{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T15:04:32Z","timestamp":1778511872760,"version":"3.51.4"},"reference-count":63,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an 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-1\u03b2, IL-8, TNF-\u03b1, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1\u03b2, IL-6) and\/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.<\/jats:p>","DOI":"10.3390\/jcm10040801","type":"journal-article","created":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T04:49:01Z","timestamp":1613537341000},"page":"801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Novel Coronavirus Disease 2019 (COVID-19) and Cytokine Storms for More Effective Treatments from an Inflammatory Pathophysiology"],"prefix":"10.3390","volume":"10","author":[{"given":"Shumpei","family":"Yokota","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Yokohama City University, Yokohama 236-0004, Japan"},{"name":"Fuji-Toranomon Children\u2019s Center, Gotemba 412-0045, Japan"},{"name":"Japan Medical Research Foundation (JMRF), Tokyo 135-0063, Japan"},{"name":"Japan College of Fibromyalgia Investigation (JCFI), Tokyo 160-0022, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0568-1496","authenticated-orcid":false,"given":"Takako","family":"Miyamae","sequence":"additional","affiliation":[{"name":"Pediatric Rheumatology, Institute of Rheumatology, Tokyo Women\u2019s Medical University, Tokyo 162-0054, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Kuroiwa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yokohama City University, Yokohama 236-0004, Japan"},{"name":"Chairman of Stroke Center, Teikyo University School of Medicine Mizonokuchi Hospital, Kawasaki 192-0395, Japan"},{"name":"Japan Society of Neurovegetative Research (JSNR), Tokyo 170-0002, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kusuki","family":"Nishioka","sequence":"additional","affiliation":[{"name":"Japan Medical Research Foundation (JMRF), Tokyo 135-0063, Japan"},{"name":"Global Health Innovation Policy Program (GHIPP), National Graduate Institute for Policy Studies (GRIPS), Tokyo 106-0032, Japan"},{"name":"American College of Rheumatology (ACR), Atlanta, GA 30319, USA"},{"name":"St. Marianna University, Kawasaki 216-8511, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention","volume":"323","author":"Wu","year":"2020","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102434","DOI":"10.1016\/j.jaut.2020.102434","article-title":"The deadly coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in China","volume":"109","author":"Yang","year":"2020","journal-title":"J. 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