COVID-19-associated cytokine storm: Difference between revisions

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VisualWikitext

Revision as of 19:35, 11 July 2020

For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Synonyms and keywords:

Overview

Historical Perspective

The etiological agent is SARS-CoV-2, named for the similarity of its symptoms to those induced by the severe acute respiratory syndrome, causing coronavirus disease 2019 (COVID-19), is a virus identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China.^[1]^[2]
The growing number of patients however, suggest that human-to-human transmission is actively occurring.^[3]^[4]
The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020.
On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic.
Cytokine storm is suspected to be the major cause of death in previous viral pandemics :
- Influenza virus pandemic of 1918.
- H5N1 epidemic of 1991.
- SARS epidemic of 2003.

Classification

There is no established system for the classification of COVID-19-associated cytokine storm.

Pathophysiology

Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory cytokines.^[5]

Cytokines Involved in Cytokine Storm

Cytokines are small proteins that are released for cell signaling.^[5]
Cytokines types and their actions include:^[5]
- Interferons (INFs)
  - Key role in innate immunity
  - Regulation of the production of antiviral proteins
  - Regulation of the production of antiproliferative proteins
- Interleukins (ILs)
  - Regulation of immune cell differentiation and activation
  - May be pro- or anti-inflammatory
- Chemokines
  - Act as chemotaxins
  - Recruitment of leukocytes
- Colony-stimulating factors
  - Induction of hematopoietic progenitor cell proliferation and differentiation
- Tumor necrosis factor (TNF)
  - Activation of T cells (cytotoxic)

Pathogenesis of Cytokine Storm

Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory cytokines.^[5]
During sepsis, cytokine storm may be the cause of tissue or organ injury.^[6]

Cytokine storm causes inflammation, which in the beginning of the disease is local and later spreads around by the systemic circulation. This is followed by repair and restoration of tissues, organs and their functions. However, in severe or some inflammations, the repair is with fibrosis which may lead to permanent dysfunction of organs.^[5]
Lung damage caused by pathogens (such as SARS-CoV and influenza virus) may lead to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).
Cytokines profiles change over time in patients with sepsis:^[5]
- In the early stages of the infection (minutes to hours), cytokines such as TNF and IL-1, and chemokines such as IL-8 and MCP-1 (CCL2) increase.
- Then, an increase in IL-6 is followed.
- Later, IL-10 (anti-inflammatory cytokine) increases.

Proinflammatory cytokines that have a role in ARDS include:^[7]^[8]^[9]^[10]
- IL-1β
- IL-6
- IL-8 (CXCL8)
- CCL-2 (MCP-1)
- CCL-3 (Macrophage inflammatory protein-1A)
- CCL-5
- IFNγ -induced protein 10 (IP-10, CXCL10)
- Granulocytemacrophage colony-stimulating factor (GM-CSF)

Cytokine storm (dysregulated and excessive release of cytokines) has been associated with ARDS in SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV) infections.^[11]

It has been suggested that the pathogenesis of severe COVID-19 infection may be due to cytokine storm and suppression of Th1 antiviral responses since the following findings have been reported to be associated with severe COVID-19 infection:^[12]^[13]
- Increase in pro-inflammatory cytokines (such as IL-6)
- Increase in IL-10 (a cytokine produced by Th2) and suppression in Th1 antiviral responses
- Decrease in CD+8 T-cells

It has been reported that in patients with COVID-19 there is increase in IL-1B, IFN-γ , IP-10, and monocyte hemoattractant protein 1 (MCP-1) and COVID-19 patients in the intensive care unit (ICU) have increased levels of granulocyte colony-stimulating factor, IP-10, MCP-1, macrophage inflammatory protein-1A, and TNF-α compared to those in general wards. However, in contrast to SARS infection, patients with COVID-19 infection have high levels of IL-4 and IL-10 (secreted by Th2 cells), which are antiinflammatory cytokines.^[14]


Some of The Cytokines Involved in COVID-19-Associated-Cytokine Storm^[12]^[13]^[14]^[15]
Proinflammatory	Interferones	IFN-γ
	Interleukines	IL-1β IL-6
	Chemokines	CCL-2 (MCP-1) CCL-3 (Macrophage inflammatory protein-1A) CCL-5 IL-8 (CXCL8) IP-10 (CXCL10)
	Colony-stimulating factors	GM-CSF
	Tumor necrosis factor	TNF-α
Anti-inflammatory	Interleukines	IL-4 IL-10

Causes

Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus called SARS-CoV-2 and is the cause of cytokine storm in COVID-19 infection.

Epidemiology and Demographics

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

OR

In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

OR

In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.

Patients of all age groups may develop [disease name].

OR

The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

OR

[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

OR

[Chronic disease name] is usually first diagnosed among [age group].

OR

[Acute disease name] commonly affects [age group].

There is no racial predilection to [disease name].

OR

[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].

[Disease name] affects men and women equally.

OR

[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.

The majority of [disease name] cases are reported in [geographical region].

OR

[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Risk Factors

There are no established risk factors for COVID-19-associated Cytokine storm].

Screening

There is insufficient evidence to recommend routine screening for COVID-19 related cytokine storm.

Natural History, Complications, and Prognosis

Cytokine storm has no definition.it denotes a hyperactive immune response characterized by release of interferons, interleukins, TNF, chemokines and several other mediators. Since the SARS-Cov-1 cytokine elevation was associated with various adverse features.^[16]^[17]
The characteristic of this phenomena could be considered as an indicator of adverse clinical outcome such as ARDs, Shock and ARF.^[18]

Diagnosis

Diagnostic Study of Choice

Most important Cytokine concentration rise is :^[19]

History and Symptoms

COVID-19 infected individual whom go through more adverse clinical manifestation, such as ARDS and high inflammatory states are more likely to undergo cytokine elevation.
For COVID-19 associated history and symptoms click here.

Physical Examination

For COVID-19 Physical examination click here.

Laboratory Findings

According to many reviews done so far, Interleukin-6 is the best indicator of cytokine storm.
Below is different studies revealing cytokine level in healthy and severe infected individuals:

Plasma IL-6 concenteration reported in COVID-19
Report	Total population(IL-6 level pg/ml)	Severe infection (IL-6 level pg/ml)
Zhou et al^[20]	191 (5-11)	54 (8-14)
Wu et al^[21]	123 (6-9)	84 (6-11)
Mo et al^[22]	155 (17-96)	85 (31-165)

Electrocardiogram

There are no ECG findings regarding to COVID-19-associated Cytokine storm.

X-ray

There are no x-ray findings regarding to COVID-19-associated Cytokine storm.

Echocardiography or Ultrasound

There are no echocardiography or ultrasound findings regarding to COVID-19-associated Cytokine storm.

CT scan

There are no CT scan findings regarding to COVID-19-associated Cytokine storm.

MRI

There are no MRI findings regarding to COVID-19-associated Cytokine storm.

Other Imaging Findings

There are no other imaging findings regarding to COVID-19-associated Cytokine storm.

Treatment

Medical Therapy

There is no proven treatment suggested until now.

Potential therapies for reducing inflammation are:
- Corticosteroids:^[23]
  - Systemic use of corticosteroid use is not recomended by WHO based on evidence from patients with MERS and ARDS.
- Tocilizumab:^[24]^[25]^[26]^[27]
  - Toclizumab is an FDA approved drug used for cytokine release syndrome after Chimeric Antigen Receptor.infusion. which cause cytokine release storm.
  - It is IL-6 Receptor antibody, which is effective in similar clinical manifestations.
  - In some off label studies, it is shown that tocolizumab can cause improvement in patients.
- Etoposide:^[28]
  - Etoposide is used for suppressing cytokine release in hemophagocytic lymphohistiocytosis
  - In patients with severe disease etoposide can inhibit overwhelming inflamation.
- Ruxolitinib:^[29]
  - Jack1/2 inhibitor
  - It is used in hemophagocytic lymphohistiocytosis
  - In a prospective randomized trial it was shown to reduce levels of 7 cytokines compared to control group, which caused faster improvement in patients with sever infection.

Surgery

Surgical intervention is not recommended for the management of COVID-19-associated cytokine storm.

Primary Prevention

There are no established measures for the primary prevention of COVID-19-associated cytokine storm.

Secondary Prevention

There are no established measures for the secondary prevention of COVID-19-associated cytokine storm.

References

↑ https://www.cdc.gov/coronavirus/2019-ncov/about/index.html. Missing or empty |title= (help)
↑ Lu, Jian; Cui, Jie; Qian, Zhaohui; Wang, Yirong; Zhang, Hong; Duan, Yuange; Wu, Xinkai; Yao, Xinmin; Song, Yuhe; Li, Xiang; Wu, Changcheng; Tang, Xiaolu (2020). "On the origin and continuing evolution of SARS-CoV-2". National Science Review. doi:10.1093/nsr/nwaa036. ISSN 2095-5138.
↑ Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. ISSN 0140-6736.
↑ https://www.cdc.gov/coronavirus/2019-ncov/about/transmission.html. Missing or empty |title= (help)
↑ ^5.0 ^5.1 ^5.2 ^5.3 ^5.4 ^5.5 Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG (2012). "Into the eye of the cytokine storm". Microbiol Mol Biol Rev. 76 (1): 16–32. doi:10.1128/MMBR.05015-11. PMC 3294426. PMID 22390970.
↑ Chousterman BG, Swirski FK, Weber GF (2017). "Cytokine storm and sepsis disease pathogenesis". Semin Immunopathol. 39 (5): 517–528. doi:10.1007/s00281-017-0639-8. PMID 28555385.
↑ Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J; et al. (2005). "Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome". Am J Respir Crit Care Med. 171 (8): 850–7. doi:10.1164/rccm.200407-857OC. PMID 15657466.
↑ Cameron MJ, Bermejo-Martin JF, Danesh A, Muller MP, Kelvin DJ (2008). "Human immunopathogenesis of severe acute respiratory syndrome (SARS)". Virus Res. 133 (1): 13–9. doi:10.1016/j.virusres.2007.02.014. PMC 7114310 Check |pmc= value (help). PMID 17374415.
↑ Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, Leung BP; et al. (2005). "Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome". BMC Immunol. 6: 2. doi:10.1186/1471-2172-6-2. PMC 546205. PMID 15655079.
↑ Ye Q, Wang B, Mao J (2020). "The pathogenesis and treatment of the `Cytokine Storm' in COVID-19". J Infect. 80 (6): 607–613. doi:10.1016/j.jinf.2020.03.037. PMC 7194613 Check |pmc= value (help). PMID 32283152 Check |pmid= value (help).
↑ Channappanavar R, Perlman S (2017). "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology". Semin Immunopathol. 39 (5): 529–539. doi:10.1007/s00281-017-0629-x. PMC 7079893 Check |pmc= value (help). PMID 28466096.
↑ ^12.0 ^12.1 Liu J, Li S, Liu J, Liang B, Wang X, Wang H; et al. (2020). "Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients". EBioMedicine. 55: 102763. doi:10.1016/j.ebiom.2020.102763. PMC 7165294 Check |pmc= value (help). PMID 32361250 Check |pmid= value (help).
↑ ^13.0 ^13.1 Kuppalli K, Rasmussen AL (2020). "A glimpse into the eye of the COVID-19 cytokine storm". EBioMedicine. 55: 102789. doi:10.1016/j.ebiom.2020.102789. PMC 7204696 Check |pmc= value (help). PMID 32388462 Check |pmid= value (help).
↑ ^14.0 ^14.1 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y; et al. (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. PMC 7159299 Check |pmc= value (help). PMID 31986264.
↑ Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M (2020). "The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system". Cytokine Growth Factor Rev. 53: 25–32. doi:10.1016/j.cytogfr.2020.05.003. PMC 7211650 Check |pmc= value (help). PMID 32446778 Check |pmid= value (help).
↑ Calfee, Carolyn S; Delucchi, Kevin; Parsons, Polly E; Thompson, B Taylor; Ware, Lorraine B; Matthay, Michael A (2014). "Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials". The Lancet Respiratory Medicine. 2 (8): 611–620. doi:10.1016/S2213-2600(14)70097-9. ISSN 2213-2600.
↑ Famous, Katie R.; Delucchi, Kevin; Ware, Lorraine B.; Kangelaris, Kirsten N.; Liu, Kathleen D.; Thompson, B. Taylor; Calfee, Carolyn S. (2017). "Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy". American Journal of Respiratory and Critical Care Medicine. 195 (3): 331–338. doi:10.1164/rccm.201603-0645OC. ISSN 1073-449X.
↑ Sinha, Pratik; Delucchi, Kevin L.; Thompson, B. Taylor; McAuley, Daniel F.; Matthay, Michael A.; Calfee, Carolyn S. (2018). "Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study". Intensive Care Medicine. 44 (11): 1859–1869. doi:10.1007/s00134-018-5378-3. ISSN 0342-4642.
↑ Schultz, Duane R.; Arnold, Patricia I. (1990). "Properties of four acute phase proteins: C-reactive protein, serum amyloid a protein, α1-acid glycoprotein, and fibrinogen". Seminars in Arthritis and Rheumatism. 20 (3): 129–147. doi:10.1016/0049-0172(90)90055-K. ISSN 0049-0172.
↑ Zhou, Fei; Yu, Ting; Du, Ronghui; Fan, Guohui; Liu, Ying; Liu, Zhibo; Xiang, Jie; Wang, Yeming; Song, Bin; Gu, Xiaoying; Guan, Lulu; Wei, Yuan; Li, Hui; Wu, Xudong; Xu, Jiuyang; Tu, Shengjin; Zhang, Yi; Chen, Hua; Cao, Bin (2020). "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study". The Lancet. 395 (10229): 1054–1062. doi:10.1016/S0140-6736(20)30566-3. ISSN 0140-6736.
↑ Wu, Chaomin; Chen, Xiaoyan; Cai, Yanping; Xia, Jia’an; Zhou, Xing; Xu, Sha; Huang, Hanping; Zhang, Li; Zhou, Xia; Du, Chunling; Zhang, Yuye; Song, Juan; Wang, Sijiao; Chao, Yencheng; Yang, Zeyong; Xu, Jie; Zhou, Xin; Chen, Dechang; Xiong, Weining; Xu, Lei; Zhou, Feng; Jiang, Jinjun; Bai, Chunxue; Zheng, Junhua; Song, Yuanlin (2020). "Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China". JAMA Internal Medicine. 180 (7): 934. doi:10.1001/jamainternmed.2020.0994. ISSN 2168-6106.
↑ Zhang, Yongxi; Wang, Fan; Cao, Qian; Zheng, Ruiying; Chen, Xiaoping; Ma, Zhiyong; Song, Shihui; Chen, Tielong; Luo, Mingqi; Liang, Ke; Gao, Shicheng; Cheng, Zhenshun; Xiong, Yong; Wang, Hongling; Zhao, Qiu; Deng, Liping; Xiao, Yu; Xing, Yuanyuan; Mo, Pingzheng (2020). "Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China". Clinical Infectious Diseases. doi:10.1093/cid/ciaa270. ISSN 1058-4838.
↑ Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. ISSN 0140-6736.
↑ Le, Robert Q.; Li, Liang; Yuan, Weishi; Shord, Stacy S.; Nie, Lei; Habtemariam, Bahru A.; Przepiorka, Donna; Farrell, Ann T.; Pazdur, Richard (2018). "FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome". The Oncologist. 23 (8): 943–947. doi:10.1634/theoncologist.2018-0028. ISSN 1083-7159.
↑ Xu, Xiao-Jun; Tang, Yong-Min (2014). "Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells". Cancer Letters. 343 (2): 172–178. doi:10.1016/j.canlet.2013.10.004. ISSN 0304-3835.
↑ Campins L, Boixeda R, Perez-Cordon L, Aranega R, Lopera C, Force L (2020). "Early tocilizumab treatment could improve survival among COVID-19 patients". Clin Exp Rheumatol. 38 (3): 578. PMID 32456769 Check |pmid= value (help).
↑ Morena, Valentina; Milazzo, Laura; Oreni, Letizia; Bestetti, Giovanna; Fossali, Tommaso; Bassoli, Cinzia; Torre, Alessandro; Cossu, Maria Vittoria; Minari, Caterina; Ballone, Elisabetta; Perotti, Andrea; Mileto, Davide; Niero, Fosca; Merli, Stefania; Foschi, Antonella; Vimercati, Stefania; Rizzardini, Giuliano; Sollima, Salvatore; Bradanini, Lucia; Galimberti, Laura; Colombo, Riccardo; Micheli, Valeria; Negri, Cristina; Ridolfo, Anna Lisa; Meroni, Luca; Galli, Massimo; Antinori, Spinello; Corbellino, Mario (2020). "Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy". European Journal of Internal Medicine. 76: 36–42. doi:10.1016/j.ejim.2020.05.011. ISSN 0953-6205.
↑ La Rosée, Paul (2015). "Treatment of hemophagocytic lymphohistiocytosis in adults". Hematology. 2015 (1): 190–196. doi:10.1182/asheducation-2015.1.190. ISSN 1520-4391.
↑ Cao, Yang; Wei, Jia; Zou, Liang; Jiang, Tiebin; Wang, Gaoxiang; Chen, Liting; Huang, Liang; Meng, Fankai; Huang, Lifang; Wang, Na; Zhou, Xiaoxi; Luo, Hui; Mao, Zekai; Chen, Xing; Xie, Jungang; Liu, Jing; Cheng, Hui; Zhao, Jianping; Huang, Gang; Wang, Wei; Zhou, Jianfeng (2020). "Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial". Journal of Allergy and Clinical Immunology. 146 (1): 137–146.e3. doi:10.1016/j.jaci.2020.05.019. ISSN 0091-6749.

Template:WikiDoc Sources

[1] ttps://www.cdc.gov/coronavirus/2019-ncov/about/index.html. Missing or empty |title= (help)

[LuCui2020-2] Lu, Jian; Cui, Jie; Qian, Zhaohui; Wang, Yirong; Zhang, Hong; Duan, Yuange; Wu, Xinkai; Yao, Xinmin; Song, Yuhe; Li, Xiang; Wu, Changcheng; Tang, Xiaolu (2020). "On the origin and continuing evolution of SARS-CoV-2". National Science Review. doi:10.1093/nsr/nwaa036. ISSN 2095-5138.

[HuangWang2020-3] Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. ISSN 0140-6736.

[4] ttps://www.cdc.gov/coronavirus/2019-ncov/about/transmission.html. Missing or empty |title= (help)

[pmid22390970-5] 5.0 ^5.1 ^5.2 ^5.3 ^5.4 ^5.5 Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG (2012). "Into the eye of the cytokine storm". Microbiol Mol Biol Rev. 76 (1): 16–32. doi:10.1128/MMBR.05015-11. PMC 3294426. PMID 22390970.

[pmid28555385-6] Chousterman BG, Swirski FK, Weber GF (2017). "Cytokine storm and sepsis disease pathogenesis". Semin Immunopathol. 39 (5): 517–528. doi:10.1007/s00281-017-0639-8. PMID 28555385.

[pmid15657466-7] Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J; et al. (2005). "Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome". Am J Respir Crit Care Med. 171 (8): 850–7. doi:10.1164/rccm.200407-857OC. PMID 15657466.

[pmid17374415-8] Cameron MJ, Bermejo-Martin JF, Danesh A, Muller MP, Kelvin DJ (2008). "Human immunopathogenesis of severe acute respiratory syndrome (SARS)". Virus Res. 133 (1): 13–9. doi:10.1016/j.virusres.2007.02.014. PMC 7114310 Check |pmc= value (help). PMID 17374415.

[pmid15655079-9] Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, Leung BP; et al. (2005). "Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome". BMC Immunol. 6: 2. doi:10.1186/1471-2172-6-2. PMC 546205. PMID 15655079.

[pmid32283152-10] Ye Q, Wang B, Mao J (2020). "The pathogenesis and treatment of the `Cytokine Storm' in COVID-19". J Infect. 80 (6): 607–613. doi:10.1016/j.jinf.2020.03.037. PMC 7194613 Check |pmc= value (help). PMID 32283152 Check |pmid= value (help).

[pmid28466096-11] Channappanavar R, Perlman S (2017). "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology". Semin Immunopathol. 39 (5): 529–539. doi:10.1007/s00281-017-0629-x. PMC 7079893 Check |pmc= value (help). PMID 28466096.

[pmid32361250-12] 12.0 ^12.1 Liu J, Li S, Liu J, Liang B, Wang X, Wang H; et al. (2020). "Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients". EBioMedicine. 55: 102763. doi:10.1016/j.ebiom.2020.102763. PMC 7165294 Check |pmc= value (help). PMID 32361250 Check |pmid= value (help).

[pmid32388462-13] 13.0 ^13.1 Kuppalli K, Rasmussen AL (2020). "A glimpse into the eye of the COVID-19 cytokine storm". EBioMedicine. 55: 102789. doi:10.1016/j.ebiom.2020.102789. PMC 7204696 Check |pmc= value (help). PMID 32388462 Check |pmid= value (help).

[pmid31986264-14] 14.0 ^14.1 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y; et al. (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. PMC 7159299 Check |pmc= value (help). PMID 31986264.

[pmid32446778-15] Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M (2020). "The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system". Cytokine Growth Factor Rev. 53: 25–32. doi:10.1016/j.cytogfr.2020.05.003. PMC 7211650 Check |pmc= value (help). PMID 32446778 Check |pmid= value (help).

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 There is no established system for the classification of COVID-19-associated cytokine storm.
 ==Pathophysiology==
+Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory [[Cytokine|cytokines]].<ref name="pmid22390970">{{cite journal| author=Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG| title=Into the eye of the cytokine storm. | journal=Microbiol Mol Biol Rev | year= 2012 | volume= 76 | issue= 1 | pages= 16-32 | pmid=22390970 | doi=10.1128/MMBR.05015-11 | pmc=3294426 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22390970  }} </ref>
+=== Cytokines Involved in Cytokine Storm ===
+*[[Cytokine|Cytokines]] are small [[Protein|proteins]] that are released for [[cell signaling]].<ref name="pmid22390970" />
+*[[Cytokine|Cytokines]] types and their actions include:<ref name="pmid22390970" />
+**'''Interferons''' '''(INFs)'''
+*** Key role in [[Innate immune system|innate immunity]]
+*** Regulation of the production of antiviral [[Protein|proteins]]
+*** Regulation of the production of antiproliferative [[Protein|proteins]]
+**'''Interleukins''' '''(ILs)'''
+*** Regulation of immune cell [[differentiation]] and activation
+*** May be pro- or anti-[[Inflammation|inflammatory]]
+**'''Chemokines'''
+*** Act as chemotaxins
+*** Recruitment of [[White blood cells|leukocytes]]
+**'''Colony-stimulating factors'''
+*** Induction of [[Hematopoietic stem cell|hematopoietic progenitor cell]] [[Cell growth|proliferation]] and [[differentiation]]
+**'''Tumor necrosis factor (TNF)'''
+*** Activation of [[T cell|T cells]] ([[Cytotoxic T cell|cytotoxic]])
+*
+*
+*
+*
+=== Pathogenesis of Cytokine Storm ===
+* Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory [[Cytokine|cytokines]].<ref name="pmid22390970" />
+* During [[sepsis]], cytokine storm may be the cause of tissue or organ injury.<ref name="pmid28555385">{{cite journal| author=Chousterman BG, Swirski FK, Weber GF| title=Cytokine storm and sepsis disease pathogenesis. | journal=Semin Immunopathol | year= 2017 | volume= 39 | issue= 5 | pages= 517-528 | pmid=28555385 | doi=10.1007/s00281-017-0639-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28555385  }} </ref>
+*Cytokine storm causes [[inflammation]], which in the beginning of the disease is [[local]] and later spreads around by the [[systemic circulation]]. This is followed by repair and restoration of tissues, [[Organ (anatomy)|organs]] and their functions. However, in severe or some [[Inflammation|inflammations]], the repair is with [[fibrosis]] which may lead to permanent dysfunction of organs.<ref name="pmid22390970" />
+*Lung damage caused by pathogens (such as [[SARS-CoV]] and [[influenza virus]]) may lead to acute lung injury (ALI) or [[Acute respiratory distress syndrome|acute respiratory distress syndrome (ARDS)]].
+* [[Cytokine|Cytokines]] profiles change over time in patients with [[sepsis]]:<ref name="pmid22390970" />
+** In the early stages of the infection (minutes to hours),  [[Cytokine|cytokines]]  such as [[Tumor necrosis factors|TNF]] and [[IL-1]], and [[Chemokine|chemokines]] such as [[Interleukin 8|IL-8]] and [[CCL2|MCP-1 (CCL2)]] increase.
+** Then, an increase in [[Interleukin 6|IL-6]] is followed.
+** Later, [[Interleukin 10|IL-10]] (anti-[[Inflammation|inflammatory]] cytokine) increases.
+* Proinflammatory [[Cytokine|cytokines]] that have a role in [[Acute respiratory distress syndrome|ARDS]] include:<ref name="pmid15657466">{{cite journal| author=Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J | display-authors=etal| title=Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. | journal=Am J Respir Crit Care Med | year= 2005 | volume= 171 | issue= 8 | pages= 850-7 | pmid=15657466 | doi=10.1164/rccm.200407-857OC | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15657466  }} </ref><ref name="pmid17374415">{{cite journal| author=Cameron MJ, Bermejo-Martin JF, Danesh A, Muller MP, Kelvin DJ| title=Human immunopathogenesis of severe acute respiratory syndrome (SARS). | journal=Virus Res | year= 2008 | volume= 133 | issue= 1 | pages= 13-9 | pmid=17374415 | doi=10.1016/j.virusres.2007.02.014 | pmc=7114310 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17374415  }} </ref><ref name="pmid15655079">{{cite journal| author=Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, Leung BP | display-authors=etal| title=Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. | journal=BMC Immunol | year= 2005 | volume= 6 | issue=  | pages= 2 | pmid=15655079 | doi=10.1186/1471-2172-6-2 | pmc=546205 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15655079  }} </ref><ref name="pmid32283152">{{cite journal| author=Ye Q, Wang B, Mao J| title=The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. | journal=J Infect | year= 2020 | volume= 80 | issue= 6 | pages= 607-613 | pmid=32283152 | doi=10.1016/j.jinf.2020.03.037 | pmc=7194613 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32283152  }} </ref>
+**IL-1β
+**[[Interleukin 6|IL-6]]
+**[[IL-8|IL-8 (CXCL8)]]
+**[[CCL2|CCL-2 (MCP-1)]]
+**[[CCL3|CCL-3 (Macrophage inflammatory protein-1A)]]
+**[[CCL5|CCL-5]]
+**IFNγ -induced protein 10 (IP-10, CXCL10)
+**[[Granulocyte macrophage colony stimulating factor|Granulocytemacrophage colony-stimulating factor (GM-CSF)]]
+* Cytokine storm (dysregulated and excessive release of [[Cytokine|cytokines]]) has been associated with [[Acute respiratory distress syndrome|ARDS]] in [[SARS coronavirus|SARS coronavirus (SARS-CoV)]] and [[Middle East respiratory syndrome coronavirus infection causes|MERS coronavirus (MERS-CoV)]] infections.<ref name="pmid28466096">{{cite journal| author=Channappanavar R, Perlman S| title=Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. | journal=Semin Immunopathol | year= 2017 | volume= 39 | issue= 5 | pages= 529-539 | pmid=28466096 | doi=10.1007/s00281-017-0629-x | pmc=7079893 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28466096  }} </ref>
+*It has been suggested that  the [[pathogenesis]] of severe [[COVID-19]] infection may be due to cytokine storm and suppression of [[T helper cell|Th1]] antiviral responses since the following findings have been reported to be associated with severe [[COVID-19]] infection:<ref name="pmid32361250">{{cite journal| author=Liu J, Li S, Liu J, Liang B, Wang X, Wang H | display-authors=etal| title=Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. | journal=EBioMedicine | year= 2020 | volume= 55 | issue=  | pages= 102763 | pmid=32361250 | doi=10.1016/j.ebiom.2020.102763 | pmc=7165294 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32361250  }} </ref><ref name="pmid32388462">{{cite journal| author=Kuppalli K, Rasmussen AL| title=A glimpse into the eye of the COVID-19 cytokine storm. | journal=EBioMedicine | year= 2020 | volume= 55 | issue=  | pages= 102789 | pmid=32388462 | doi=10.1016/j.ebiom.2020.102789 | pmc=7204696 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32388462  }} </ref>
+**Increase in pro-inflammatory [[Cytokine|cytokines]] (such as [[Interleukin 6|IL-6]])
+**Increase in [[Interleukin 10|IL-10]] (a [[cytokine]] produced by  [[T helper cell|Th2]]) and suppression in [[T helper cell|Th1]] antiviral responses
+**Decrease in [[Cytotoxic T cell|CD+8 T-cells]]
+*It has been reported that in patients with [[COVID-19]] there is increase in IL-1B, IFN-γ , IP-10, and [[CCL2|monocyte hemoattractant protein 1 (MCP-1)]] and [[COVID-19]]  patients in the [[Intensive care unit|intensive care unit (ICU)]] have increased levels of [[granulocyte  colony-stimulating factor]], IP-10, [[CCL2|MCP-1]], macrophage inflammatory  protein-1A, and [[Tumor necrosis factor-alpha|TNF-α]] compared to those in general wards. However, in contrast to [[Severe acute respiratory syndrome|SARS infection]], patients with [[COVID-19]] infection have high levels of  [[Interleukin 4|IL-4]] and [[Interleukin 10|IL-10]] (secreted  by [[Th2|Th2 cells]]), which are antiinflammatory [[Cytokine|cytokines]].<ref name="pmid31986264">{{cite journal| author=Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y | display-authors=etal| title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. | journal=Lancet | year= 2020 | volume= 395 | issue= 10223 | pages= 497-506 | pmid=31986264 | doi=10.1016/S0140-6736(20)30183-5 | pmc=7159299 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31986264  }} </ref>
+{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
+|+
+!colspan="9" style="background: #4479BA; text-align: center;" |{{fontcolor|#000|'''Some of The Cytokines Involved in COVID-19-Associated-Cytokine Storm'''}}<ref name="pmid32361250" /><ref name="pmid32388462" /><ref name="pmid31986264" /><ref name="pmid32446778">{{cite journal| author=Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M| title=The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. | journal=Cytokine Growth Factor Rev | year= 2020 | volume= 53 | issue=  | pages= 25-32 | pmid=32446778 | doi=10.1016/j.cytogfr.2020.05.003 | pmc=7211650 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32446778  }} </ref>
+|-
+| rowspan="5" style="padding: 5px 5px; background: #4479BA;" align="center" |{{fontcolor|#000|'''Proinflammatory'''}}
+|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Interferones'''
+|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+* IFN-γ
+|-
+|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Interleukines'''
+|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+*IL-1β
+* IL-6
+|-
+|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Chemokines'''
+|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+*CCL-2 (MCP-1)
+* CCL-3 (Macrophage inflammatory protein-1A)
+* CCL-5
+* IL-8 (CXCL8)
+* IP-10 (CXCL10)
+|-
+|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Colony-stimulating'''
+'''factors  '''
+|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+* GM-CSF
+|-
+|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Tumor necrosis'''
+'''factor  '''
+|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+* TNF-α
+|-
+|style="padding: 5px 5px; background: #4479BA;" align="center" |{{fontcolor|#000|'''Anti-inflammatory'''}}
+|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Interleukines'''
+|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+*IL-4
+* IL-10
+|}
 ==Causes==
 [[COVID-19|Coronavirus disease 2019 (COVID-19)]] is caused by a novel [[coronavirus]] called [[SARS-CoV-2]] and is the cause of cytokine storm in [[COVID-19]] infection.