COVID-19: cytokine storm and anticytokine therapy


  • M.V. Bondar Shupyk National University of Public Health of Ukraine, Kyiv, Ukraine
  • M.M. Pylypenko Shupyk National University of Public Health of Ukraine, Kyiv, Ukraine
  • O.A. Loskutov Shupyk National University of Public Health of Ukraine, Kyiv, Ukraine



COVID-19, pro-inflammatory cytokine, anti-inflammatory cytokines, systemic inflammatory response, cytokine storm, acute respiratory distress syndrome, hypercoagulation, mononuclear macrophages, anti-cytokine therapy, glucocorticoids, turmeric-based drugs, review


This review describes in detail one of the key links in the pathogenesis of COVID-19 — the overproduction of pro-inflammatory cytokines that play a key role in the formation of acute respiratory distress syndrome, disseminated intravascular coagulation, multiple organ dysfunction syndromes, and causes high mortality among patients infected with COVID-19. The article deals with the basic directions of intensive therapy for the prevention of development as well as the treatment of cytokine storm and drugs for anti-cytokine therapy. Among drugs with anti-cytokine and anti-inflammatory properties, corticosteroids have the highest evidence base for efficacy and safety. The most promising drugs that require further clinical studies are those that inhibit the activity of the main intracellular regulator of the production of proinflammatory cytokines, the nuclear transcription factor kappa B of immunocompetent cells. These include turmeric-based preparations, which are now at the final stages of the pre-registration studies.


Qing Ye, Bili Wang, Jian Hua Mau. Pathogenesis and Treatment of the “Cytokine Storm” in COVID-19. Journal of Infection. 2020. 80. 607-613.

Special Expert Group for Control of the Epidemic of Novel Coronavirus Pneumonia of the Chinese Preventive Medicine Association An update on the Epidemiological characteristics of novel Coronavirus Pneumonia (COVID-19). Clin. J. Epidemiol. 2020. 4.

Chousterman B.G. еt al. Cytokine storm and sepsis disease pathogenesis. Seminors Immunopatholog. 2017. 39(5). 517-28.

Channapanavar R. et al. Disregulate Type 1 Interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-Cov infected Mice. Cell. Host. Microbe. 2016. 19(2). 181-93. PubMed PMID: 26867177.

Карл Дреслер. Иммунология (словарь): пер. с нем. К.: Вища школа, 1988. 224 с.

Davidson S. et al. Disease-promoting effects of Type 1 Interferons in viral, bacterial and coinfection. J. Interf. Cytokine Res. 2015. 35(4). 352-64. PubMed PMID: 25714109.

Shaw A.C. et al. Are-dependent dysregulation of innate immunity. Nature Rev. Immunolog. 2013. 13(12). 875-87. PubMed PMID: 24157572.

Law H.K.W. et al. Chemokine up-regulation in SARS-coronaqvirus-infected, monocyte-derived human dendritic cells. Blood. 2005. 106(7). 2366-74. PubMed PMID: 15860669.

Cheung C.Y. et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis. J. Virol. 2005. 79(12). 7819-26. PubMed PMID: 15919935.

Tynell J. et al. Middle East respiratory syndrome coronavirus shaws poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J. Gen. Virol. 2016. 97(2). 344-55. PubMed PMID: 266022089.

Zhou J. et al. Active replication of Middele East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implication to pathogenesis. J. Infect. Diseases. 2014. 209(9). 1331-42. PubMed PMID: 24065148.

Scheuplein V.A. et al. High secretion of interferons by human plasmocytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus. J. Virol. 2015. 89(7). 3859-69. PubMed PMID: 25609809.

Lau S.K.P. et al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implication for pathoge­nesis and treatment. J. Gen. Virol. 2013. 94(Pt. 12). 2679-99. PubMed PMID: 24077366.

Smits S.L. et al. Exacerbated innate host response to SARS-CoV in aget non-human primates. PLoS Pathogens. 2010. 6(2). 100075. PubMed PMID: 20140198.

Ng D.L., Al Hossani et al. Clinicopathologic, immunohystochemical and ultrastructural findings of a fatal case Middle East respiratory syndrome coronavirus infection in the United Arab Emi­rates, April 2014. Am. J. Pathol. 2016. 186(3). 652-8. PubMed PMID: 26857507.

Chien J.Y. et al. Temporal changes in cytokine/chemokine profiles and pulmonary involment in severe acute respiratory syndrome. Respirol. (Сarlton, Vic). 2006. 11(6). 715-22. PubMed PMID: 17052299.

Wong C.K. et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exper. Immunol. 2004. 136(1). 95-103. PubMed PMID: 15030519.

Huang C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Chine. Lancet. 2020. 395(10223). 497-506.

Marchingo J.M. et al. Quantitative analysis of how Mic controle T-cell proteomes and metabolic pathway during T-cell activation. eLife. 2020. 9. 53725.

Chen L. et al. Analisis of clinic features of 29 patients with 2019 novel coronavirus pneumonia. Chin. J. Tuberc. Respir. Dis. 2020. 43.

Yang K. et al. Clinical course and out comes of critical ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered retrospective observational study. Lancet Respirat. Med. 2020. 2213-600. PubMed PMID: 32105632.

Force TADT Acute respiratjry distress syndrome: the berlin definition. JAMA. 2012. 307(23). 2526-33.

Ho J.C. et al. High-dose puls versus nonpulse corticosteroid regimens in severe acute respiratory syndrome. Am. J. Resp. Crit. Care Med. 2003. 168(2). 1449-56. PubMed PMID: 12947028.

Auyeung T.W. et al. The used of corticosteroid as treatment in SARS was associated with adverse outcomes: а retrospective cohort study. J. Infect. 2005. 51(2). 98-102. PubMed PMID: 16038758.

Villar J., Ferrando C., Martinez D. et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir. Med. 2020. 8. 267-276.

The WHO Rapid Evidence for COVID19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically ill Patients With COVID-19. A Metaanalisis. JAMA. 2020 Oct 6. 324(13). 1330-1341. Doi: 10.1001/Jama.2020.17033.

Bruno M. Tomazini, Israel S. Maia, Cavalcanti A.B. et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19. The CoDEX Randomized Clinical Trial. JAMA. 2020. 324(13). 1307-1316. Doi: 10.1001/Jama.2020. 17021.

Deqin P.F., Heming N., Meziani F. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically ill Patients With COVID-19. JAMA. 2020. 324(13). 1298-1306. doi: 10.1001/Jama.2020.

The Writing Committee for the REMAP-CAP investigators Effect of Hydrocortisone of Mortality and Organ Support in Patients with Severe COVID-19. The REMAP-CAP COVID-19 Corticosteroid Domain Randomised Clinical Trial. JAMA. 2020 Oct 6. 324(13). 1317-1329. doi: 10.1001/Jama.2020.

Zhao J.P. Expert consensus on the use of corticosteroid in patients with 2019-n Cov pneumonia. Chin. J. Tuberc. Respir. Dis. 2020.

Zhao J.P. Effectiveness of glucorticosteroid therapy in patients with severe novel coronavirus pneumonia: protocol of rando­mized controlled trial. Chin. Med. J. 2020.

Tleyjeh I.M. et al. Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis, Clinical Microbiology and Infection.

Stone J.H., Frigault M.J., Serling-Boyd N.J. et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N. Engl. J. Med. 2020. 383(24). 2333-2344. doi: 10.1056/NEJMoa2028836.

Michael S. Saag et al. Misquided Use of Hydroxychloro­qine for COVID-19. The Infusion of Politics Into Science. Jama. 2020. 324(21). 2161-2162.

Borda M.G.S., Almaida F.F., Sampio V.S. et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-Cov-2) Infection. A Randomized Clinical ­Trial. Jama Network Open. 2020. 3(423).

Fihn S.D., Perencevich E., Bredley S.M. Caution Needed on the Use of Chloroquine and Hydroxychloroquine for Coronovirus Di­sease 2019. Jama Network Open. 2020. 3(423). e209035.

Self Wesley H., Sember M.W., Lether L.M. et al. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19. A Randomized Clinical. Trial. JAMA. 2020. 324(21). 2165-2176. doi: 10.1001/Jama.2020.

Wen-tao Meng, Long Qing, Chum-Zen Li et al. Ulinastatin: A Potential Alternative to Glucocorticoid in the Treatment of Severe Decompression Sickness Frontiers in Physiology. March 2020(11). Article 273.

Xiangiun Zang, Zhaozhong Zhy, Wei Liu et al. Ulinastatin treatment for acute respiratory distress syndrome in Chine: meta-analisis of randomized controlled trial. BMC Pulmonary Medicine. 2019. 19. 196.

Hai Huang, Ping-Fang Hu, Liang-Liang Sun et al. Treatment of COVID-19 Patients With High Dose of Ulinastatin. Changzheng Hospital.

Manoharan Y., Haridas V., Vasanthakumar K.C. et al. Curcumin: a Wonder Drug as a Preventive Measure for COVID19 Management. Indian J. Clin. Biochem. 2020 Jul. 35(3). 373-375.

Geng et al. Curcumin attenuates BPA-induced insulin resistance in Hep G2 cells through suppretion of JNK/p38 pathways. Toxicol. Lett. 2017. 272. 75-83.

Varna S.R. et al. Imiquimod-induced Psoriasis-like inflammation in differentiated Human keratocytes: its evaluation using curcumin. Eur. J. Pharmacol. 2017. 813. 33-41.

Devi Y.S. et al. Ingibition of IL-6 signaling pathway by curcumin in uterine decidual cells. Plos ONE. 2015. 10. e0125627.

Panahi Y. et al. A randomized controlled trial on the anti-inflamatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann. Clin. Biochem. 2012. 49. 580-588.





Scientific Review