Document Type : Review Articles
Department 1Department of Toxicology and Pharmacology, Faculty of Pharmacy, Shiraz University of Medical Science, Shiraz, Iranof Toxicology and Pharmacology
Food and Supplements Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Background: Novel 2019 Coronavirus (covid-19) or SARSCoV-2 disease is spreading quickly throughout the globe and threatening public health. Severe acute respiratory syndrome SARS-CoV-2 may precipitate “cytokine” storm, immune system dysregulation, and hyper-coagulation that are responsible for several organ failure, morbidity, and mortality. The severity of infection symptoms is extremely variable from mild symptoms to acute respiratory distress syndrome. Overproduction of inflammatory cytokines and interplay between the immune system response and dysregulation of coagulation system are hypothesized to play a critical role in the pathological mechanism of seriously ill patients with covid-19 infection via the IL-1/IL-6 central pathway.
Methods: The role of SARS-CoV-2 virus in covid-19 disease through cytokine storm and coagulopathy has been discussed in the present brief review. The electronic databases Pubmed, Google Scholar, and SCOPUS were searched to retrieve related English-language articles published between the years 2019 and 2021.
Results: The interplay between immune system responses and coagulation pathway was observed in pathological condition of coronavirus patients, leading to abnormal condition of clot formation and increasing incidence of strokes. Indeed, in nonsurvivor patients, the levels of IL-6, IL-1, and D-dimer were higher than survivor coronavirus patients.
Conclusion: Severe SARS-CoV-2 patients with higher level of IL-1/IL-6 and coagulation abnormality confirm this hypothesis that anticytokine drugs are effective for managing cytokine storm, preventing the risk of strokes, and reducing hospitalization and mortality in covid-19 patients.
- Huet T, Beaussier H, Voisin O, Jouveshomme S, Dauriat G, Lazareth I, et al. Anakinra for severe forms of COVID-19: a cohort study. The Lancet Rheumatology. 2020; 2(7): e393-e400.
- Henry BM, De Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clinical Chemistry and Laboratory Medicine (CCLM). 2020;58(7):1021-8.
- Emami A, Javanmardi F, Pirbonyeh N, Akbari A. Prevalence of Underlying Diseases in Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis. Archives of academic emergency medicine. 2020;8(1):e35.
- 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.
- Zhang W, Du R-H, Li B, Zheng X-S, Yang X-L, Hu B, et al. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020;9(1):386-9.
- WHO. Globally, there have been 632,533,408 confirmed cases of COVID-19, including 6,592,320 deaths, reported to WHO. [Internet]. Jenova. Available from: https://covid19.who.int/.
- Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. The Lancet Respiratory Medicine. 2020; 8(6): e46-e7.
- Zhang Y, Yu L, Tang L, Zhu M, Jin Y, Wang Z, et al. A promising anti-cytokine-storm targeted therapy for COVID-19: the artificial-liver blood-purification system. Engineering (Beijing, China). 2021; 7(1): 11-13.
- D'Elia RV, Harrison K, Oyston PC, Lukaszewski RA, Clark GC. Targeting the “cytokine storm” for therapeutic benefit. Clinical and Vaccine Immunology. 2013;20(3):319-27.
- Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. The Lancet Haematology. 2020;7(6):e438.
- Bester J, Pretorius E. Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity. Scientific reports. 2016;6(1):1-10.
- Kwenandar F, Japar KV, Damay V, Hariyanto TI, Tanaka M, Lugito NPH, et al. Coronavirus Disease 2019 and Cardiovascular System: A Narrative Review. IJC Heart & Vasculature. 2020:100557.
- 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. The lancet. 2020; 28;395(10229):1054-62.
- Zhang L, Long Y, Xiao H, Yang J, Toulon P, Zhang Z. Use of D‐dimer in oral anticoagulation therapy. International journal of laboratory hematology. 2018;40(5):503-7.
- Zhang L, Yan X, Fan Q, Liu H, Liu X, Li io';h Z, et al. D‐dimer levels on admission to predict in‐hospital mortality in patients with Covid‐19. Journal of Thrombosis and Haemostasis. 2020;18(6):1324-9.
- Zhang L, Yan X, Gong Y, Zhang Z. Response to ‘the association between D‐dimer in COVID‐19 patients and mortality remains beset of uncertainties’. Journal of Thrombosis and Haemostasis. 2020;18(8):2070-1.
- Kermali M, Khalsa RK, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19–A systematic review. Life Sciences. 2020:117788.
- Magro G. COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking. Virus research. 2020:198070.
- Levi M, van der Poll T. Inflammation and coagulation. Critical care medicine. 2010;38:S26-S34.
- Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954.
- van de Veerdonk FL, Janssen NA, Grondman I, de Nooijer AH, Koeken VA, Matzaraki V, et al. A systems approach to inflammation identifies therapeutic targets in SARS-CoV-2 infection. medRxiv. 2020.
- Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clinical Infectious Diseases. 2020;71(15):762-8.
- Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine & Growth Factor Reviews. 2020.
- Nieto-Torres JL, DeDiego ML, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Fernandez-Delgado R, et al. Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis. PLOS Pathogens. 2014;10(5):e1004077.
- Thibaud S, Tremblay D, Bhalla S, Zimmerman B, Sigel K, Gabrilove J. Protective role of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID‐19. British Journal of Haematology. 2020; 190(2):e73-e76
- South K, McCulloch L, McColl BW, Elkind MS, Allan SM, Smith CJ. Preceding infection and risk of stroke: an old concept revived by the COVID-19 pandemic. International Journal of Stroke. 2020;15(7):722-32.
- Lau SKP, Lau CCY, Chan KH, Li CPY, Chen H, Jin DY, et al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. The Journal of general virology. 2013;94(Pt 12):2679-90.
- Szegedi I, Orbán-Kálmándi R, Csiba L, Bagoly Z. Stroke as a Potential Complication of COVID-19-Associated Coagulopathy: A Narrative and Systematic Review of the Literature. Journal of clinical medicine. 2020;9(10):3137.
- Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nature Reviews Immunology. 2020:1-8.
- Yao Z, Zheng Z, Wu K, Junhua Z. Immune environment modulation in pneumonia patients caused by coronavirus: SARS-CoV, MERS-CoV and SARS-CoV-2. Aging (Albany NY). 2020;12(9):7639.
- van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nature Reviews Immunology. 2017;17(7):407.
- Jenny NS, Callas PW, Judd SE, McClure LA, Kissela B, Zakai NA, et al. Inflammatory cytokines and ischemic stroke risk: The REGARDS cohort. Neurology. 2019;92(20):e2375-e84.
- Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW, Litovsky S. Systemic infections cause exaggerated local inflammation in atherosclerotic coronary arteries: clues to the triggering effect of acute infections on acute coronary syndromes. Texas Heart Institute Journal. 2007;34(1):11.
- Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nature reviews Immunology. 2013;13(1):34-45.
- Gunasekaran K, Amoah K, Rajasurya V, Buscher MG. Stroke in a young COVID-19 patient. QJM : monthly journal of the Association of Physicians. 2020;113(8):573-4.
- Wu Y, Xu X, Chen Z, Duan J, Hashimoto K, Yang L, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain, behavior, and immunity. 2020; 87:18-22.
- Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID‐19) implicate special control measures. Journal of medical virology. 2020;92(6):568-76.
- Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. New England Journal of Medicine. 2020;382(20):e60.
- Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA neurology. 2020;77(6):683-90.
- D’Anna L, Kwan J, Brown Z, Halse O, Jamil S, Kalladka D, et al. Characteristics and clinical course of Covid-19 patients admitted with acute stroke. Journal of neurology. 2020;267(11):3161-5.
- Conti P, Caraffa A, Gallenga CE, Ross R, Kritas SK, Frydas I, et al. IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra). J Biol Regul Homeost Agents. 2020;34(4).
- Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):1.
- Filocamo G, Mangioni D, Tagliabue P, Aliberti S, Costantino G, Minoia F, et al. Use of anakinra in severe COVID-19: A case report. International Journal of Infectious Diseases. 2020; 96:607-609.
- Pontali E, Volpi S, Antonucci G, Castellaneta M, Buzzi D, Tricerri F, et al. Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease. Journal of Allergy and Clinical Immunology. 2020; 146(1):213-15.
- Cavalli G, De Luca G, Campochiaro C, Della-Torre E, Ripa M, Canetti D, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology. 2020; 2(6):e325-e31.
- Alzghari SK, Acuña VS. Supportive treatment with tocilizumab for COVID-19: a systematic review. Journal of Clinical Virology. 2020;127:104380.
- Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. Journal of Thrombosis and Haemostasis. 2020;18(5):1023-6.
- Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. Journal of thrombosis and haemostasis. 2020;18(4):844-7.
- Capra R, De Rossi N, Mattioli F, Romanelli G, Scarpazza C, Sormani MP, et al. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. European journal of internal medicine. 2020; 76:31-35.
- Atal S, Fatima Z. IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? Pharmaceutical Medicine. 2020:1-9.
- Del Pozo JS-G, Galindo M, Nava E, Jordán J. A systematic review on the efficacy and safety of IL-6 modulatory drugs in the treatment of COVID-19 patients. European review for medical and pharmacological sciences. 2020;24(13):7475-84.
- Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID‐19: A single center experience. Journal of medical virology. 2020;92(7):814-8.
- Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences. 2020;117(20):10970-5.
- Gergi M, Cushman M, Littenberg B, Budd RC. Thrombo‐inflammation response to Tocilizumab in COVID‐19. Research and practice in thrombosis and haemostasis. 2020; 4(8):1262-8.
- Martinez-Sanz J, Muriel A, Ron R, Herrera S, Perez-Molina JA, Moreno S, et al. Effects of Tocilizumab on Mortality in Hospitalized Patients with COVID-19: A Multicenter Cohort Study. medRxiv. 2021; 27(2):238-43.
- Meleveedu KS, Miskovsky J, Meharg J, Abdelrahman A, Tandon R, Moody AE, et al. Tocilizumab for severe COVID-19 related illness–A community academic medical center experience. Cytokine: X. 2020;2(4):100035.
- Morena V, Milazzo L, Oreni L, Bestetti G, Fossali T, Bassoli C, et al. Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy. European journal of internal medicine. 2020; 76:36-42.