IL‐10, IL‐1β, IL‐6, MCP‐1, TNF‐α, IP‐10 and IL‐4 in COVID‐19 patients. International journal of clinical practice. 2021;75(9):e14462. DOI: 10.1111/ijcp.14462. PMID: 34107113.
Astuti I, Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020;14(4):407-12. DOI: 10.1016/j.dsx.2020.04.020. PMID: 32335367.
Carlberg C, Velleuer E, Molnar F. Molecular medicine: How science works. Cham, Switzerland: Springer Nature; 2023. DOI: 10.1007/978-3-031-27133-5.
Klomp M, Ghosh S, Mohammed S, Nadeem Khan M. From virus to inflammation, how influenza promotes lung damage. J Leukoc Biol. 2021;110(1):115-22. DOI: 10.1002/JLB.4RU0820-232R. PMID: 32895987.
Sompayrac LM. How the immune system works. 6th ed. Hoboken, NJ, USA: John Wiley & Sons; 2022. 176 p.
Rich R, Fleisher T, Shearer W, Schroeder H, Frew A, Weyand C. In: Clinical immunology: principles and practice. 5th ed. Amsterdam: Elsevier; 2019. 1504 p.
Pius-Sadowska E, Niedzwiedz A, Kulig P, Baumert B, Sobus A, Roginska D, et al. CXCL8, CCL2, and CMV seropositivity as new prognostic factors for a severe COVID-19 course. International Journal of Molecular Sciences. 2022;23(19):11338. DOI: 10.3390/ijms231911338.
Hsu RJ, Yu WC, Peng GR, Ye CH, Hu S, Chong PCT, et al. The role of cytokines and chemokines in severe acute respiratory syndrome coronavirus 2 infections. Frontiers in Immunology. 2022;13:832394. DOI: 10.3389/fimmu.2022.832394. PMID: 36232655.
Hasanvand A. COVID-19 and the role of cytokines in this disease. Inflammopharmacology. 2022;30(3):789-98. DOI: 10.1007/s10787-022-00992-2. PMID: 35505267.
Harne R, Williams B, Abdelaal HF, Baldwin SL, Coler RN. SARS-CoV-2 infection and immune responses. AIMS Microbiology. 2023;9(2):245-76. DOI: 10.3934/microbiol.2023015. PMID: 37091818.
Candido J, Hagemann T. Cancer-related inflammation. Journal of clinical immunology. 2013;33:79-84. DOI: 10.1007/s10875-012-9847-0. PMID: 23225204.
Liu Y, Tian S, Ning B, Huang T, Li Y, Wei Y. Stress and cancer: The mechanisms of immune dysregulation and management. Frontiers in immunology. 2022;13:1032294. DOI: 10.3389/fimmu.2022.1032294. PMID: 36275706.
Koyama S, Nishikawa H. Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies. Journal for Immunotherapy of Cancer. 2021;9(7):e002591. DOI: 10.1136/jitc-2021-002591. PMID: 34330764.
Medzhitov R. The spectrum of inflammatory responses. Science. 2021;374(6571):1070-5. DOI: 10.1126/science.abi5200. PMID: 34822279.
Avgaitis SS, Sid EV. The role of coronavirus infection in lung injury, which contributes to the occurrence of complicated course of community-acquired pneumonia. Reports of Vinnytsia National Medical University. 2024;28(3):545-9. DOI: 10.31393/reports-vnmedical-2024-28(3)-28. [In Ukrainian].
Кonopkina LІ, Rybalka КV. Community-Acquired Pneumonia Associated with COVID-19: Diagnostic Significance of Imaging Methods (CT, LUS) and Comparative Characteristics of CT- and LUS-Patterns. Tuberculosis, Lung Diseases, HIV Infection (Ukraine). 2023;4:39-48. DOI: 10.30978/TB-2023-4-39. [In Ukrainian].
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. DOI: 10.1016/S0140-6736(20)30566-3. PMID: 32171076.
Wang X, Tang G, Liu Y, Zhang L, Chen B, Han Y, et al. The role of IL-6 in coronavirus, especially in COVID-19. Frontiers in Pharmacology. 2022;13:1033674. DOI: 10.3389/fphar.2022.1033674. PMID: 36506506.
Mudatsir M, Fajar JK, Wulandari L, Soegiarto G, Ilmawan M, Purnamasari Y, et al. Predictors of COVID-19 severity: a systematic review and meta-analysis. F1000Research. 2021;9:1107. DOI: 10.12688/f1000research.26186.2. PMID: 33163160.
Kaiser R, Leunig A, Pekayvaz K, Popp O, Joppich M, Polewka V, et al. Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19. JCI insight. 2021;6(18):e150862. DOI: 10.1172/jci.insight.150862. PMID: 34403366.
Huang J, Li J, Zou Z, Kandathil A, Liu J, Qiu S, et al. Clinical Characteristics of 3 Patients Infected withCOVID-19: Age, Interleukin 6 (IL-6), Lymphopenia, and Variations in Chest Computed Tomography (CT). The American Journal of Case Reports. 2020;21:e924905-1. DOI: 10.12659/AJCR.924905. PMID: 33052896.
Lytvyn KY, Bilokon OO. Factors associated with variability in IL-6 levels in patients with COVID-19. Infectious diseases. 2023;2(112):9-14. DOI: 10.11603/1681-2727.2023.2.14097.
Velavan TP, Meyer CG. Mild versus severe COVID-19: Laboratory markers. International Journal of Infectious Diseases. 2020;95:304-7. DOI: 10.1016/j.ijid.2020.04.061. PMID: 32344011.
Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodriguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine & growth factor reviews. 2020;54:62-75. DOI: 10.1016/j.cytogfr.2020.06.001. PMID: 32513566.
Zhang L, Xu D, Zhang T, Hou W, Yixi L. Correlation between interleukin-6, interleukin-8, and modified early warning score of patients with acute ischemic stroke and their condition and prognosis. Annals of Palliative Medicine. 2021;10(1):148-55. DOI: 10.21037/apm-20-2200. PMID: 33440979.
Zanza C, Romenskaya T, Manetti AC, Franceschi F, La Russa R, Bertozzi G, et al. Cytokine storm in COVID-19: immunopathogenesis and therapy. Medicina. 2022;58(2):144. DOI: 10.3390/medicina58020144. PMID: 35208467.
Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Frontiers in Immunology. 2020;11:1708. DOI: 10.3389/fimmu.2020.01708. PMID: 32754163.
Soy M, Keser G, Atagündüz MP. Pathogenesis and treatment of cytokine storm in COVID-19. Turkish Journal of Biology. 2021;45(7):372-89. DOI: 10.3906/biy-2105-37. PMID: 34803441.
Potere N, Batticciotto A, Vecchie A, Porreca E, Cappelli A, Abbate A, et al. The role of IL-6 and IL-6 blockade in COVID-19. Expert Review of Clinical Immunology. 2021;17(6):601-18. DOI: 10.1080/1744666X.2021.1919086.
Zhou YZ, Teng XB, Han MF, Shi JF, Li CX, Zhang XH, et al. The value of PCT, IL-6, and CRP in the early diagnosis and evaluation of COVID-19. Eur Rev Med Pharmacol Sci. 2021;25(2):1097-100. DOI: 10.26355/EURREV_202101_24680. PMID: 33577066.
Duz ME, Balcı A, Menekse E. D-dimer levels and COVID-19 severity: Systematic Review and Meta-Analysis. 2020;68(4):353-60. DOI: 10.5578/tt.70351. PMID: 33448732.
Si D, Du B, Yang B, Jin L, Ni L, Zhang Q, et al. IL-6 and D-Dimer at Admission Predicts Cardiac Injury and Early Mortality during SARS-CoV-2. Infection. medRxiv. 2021;2021-03. DOI: 10.1101/2021.03.22.21254077.
Lowery SA, Sariol A, Perlman S. Innate immune and inflammatory responses to SARS-CoV-2: Implications for COVID-19. Cell Host & Microbe. 2021;29(7):1052-62. DOI: 10.1016/j.chom.2021.05.004. PMID: 34022154.
Boechat JL, Chora I, Morais A, Delgado L. The immune response to SARS-CoV-2 and COVID-19 immunopathology-current perspectives. Pulmonology. 2021;27(5):423-37. DOI: 10.1016/j.pulmoe.2021.03.008. PMID: 33867315.
Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin‐converting enzyme 2 (ACE2), SARS‐CoV‐2 and the pathophysiology of coronavirus disease 2019 (COVID‐19). The Journal of pathology. 2020;251(3):228-48. DOI: 10.1002/path.5471. PMID: 32418199.
Li Y, Zhou W, Yang L, You R. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacological research. 2020;157:104833. DOI: 10.1016/j.phrs.2020.104833. PMID: 32302706.
Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host & Microbe. 2020;27(6):992-1000. DOI: 10.1016/j.chom.2020.04.009. PMID: 32320677.
Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Frontiers in immunology. 2019;10:119. DOI: 10.3389/fimmu.2019.00119. PMID: 30774631.
Rahman A, Tabassum T, Araf Y, Al Nahid A, Ullah MA, Hosen MJ. Silent hypoxia in COVID-19: pathomechanism and possible management strategy. Molecular biology reports. 2021;48(4):3863-9. DOI: 10.1007/s11033-021-06358-1. PMID: 33891272.
Kashani KB. Hypoxia in COVID-19: sign of severity or cause for poor outcomes. Mayo Clinic Proceedings. 2020;95(6):1094-6. DOI: 10.1016/j.mayocp.2020.04.021. PMID: 32498766.
Frisoni P, Neri M, D’Errico S, Alfieri L, Bonuccelli D, Cingolani M, et al. Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1β, IL-6, IL-15 and TNF-α. Forensic Science, Medicine and Pathology. 2022;18(1):4-19. DOI: 10.1007/s12024-021-00414-9. PMID: 34463916.
Hu B, Huang S, Yin L. The cytokine storm and COVID‐19. Journal of medical virology. 2021;93(1):250-6. DOI: 10.1002/jmv.26232. PMID: 32592501.
Serebrovska ZO, Chong EY, Serebrovska TV, Tumanovska LV, Xi L. Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets. Acta Pharmacologica Sinica. 2020;41(12):1539-46. DOI: 10.1038/s41401-020-00554-8. PMID: 33110240.
Jahani M, Dokaneheifard S, Mansouri K. Hypoxia: A key feature of COVID-19 launching activation of HIF-1 and cytokine storm. Journal of inflammation. 2020;17:1-10. DOI: 10.1186/s12950-020-00263-3. PMID: 33139969.
Veronese N, Demurtas J, Yang L, Tonelli R, Barbagallo M, Lopalco P, et al. Use of corticosteroids in coronavirus disease 2019 pneumonia: a systematic review of the literature. Frontiers in medicine. 2020;7:170. DOI: 10.3389/fmed.2020.00170. PMID: 32391369.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet respiratory medicine. 2020;8(4):420-2. DOI: 10.1016/S2213-2600(20)30076-X. PMID: 32085846.
Zanza C, Romenskaya T, Manetti AC, Franceschi F, La Russa R, Bertozzi G, et al. Cytokine storm in COVID-19: immunopathogenesis and therapy. Medicina. 2022;58(2):144. DOI: 10.3390/medicina58020144. PMID: 35208467.
Kim JS, Lee JY, Yang JW, Lee KH, Effenberger M, Szpirt W, et al. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021;11(1):316-29. DOI: 10.7150/thno.49713. PMID: 35208467
Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: the current evidence and treatment strategies. Frontiers in Immunology. 2020;11:1708. DOI: 10.3389/fimmu.2020.01708. PMID: 32754163.
Saha A, Sharma AR, Bhattacharya M, Sharma G, Lee SS, Chakraborty C. Tocilizumab: a therapeutic option for the treatment of cytokine storm syndrome in COVID-19. Archives of Medical Research. 2020;51(6):595-7. DOI: 10.1016/j.arcmed.2020.05.009. PMID: 32482373.
Fenoglio D, Dentone C, Parodi A, Di Biagio A, Bozzano F, Vena A, et al. Characterization of T lymphocytes in severe COVID‐19 patients. Journal of Medical Virology. 2021;93(9):5608-13. DOI: 10.1002/jmv.27037. PMID: 33913544.
Kwiecien I, Rutkowska E, Klos K, Wiesik-Szewczyk E., Jahnz-Rozyk K, Rzepecki P, Chcialowski A. Maturation of T and B Lymphocytes in the Assessment of the Immune Status in COVID-19 Patients. Cells. 2020;9(12):2615. DOI: 10.3390/cells9122615.
Konopkina LI, Shchudro OO. Сardiovascular system status in patients with dyspnea after COVID-19-associated pneumonia. Ukrainian Pulmonology Journal. 2022;31(4):14-21. DOI: 10.31215/2306-4927-2023-31-4-14-21. [In Ukrainian].
Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Review of Hematology. 2020;13(11):1265-75. DOI: 10.1080/17474086.2020.1831383. PMID: 33291439.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.