key: cord-294854-rvrgcugn
authors: Hu, Biying; Huang, Shaoying; Yin, Lianghong
title: The cytokine storm and COVID‐19
date: 2020-06-27
journal: J Med Virol
DOI: 10.1002/jmv.26232
sha: 
doc_id: 294854
cord_uid: rvrgcugn

Coronavirus disease 2019 (COVID‐19), which began in Wuhan, China in December 2019 has caused a large global pandemic and poses a serious threat to public health. More than four million cases of COVID‐19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have been confirmed as of May 11, 2020. SARS‐CoV‐2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact. A growing body of clinical data suggests that a cytokine storm is associated with COVID‐19 severity and is also a crucial cause of death from COVID‐19. In the absence of antivirals and vaccines for COVID‐19, there is an urgent need to understand the cytokine storm in COVID‐19. Here, we have reviewed the current understanding of the features of SARS‐CoV‐2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID‐19. Additionally, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID‐19. This article is protected by copyright. All rights reserved.

An outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread throughout the world 1 . The initial symptoms of COVID-19 mainly include fever, cough, myalgia, fatigue, or dyspnea. In the later stages of the disease, dyspnea may occur and gradually develop into acute respiratory distress syndrome (ARDS) or multiple organ failure (MOF) 2 . It has been reported that a cytokine storm is Accepted Article associated with the deterioration of many infectious diseases, including severe acute respiratory syndrome (SARS) 3 and Middle East respiratory syndrome (MERS) 4 . The cytokine storm caused by has been suggested to be associated with COVID-19 severity 2, 5 . However, there is currently a limited understanding of the cytokine storm in severe COVID-19. Therefore, here, we have discussed the current findings and treatment strategies for the cytokine storm in severe COVID-19.

SARS-CoV-2 is the newest coronavirus known to infect humans. SARS-CoV, MERS-CoV, and SARS-CoV-2 cause severe pneumonia, while other human coronaviruses, including 229E, OC43, HKU1, and NL63, cause only the common cold 6 . SARS-CoV-2 belongs to the genus Betacoronavirus, which also includes SARS-CoV and MERS-CoV, both of which have caused SARS and MERS, respectively 7 . SARS-CoV-2, SARS-CoV, and MERS-CoV have similarities and differences. Genetic sequence analysis has revealed that SARS-CoV-2 shares 79% sequence identity with SARS-CoV and 50% identity with MERS-CoV 8 . The genomes of SARS-CoV-2 and the bat coronavirus RaTG13 are 96.2% homologous 9 . As of May 11, 2020, COVID-19 has resulted in 278,892 deaths and 4,006,257 cases, with an approximate case fatality rate of 7.0% 10 . SARS-CoV and MERS-CoV had a case fatality rate of 9.6% (774/8,096) and 34.4% (858/2,494), respectively 11 . The reproduction number (R0) of COVID-19 is thought to be This article is protected by copyright. All rights reserved. Accepted Article between 2 and 2.5 12 , which is slightly higher than of SARS (1.7.1.9) and MERS (<1) 13 . COVID-19 appears to be more infectious than SARS and MERS, but may be less severe. The origins of SARS-CoV, MERS-CoV, and SARS-CoV-2 are considered to be zoonotic. Both SARS-CoV and MERS-CoV originated in bats and spread directly to humans from marked palm civets and dromedary camels, respectively 14 . However, the origin of SARS-CoV-2 remains unclear.

SARS-CoV-2 has been reported to be transmitted between humans through direct contact, aerosol droplets, the fecal-oral route, and intermediate viruses from symptomatic and asymptomatic patients 15 . SARS-CoV and MERS-CoV are also thought to spread from infected to non-infected individuals through direct or indirect contact 15 19 proposed that SARS-CoV-2 infection triggers an excessive immune response known as a cytokine storm in cases of severe COVID-19. A cytokine storm is a potentially fatal immune disease characterized by the high-level activation of immune cells and excessive production of massive inflammatory cytokines and chemical mediators 20 . It is considered to be the main cause of disease severity and death in Accepted Article COVID-19 patients 5 , and is related to high levels of circulating cytokines, severe lymphopenia, thrombosis, and massive mononuclear cell infiltration in multiple organs 21 .

It has been found that SARS-CoV-2 genomes from different parts of the world have evolved in different clusters 22, 23 . Forster et al. 23 reported there to be at least three central variants of SARS-CoV-2 globally, named A, B, and C. The A type is the most similar to the bat coronavirus and is mainly found in the United States and Australia. The B type is more common in East Asia and has evolved through several mutations. The C type is primarily found in Europe. Different viral isolates exhibit significant differences in pathogenicity and viral load 24 .

Notably, given the diverse clinical symptoms of patients, it will be challenging to establish a genotype-phenotype relationship. With new sequences being uploaded to the GIASID (Global initiative on sharing all influenza data) every day, new results may be produced as more data become available. The emergence of variants may add to the challenges of vaccine development.

Pathological alterations in COVID-19 patients include pulmonary edema, diffuse alveolar injury with the formation of hyaline membranes, the presence of reactive type II pneumocyte hyperplasia, proteinaceous aggregates, fibrinous Accepted Article exudates, monocytes and macrophages within alveolar spaces, and inflammatory infiltration of interstitial mononuclear cells [25] [26] [27] [28] . Electron microscopy has revealed the presence of SARS-CoV-2 virus particles in bronchial and alveolar type II epithelial cells, but not in other tissues 26, 27 . Therefore, although a PCR test may be negative from blood or throat swabs, SARS-CoV-2 viral inclusions may be detected in the lungs. Immunohistochemical staining indicated that CD68 + macrophages, CD20 + B cells, and CD8 + T cells infiltrated the alveolar cavity and alveoli 26 . The levels of CD8 ＋ T cells may be slightly higher than that of CD4 ＋ T cells within the alveolar septa 29 

Cellular entry of SARS-CoV-2 depends on the binding of S proteins covering the surface of the virion to the cellular ACE2 receptor 9, 33 and on S protein This article is protected by copyright. All rights reserved.

priming by TMPRSS2, a host membrane serine protease 33 Table 1 , and cytokine secretion patterns based on COVID-19 severity are shown in Table 2 .

Prevention and mitigation of the cytokine storm may be the crux to saving patients with severe COVID-19. Currently, many therapies are being evaluated in clinical trials due to a lack of high-quality evidence.

Corticosteroids inhibit the host inflammatory response and suppress the immune response and pathogen clearance 46 Overall, although evidence indicates a potential role for the use of corticosteroids This article is protected by copyright. All rights reserved.

in patients with severe COVID-19, caution should be exercised given the possibilities of viral rebound and adverse events.

Given their in vitro antiviral effects and anti-inflammatory properties, CQ and its analog HCQ are considered to be potential therapies for COVID-19.

Considering the severe side effects of CQ, HCQ may be a better therapeutic option. CQ and HCQ are able to reduce CD154 expression in T cells 52 However, the risks associated with TCZ (e.g., severe infections, thrombocytopenia, neutropenia, liver damage) should also be noted 64 . It is unclear whether there are different effects between IL-6 antagonists (siltuximab) and

IL-6R antagonists (TCZ). Siltuximab binds to sIL-6 and inhibits only cis and trans signaling. TCZ binds to both mIL-6R and sIL-6R and inhibits both cis and trans signaling and trans presentation 40, 65 . Of note, IL-6 inhibitors are not able to bind to IL-6 produced by viruses such as HIV and human herpesvirus-8 65 . Currently, the application of TCZ for COVID-19 treatment is under study. The three drugs mentioned above (corticosteroids, HCQ, TCZ) are immunosuppressants. Owing to overall damage to the immune system caused by autoimmune diseases and the iatrogenic effects of immunosuppressants, the risk of infection in patients with autoimmune diseases will be increased compared to the general population.

Currently, rheumatology societies 66-69 recommend the use of immunosuppressive drugs (except glucocorticoids) to be suspended in COVID-19 patients.

MSCs have a wide range of immune regulatory functions and can inhibit the abnormal activation of T lymphocytes and macrophages and the secretion of pro-inflammatory cytokines 70 . MSC therapy was found to significantly reduce the mortality of patients with H7N9-induced ARDS and had no harmful side effects 71 .

A clinical trial of MSC therapy revealed that MSCs were able to rapidly and significantly improve the clinical symptoms of COVID-19 without any observed adverse effects 72 . Although side effects of MSC treatment are rarely reported, the safety and effectiveness of this treatment require further investigation.

Anakinra, an IL-1 receptor antagonist that blocks the activity of pro-inflammatory cytokines IL-1α and IL-1β, has been reported to improve respiratory function and increase the survival rate of COVID-19 patients 73 . IL-1 receptor antagonists increase the risk of bacterial infections, but this is extremely rare for anakinra 65 . Janus kinase (JAK) inhibitors can inhibit inflammatory cytokines and reduce the ability of viruses to infect cells 74 Table 3 .

The cytokine storm leads to deleterious clinical manifestations or even acute mortality in critically ill patients with COVD-19. Impaired acquired immune This article is protected by copyright. All rights reserved.

responses and uncontrolled inflammatory innate responses may be associated with the mechanism of the cytokine storm in COVID-19. Early control of the cytokine storm through therapies such as immunomodulators and cytokine antagonists is essential to improve the survival rate of COVID-19 patients. Although many research articles are published each month, majority of the existing literature about COVID-19 comes from descriptive works. Additionally, high-quality evidence will be necessary to understand and treat the cytokine storm of COVID-19. 

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We thank all the doctors and nurses who have bravely fought the virus during the COVID-19 pandemic.

The authors declare no conflicts of interest. 1