Novel coronavirus disease (COVID-19) and cytokine storms. For more effective treatments from the viewpoints of an inflammatory pathophysiology perspective


Novel Coronavirus Disease (COVID-19) swept the world and led to a global pandemic. SARS-CoV-2, which is thought to have derived from bats as their reservoir hosts, has over time and similarly as with SARS-CoV, combined with human angiotensin converting enzyme 2 (ACE2). Thus, this caused infections in cells and established them into a human infectious disease (COVID-19).

Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines such as G-CSF, IP10, MCPl, to develop an increase the inflammatory responses.

In the case of COVID-19, it revealed that excessive inflammatory responses occur, and that the exaggerated proinflammatory cytokines and chemokines are detected in COVID-19 patients' sera resulting in cytokine release syndrome (CRS) or cytokine storm (CS). This causes coagulation abnormalities, excessive oxidation development, vital organ damages, immune system failure, and finally, progresses to disseminated intravascular coagulation (DIC) and multiple organ failure (MOF).

Additionally, excessive inflammatory responses lead to mitochondrial dysfunction due to progressive and persistent stress which leads to cells and mitochondrial fracturing products containing mitochondrial DNA and damaged cell debris which in turn are involved in the chronic excessive inflammation as damage-associated molecular patterns (DAMPs). Thus, respiratory infection progressively leads to DIC from acute respiratory distress syndrome (ARDS) including vascular endothelial cell damages and coagulation-fibrinolysis system disorders. Then, this worsens to central nervous system disorders, renal failure, liver failure, and finally to MOF.

With regards to treatments for COVID-19, the followings are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. Firstly, the administering of Favipiravir for the suppression of SARS-CoV-2, and Nafamostat for the inhibition of ACE2 function should be considered. Then, the administration of anti-rheumatic drugs (monoclonal antibodies which combine with the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as Tocilizumab). Finally, melatonin may be effective under recognition of the pathology of CRS/CS for the improvement of mitochondrial function.

The paper will further explore these subjects with reports mostly from China and Europe.

Keywords:COVID-19, SARS-CoV-2, cytokine storm, IL-1β, IL-6

Funding. The study was not sponsored.

Conflict of interest. The authors declare no conflicts of interest associated with this manuscript. Yokota S. was involved with the development of Tocilizumab for juvenile idiopathic arthritis (JIA), but has no conflict of interest directly relevant to the content of this article.

Contribution. The authors contributed equally to this article.

For citation: Yokota S., Kuroiwa Y., Nishioka K. Novel coronavirus disease (COVID-19) and cytokine storms. For more effective treatments from the viewpoints of an inflammatory pathophysiology perspective. Infektsionnye bolezni: novosti, mneniya, obuchenie [Infectious Diseases: News, Opinions, Training]. 2020; 9 (4): 13-25. DOI: (in Russian)


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Yushchuk Nikolay Dmitrievich
Academician of the Russian Academy of Sciences, Professor, head of the Infectious Diseases and Epidemiology Department, President of the Moscow State University of Medicine and Dentistry named after A.I. Evdokimov, Board member of the National Scientific Infectiologists? Society.
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