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VisualWikitext

Latest revision as of 19:44, 3 August 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: Shakiba Hassanzadeh, MD [2] Ramyar Ghandriz MD [3] Ifrah Fatima, M.B.B.S [4]

Synonyms and keywords: IL-6 rise in COVID-19, severe inflammatory response in COVID-19, sars cov-2 related hyperimmune response

Overview

Cytokine storms are suspected to be the major cause of death in the previous influenza virus pandemic of 1918, H5N1 epidemic of 1991 and SARS epidemic of 2003. A cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of pro-inflammatory cytokines. Cytokine storms (dysregulated and excessive release of cytokines) have been associated with ARDS in SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV) infections. The characteristic of this phenomenon could be considered as an indicator of adverse clinical outcomes such as ARDS, shock, and ARF. 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 anti-inflammatory cytokines. Potential therapies suggested for cytokine storm include: Corticosteroids, tocilizumab, etoposide and ruxolitinib.

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]
The rapidly increasing number of patients suggest that human-to-human transmission is actively occurring.^[2]
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.
The term cytokine storm was first used in 1993 by Ferrera et all, to describe the pathophysiology of graft versus host disease (GVHD). ^[3]^[4]
Later, the term was used for pancreatitis, where there is an excessive release of cytokines.
It has been implicated in a number of infectious as well as non-infectious diseases.
In the context of infectious diseases, it was first used to describe influenza encephalopathy in 2003. It was also used to describe the pathophysiology of cytomegalovirus, epstein-Barr virus-associated hemophagocytic lymphohistiocytosis, group A streptococcus, influenza virus, variola virus, and severe acute respiratory syndrome coronavirus (SARS-CoV).
Cytokine storms are believed to cause a disproportionate number of deaths in young individuals. It is suspected to be the major cause of death in previous viral pandemics :^[5]
- Influenza virus pandemic of 1918.
- H5N1 epidemic (Avian influenza) of 1991.
- SARS epidemic of 2003. ^[6]
It is also implicated in other rare viral diseases like variola infection, hantavirus pulmonary syndrome, marburg virus, ebola viruses, lassa and junin viruses, dengue viruses etc. ^[7]

Classification

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

Pathophysiology

A cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of pro-inflammatory cytokines.

Cytokines Involved in Cytokine Storm

Cytokines are small proteins that are released for cell signaling.
Cytokines types and their actions include:^[8]
- 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 chemo-attractants
  - 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

A cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of pro-inflammatory cytokines.
During sepsis, cytokine storm may be the cause of tissue or organ injury.^[9]

A cytokine storm causes inflammation, which at the beginning of the disease is local and later spreads around by the systemic circulation. This is followed by the 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.
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:^[8]
- 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.

Pro-inflammatory cytokines that have a role in ARDS include:^[10]^[11]^[12]^[13]
- IL-1β
- IL-6
- IL-8 (CXCL8)
- CCL-2 (MCP-1)
- CCL-3 (Macrophage inflammatory protein-1A)
- CCL-5
- IFN-γ-induced protein10 (IP-10, CXCL10)
- Granulocytemacrophage colony-stimulating factor (GM-CSF)

Cytokine storms (dysregulated and excessive release of cytokines) have been associated with ARDS in SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV) infections.^[14]
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:^[15]^[16]
- 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 anti-inflammatory cytokines.^[17]^[15]^[18]^[17]^[16]


Some of The Cytokines Involved in COVID-19-Associated-Cytokine Storm
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.

Differentiating COVID-19 cytokine storm from other Diseases

The most appropriate marker of cytokine storm is an increase in IL-6 level.
Following is a list of diseases that can cause an increase in IL-6 level and cytokine storm :^[19]

Epidemiology and Demographics

Estimation of an accurate number of severe acute inflammation cases is hard due to the lack of a global system to define the severity of the disease.
Below is a comparison of different studies on the cytokine level of IL-6 in healthy and severely infected individuals:

Plasma IL-6 concenteration reported in COVID-19
Report	Total population(IL-6 level range pg/ml)	Severe infection (IL-6 level range 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)

For more information about COVID-19 epidemiology and demographics please click here.

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 SARS-Cov-1, cytokine elevation was associated with various adverse features.^[23]^[24]
The characteristic of this phenomena could be considered as an indicator of adverse clinical outcomes such as ARDS, shock and ARF.^[25]
Hyper immunity caused by cytokine storm leading to multi-organ failure in COVID-19 is not fully proved yet, but from previous viral epidemics, it is highly suggested to be considered as a reason to this outcome.
For more information about COVID-19 natural history,complication and prognosis please click here.

Diagnosis

Diagnostic Study of Choice

The most important cytokines that increase are :^[26]

The suggested strategy is to measure the so-called cytokines.

History and Symptoms

COVID-19 infected individuals who go through more adverse clinical manifestations, 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, Interleukin-6 is the best indicator of the cytokine storm.
IL-6 concentration has been reported by many studies and is believed to be at a maximal cut of 80 pg/ml in a severe form of the disease.
Patients with higher levels of IL-6 are at a greater chance of severe disease.^[22]

Electrocardiogram

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

X-ray

COVID-19 associated cytokine storm leads to Acute respiratory distress syndrome(ARDS).
X-ray Findings related to COVID-19 ARDS are:
- Ground-glass opacification and consolidation
- Early findings on the chest radiograph include normal or diffuse alveolar opacities (consolidation), which are often bilateral and which obscure the pulmonary vascular markings.
- Later, these opacities progress to more extensive consolidation that is diffuse, and they are often asymmetrical.

Bilateral alveolar consolidation with panlobar change, with typical radiological findings of ARDS.^[27]

Echocardiography or Ultrasound

There are no echocardiography or ultrasound findings regarding the COVID-19-associated cytokine storm.

CT scan

COVID-19 associated cytokine storm Leads to ARDS.
Multifocal ground glass opacity would be found at both lungs.

Multifocal ground glass, mainly in the periphery of both lungs.^[28]

MRI

There are no MRI findings regarding the COVID-19-associated cytokine storm.

Other Imaging Findings

There are no other imaging findings regarding the COVID-19-associated cytokine storm.

Treatment

Medical Therapy

Currently, no proven treatment has been suggested.
Potential therapies for reducing inflammation are:
- Corticosteroids:^[29]^[30]
  - Currently in the U.K. there is an ongoing trial (RECOVERY Trial) that Suggest Systemic low dose Dexamethasone decreases mortality by one third.
  - Dexamethasone administered as an oral (liquid or tablets) or intravenous preparation. In pregnancy or breastfeeding women, prednisolone (or intravenous hydrocortisone) should be used.
  - The suggested dosage is 6 mg once daily for 10 days
- Azithromycin: ^[31]
  - Azithromycin Have shown anti inflammatory effects against Ebola, respiratory syncytial virus and Influenza H1N1.
  - Azithromycin 500mg by mouth (or nasogastric tube) or intravenously once daily for 10 days is recommended.
- Remdesivir:^[32]^[33]
  - In a first COVID-19 treatment EMA’s human medicines committee (CHMP) recommended remdesivir for EU authorization in a preliminary report.
  - A total of 1063 patients underwent randomization in the remdesivir double-blind, placebo-controlled trial.
  - Intravenous remdesivir used in adult hospitalized COVID-19 patients in a double-blind, randomized, placebo-controlled trial.
  - Dosage of remdesivir is 200 mg loading dose on day 1, which is followed by 100 mg daily for up to 9 additional days or a placebo for up to 10 days in the random trail.
  - Preferred regimen in pediatric population who are weighing 3.5 kg to less than 40kg: Remdesivir injection, 100 mg, lyophilized powder which includes a single loading dose of remdesivir 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once daily from Day 2
- Tocilizumab:^[34]^[35]^[36]^[37]
  - Tocilizumab is an FDA approved drug used for cytokine release syndrome after chimeric antigen receptor infusion, which cause cytokine release storm.
  - It is an IL-6 receptor antibody, which is effective in similar clinical manifestations.
  - In some off label studies, it has been shown that tocilizumab can cause improvement in patients.
  - intravenous infusion with the dose determined by body weight
    - 8 mg/kg (maximum: 800 mg/dose) as a single dose; may repeat dose in 8 to 12 hours if signs/symptoms worsen or do not improve.
    - 8 mg/kg (maximum: 800 mg/dose) every 12 hours for 2 doses.
    - 8 mg/kg as a single dose.
    - 4 to 8 mg/kg (usual dose: 400 mg/dose; maximum: 800 mg/dose) as a single dose; may repeat dose in ≥12 hours in patients who remain febrile within 24 hours of initial dose.
- Etoposide:^[38]
  - Etoposide is used for suppressing cytokine release in hemophagocytic lymphohistiocytosis.
  - In patients with severe disease, etoposide can inhibit overwhelming inflammation.
  - the suggested dosage is Etoposide 150 mg/m2 daily days 1 and 4
- Ruxolitinib:^[39]
  - Jack1/2 inhibitor.
  - It is used in hemophagocytic lymphohistiocytosis.
  - In a prospective randomized trial, it was shown that it reduces the levels of seven cytokines compared to the control group, and resulted in faster improvement in patients with severe infection.
  - the suggested dose is 5 mg twice daily.^[40]
- Lopinavir-Ritonavir:^[41]
  - Lopinavir 400 mg every 12 hours for ten days
  - Ritonavir 100 mg every 12 hours for ten days

Surgery

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

Primary Prevention

Since there is no vaccine for COVID-19 there are plenty of primary prevention suggested from CDC such as:^[42]
- Hand washing every 10 minutes.
- Using alcoholic hand sanitizer.
- Self quarantine for two weeks if symptomatic.
To view the primary prevention measures of COVID-19, click here.

Secondary Prevention

WHO recommends home care for patients with suspected COVID-19 who present with mild symptoms:^[43]
- Family members of an infected patient are better to wear masks.
- Using separate bathroom and bedroom by the infected person.
- Using antipyretics and analgesics for fever, myalgias, and headaches
To view the secondary prevention measures of COVID-19, click here.

References

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↑ Horby, Peter; Lim, Wei Shen; Emberson, Jonathan; Mafham, Marion; Bell, Jennifer; Linsell, Louise; Staplin, Natalie; Brightling, Christopher; Ustianowski, Andrew; Elmahi, Einas; Prudon, Benjamin; Green, Christopher; Felton, Timothy; Chadwick, David; Rege, Kanchan; Fegan, Christopher; Chappell, Lucy C; Faust, Saul N; Jaki, Thomas; Jeffery, Katie; Montgomery, Alan; Rowan, Kathryn; Juszczak, Edmund; Baillie, J Kenneth; Haynes, Richard; Landray, Martin J (2020). doi:10.1101/2020.06.22.20137273. Missing or empty |title= (help)
↑ Bleyzac, Nathalie; Goutelle, Sylvain; Bourguignon, Laurent; Tod, Michel (2020). "Azithromycin for COVID-19: More Than Just an Antimicrobial?". Clinical Drug Investigation. 40 (8): 683–686. doi:10.1007/s40261-020-00933-3. ISSN 1173-2563.
↑ Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.; Mehta, Aneesh K.; Zingman, Barry S.; Kalil, Andre C.; Hohmann, Elizabeth; Chu, Helen Y.; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W.; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F.; Paredes, Roger; Sweeney, Daniel A.; Short, William R.; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-don; Ruiz-Palacios, Guillermo M.; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G.; Atmar, Robert L.; Creech, C. Buddy; Lundgren, Jens; Babiker, Abdel G.; Pett, Sarah; Neaton, James D.; Burgess, Timothy H.; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H. Clifford (2020). "Remdesivir for the Treatment of Covid-19 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2007764. ISSN 0028-4793.
↑ Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.; Mehta, Aneesh K.; Zingman, Barry S.; Kalil, Andre C.; Hohmann, Elizabeth; Chu, Helen Y.; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W.; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F.; Paredes, Roger; Sweeney, Daniel A.; Short, William R.; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-don; Ruiz-Palacios, Guillermo M.; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G.; Atmar, Robert L.; Creech, C. Buddy; Lundgren, Jens; Babiker, Abdel G.; Pett, Sarah; Neaton, James D.; Burgess, Timothy H.; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H. Clifford (2020). "Remdesivir for the Treatment of Covid-19 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2007764. ISSN 0028-4793.
↑ 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.
↑ La Rosée, F.; Bremer, H. C.; Gehrke, I.; Kehr, A.; Hochhaus, A.; Birndt, S.; Fellhauer, M.; Henkes, M.; Kumle, B.; Russo, S. G.; La Rosée, P. (2020). "The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation". Leukemia. 34 (7): 1805–1815. doi:10.1038/s41375-020-0891-0. ISSN 0887-6924.
↑ "A Trial of Lopinavir–Ritonavir in Covid-19". New England Journal of Medicine. 382 (21): e68. 2020. doi:10.1056/NEJMc2008043. ISSN 0028-4793.
↑ https://www.cdc.gov/coronavirus/2019-ncov/index.html. Missing or empty |title= (help)
↑ "Home care for patients with COVID-19 presenting with mild symptoms and management of their contacts".

[LuCui2020-1] 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.

[HuangWang2020-2] 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.

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[pmid32283152-13] 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).

[pmid28466096-14] 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.

[pmid32361250-15] 15.0 ^15.1 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).

[pmid32388462-16] 16.0 ^16.1 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).

[pmid31986264-17] 17.0 ^17.1 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.

[pmid32446778-18] 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).

[Magro2020-19] Magro, Giuseppe (2020). "Cytokine Storm: Is it the only major death factor in COVID-19 patients? Coagulation role". Medical Hypotheses. 142: 109829. doi:10.1016/j.mehy.2020.109829. ISSN 0306-9877.

[ZhouYu2020-20] 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.

[WuChen2020-21] 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.

[ZhangWang2020-22] 22.0 ^22.1 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.

[CalfeeDelucchi2014-23] 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.

[FamousDelucchi2017-24] 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.

[SinhaDelucchi2018-25] 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.

[SchultzArnold1990-26] 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.

[27] ="urlCOVID-19 - rapidly progressive acute respiratory distress syndrome (ARDS) | Radiology Case | Radiopaedia.org">"COVID-19 - rapidly progressive acute respiratory distress syndrome (ARDS) | Radiology Case | Radiopaedia.org".

[28] ="urlCOVID-19 pneumonia | Radiology Case | Radiopaedia.org">"COVID-19 pneumonia | Radiology Case | Radiopaedia.org".

[HuangWang20202-29] 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.

[HorbyLim2020-30] Horby, Peter; Lim, Wei Shen; Emberson, Jonathan; Mafham, Marion; Bell, Jennifer; Linsell, Louise; Staplin, Natalie; Brightling, Christopher; Ustianowski, Andrew; Elmahi, Einas; Prudon, Benjamin; Green, Christopher; Felton, Timothy; Chadwick, David; Rege, Kanchan; Fegan, Christopher; Chappell, Lucy C; Faust, Saul N; Jaki, Thomas; Jeffery, Katie; Montgomery, Alan; Rowan, Kathryn; Juszczak, Edmund; Baillie, J Kenneth; Haynes, Richard; Landray, Martin J (2020). doi:10.1101/2020.06.22.20137273. Missing or empty |title= (help)

[BleyzacGoutelle2020-31] Bleyzac, Nathalie; Goutelle, Sylvain; Bourguignon, Laurent; Tod, Michel (2020). "Azithromycin for COVID-19: More Than Just an Antimicrobial?". Clinical Drug Investigation. 40 (8): 683–686. doi:10.1007/s40261-020-00933-3. ISSN 1173-2563.

[BeigelTomashek2020-32] Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.; Mehta, Aneesh K.; Zingman, Barry S.; Kalil, Andre C.; Hohmann, Elizabeth; Chu, Helen Y.; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W.; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F.; Paredes, Roger; Sweeney, Daniel A.; Short, William R.; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-don; Ruiz-Palacios, Guillermo M.; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G.; Atmar, Robert L.; Creech, C. Buddy; Lundgren, Jens; Babiker, Abdel G.; Pett, Sarah; Neaton, James D.; Burgess, Timothy H.; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H. Clifford (2020). "Remdesivir for the Treatment of Covid-19 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2007764. ISSN 0028-4793.

[BeigelTomashek20202-33] Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.; Mehta, Aneesh K.; Zingman, Barry S.; Kalil, Andre C.; Hohmann, Elizabeth; Chu, Helen Y.; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W.; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F.; Paredes, Roger; Sweeney, Daniel A.; Short, William R.; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-don; Ruiz-Palacios, Guillermo M.; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G.; Atmar, Robert L.; Creech, C. Buddy; Lundgren, Jens; Babiker, Abdel G.; Pett, Sarah; Neaton, James D.; Burgess, Timothy H.; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H. Clifford (2020). "Remdesivir for the Treatment of Covid-19 — Preliminary Report". New England Journal of Medicine. doi:10.1056/NEJMoa2007764. ISSN 0028-4793.

[LeLi2018-34] 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.

[XuTang2014-35] 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.

[pmid32456769-36] 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).

[MorenaMilazzo2020-37] 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_Rosée2015-38] 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.

[CaoWei2020-39] 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.

[La_RoséeBremer2020-40] La Rosée, F.; Bremer, H. C.; Gehrke, I.; Kehr, A.; Hochhaus, A.; Birndt, S.; Fellhauer, M.; Henkes, M.; Kumle, B.; Russo, S. G.; La Rosée, P. (2020). "The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation". Leukemia. 34 (7): 1805–1815. doi:10.1038/s41375-020-0891-0. ISSN 0887-6924.

[41] "A Trial of Lopinavir–Ritonavir in Covid-19". New England Journal of Medicine. 382 (21): e68. 2020. doi:10.1056/NEJMc2008043. ISSN 0028-4793.

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

[43] "Home care for patients with COVID-19 presenting with mild symptoms and management of their contacts".

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+{| class="infobox" style="position: flexible; top: 20%; right: 2px; margin: 0 0 0 0; border: 0; float: right;"
+|-
+| {{#ev:youtube|https://www.youtube.com/watch?v=AXP9qQ_a0fw}}
+|-
+|}
 __NOTOC__
 {{Main|COVID-19}}
 '''For COVID-19 frequently asked inpatient questions, click [[COVID-19 frequently asked inpatient questions|here]]'''<br>
 '''For COVID-19 frequently asked outpatient questions, click [[COVID-19 frequently asked outpatient questions|here]]'''<br>
-{{COVID-19}}
+{{SI}}
-{{CMG}}; {{AE}} {{SHA}}
+{{CMG}}; {{AE}} {{SHA}} {{RG}} {{IF}}
-{{SK}}
+{{SK}} IL-6 rise in COVID-19, severe inflammatory response in COVID-19, sars cov-2 related hyperimmune response
 ==Overview==
-[[Cytokine storm]] is suspected to be the major cause of death in previous viral pandemics  [[Influenza]] [[virus]] [[pandemic]] of 1918, [[H5N1]] [[epidemic]] of 1991 and [[SARS]] [[epidemic]] of 2003.Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory [[Cytokine|cytokines]].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.The characteristic of this phenomena could be considered as an indicator of adverse clinical outcomes such as ARDs, shock and ARF.
+[[Cytokine storm]]<nowiki/>s are suspected to be the major cause of death in the previous [[influenza]] [[virus]] [[pandemic]] of 1918, [[H5N1]] [[epidemic]] of 1991 and [[SARS]] [[epidemic]] of 2003. A [[cytokine storm]] is an [[immune reaction]] that is characterized by dysregulated and excessive release of pro-[[inflammatory]] [[Cytokine|cytokines]]. [[Cytokine storm|Cytokine storms]] (dysregulated and excessive release of [[Cytokine|cytokines]]) have 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. The characteristic of this phenomenon could be considered as an indicator of adverse clinical outcomes such as [[ARDS]], [[shock]], and [[Acute kidney injury|ARF]]. It has been reported that in patients with [[COVID-19]] there is increase in IL-1B, [[Interferon|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 [[anti-inflammatory]] [[Cytokine|cytokines]]. Potential therapies suggested for [[cytokine storm]] include: [[Corticosteroids]], [[tocilizumab]], [[etoposide]] and [[ruxolitinib]].
 ==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.<ref>{{Cite web|url=https://www.cdc.gov/coronavirus/2019-ncov/about/index.html|title=|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref name="LuCui2020">{{cite journal|last1=Lu|first1=Jian|last2=Cui|first2=Jie|last3=Qian|first3=Zhaohui|last4=Wang|first4=Yirong|last5=Zhang|first5=Hong|last6=Duan|first6=Yuange|last7=Wu|first7=Xinkai|last8=Yao|first8=Xinmin|last9=Song|first9=Yuhe|last10=Li|first10=Xiang|last11=Wu|first11=Changcheng|last12=Tang|first12=Xiaolu|title=On the origin and continuing evolution of SARS-CoV-2|journal=National Science Review|year=2020|issn=2095-5138|doi=10.1093/nsr/nwaa036}}</ref>
+* The etiological agent is [[SARS-CoV-2]], named for the similarity of its [[Symptom|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.<ref name="LuCui2020">{{cite journal|last1=Lu|first1=Jian|last2=Cui|first2=Jie|last3=Qian|first3=Zhaohui|last4=Wang|first4=Yirong|last5=Zhang|first5=Hong|last6=Duan|first6=Yuange|last7=Wu|first7=Xinkai|last8=Yao|first8=Xinmin|last9=Song|first9=Yuhe|last10=Li|first10=Xiang|last11=Wu|first11=Changcheng|last12=Tang|first12=Xiaolu|title=On the origin and continuing evolution of SARS-CoV-2|journal=National Science Review|year=2020|issn=2095-5138|doi=10.1093/nsr/nwaa036}}</ref>
-*The growing number of [[patients]] however, suggest that human-to-human transmission is actively occurring.<ref name="HuangWang2020">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref><ref>{{Cite web|url=https://www.cdc.gov/coronavirus/2019-ncov/about/transmission.html|title=|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
+*The rapidly increasing number of [[patients]] suggest that human-to-human transmission is actively occurring.<ref name="HuangWang2020">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref>
 *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]].
+*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 :
+*The term [[cytokine storm]] was first used in 1993 by Ferrera et all, to describe the [[pathophysiology]] of [[Graft versus host disease|graft versus host disease (]][[Graft-versus-host disease|GVHD]]). <ref name="pmid17551531">{{cite journal| author=Clark IA| title=The advent of the cytokine storm. | journal=Immunol Cell Biol | year= 2007 | volume= 85 | issue= 4 | pages= 271-3 | pmid=17551531 | doi=10.1038/sj.icb.7100062 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17551531  }} </ref><ref name="pmid8442093">{{cite journal| author=Ferrara JL, Abhyankar S, Gilliland DG| title=Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. | journal=Transplant Proc | year= 1993 | volume= 25 | issue= 1 Pt 2 | pages= 1216-7 | pmid=8442093 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8442093  }} </ref>
+* Later, the term was used for [[pancreatitis]], where there is an excessive release of [[cytokines]].
+* It has been implicated in a number of [[Infection|infectious]] as well as non-infectious diseases.
+* In the context of [[Infectious disease|infectious diseases]], it was first used to describe [[influenza]] [[encephalopathy]] in 2003. It was also used to describe the [[pathophysiology]] of  [[cytomegalovirus]], [[Epstein Barr virus|epstein-Barr virus]]-associated [[hemophagocytic lymphohistiocytosis]], [[group A streptococcus]], [[influenza virus]], [[variola virus]], and [[severe acute respiratory syndrome]] coronavirus ([[SARS-CoV]]).
+* [[Cytokine storm]]<nowiki/>s are believed to cause a disproportionate number of deaths in young individuals. It is suspected to be the major cause of death in previous viral pandemics :<ref name="pmid15872196">{{cite journal| author=Osterholm MT| title=Preparing for the next pandemic. | journal=N Engl J Med | year= 2005 | volume= 352 | issue= 18 | pages= 1839-42 | pmid=15872196 | doi=10.1056/NEJMp058068 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15872196  }} </ref>
 **[[Influenza]] [[virus]] [[pandemic]] of 1918.
-**[[H5N1]] [[epidemic]] of 1991.
+**[[H5N1]] [[epidemic]] (Avian influenza) of 1991.
-**[[SARS]] [[epidemic]] of 2003.
+**[[SARS]] [[epidemic]] of 2003. <ref name="pmid15602737">{{cite journal| author=Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC | display-authors=etal| title=An interferon-gamma-related cytokine storm in SARS patients. | journal=J Med Virol | year= 2005 | volume= 75 | issue= 2 | pages= 185-94 | pmid=15602737 | doi=10.1002/jmv.20255 | pmc=7166886 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15602737  }} </ref>
+* It is also implicated in other rare viral diseases like [[variola]] infection, [[hantavirus]] pulmonary syndrome, [[marburg virus]], [[Ebola virus|ebola viruses]], [[Lassa fever|lassa]] and [[Junin virus|junin]] viruses, [[dengue]] viruses etc. <ref name="pmid9878011">{{cite journal| author=Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE | display-authors=etal| title=High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome. | journal=J Infect Dis | year= 1999 | volume= 179 | issue= 2 | pages= 295-302 | pmid=9878011 | doi=10.1086/314597 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9878011  }} </ref>
 ==Classification==
-There is no established system for the classification of COVID-19-associated cytokine storm.
+*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]].
+*A [[cytokine storm]] is an [[immune reaction]] that is characterized by dysregulated and excessive release of pro-[[inflammatory]] [[Cytokine|cytokines]].
 === Cytokines Involved in Cytokine Storm ===
 *[[Cytokine|Cytokines]] are small [[Protein|proteins]] that are released for [[cell signaling]].
 *[[Cytokine|Cytokines]] types and their actions include:<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>
 **'''Interferons''' '''(INFs)'''
 *** Key role in [[Innate immune system|innate immunity]]
-*** Regulation of the production of antiviral [[Protein|proteins]]
+*** Regulation of the production of [[antiviral]] [[Protein|proteins]]
 *** Regulation of the production of antiproliferative [[Protein|proteins]]
 **'''Interleukins''' '''(ILs)'''
@@ Line 39: / Line 48: @@
 *** May be pro- or anti-[[Inflammation|inflammatory]]
 **'''Chemokines'''
-*** Act as chemotaxins
+*** Act as chemo-attractants
 *** Recruitment of [[White blood cells|leukocytes]]
 **'''Colony-stimulating factors'''
@@ Line 45: / Line 54: @@
 **'''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]].
+*A [[cytokine storm]] is an [[immune reaction]] that is characterized by dysregulated and excessive release of pro-inflammatory [[Cytokine|cytokines]].
-* 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>
+* During [[sepsis]], [[cytokine storm]] may be the cause of [[Tissue (biology)|tissue]] or [[Organ (anatomy)|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.
+*A [[cytokine storm]] causes [[inflammation]], which at the beginning of the disease is [[local]] and later spreads around by the [[systemic circulation]]. This is followed by the 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 [[Organ (anatomy)|organs]].
-*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)]].
+*[[Lung]] damage caused by [[Pathogen|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.
+** 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>
+* Pro-inflammatory [[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
+**[[IL-1|IL-1β]]
 **[[Interleukin 6|IL-6]]
 **[[IL-8|IL-8 (CXCL8)]]
@@ Line 71: / Line 74: @@
 **[[CCL3|CCL-3 (Macrophage inflammatory protein-1A)]]
 **[[CCL5|CCL-5]]
-**IFNγ -induced protein 10 (IP-10, CXCL10)
+**[[Interferon|IFN]]-γ-induced protein10 (IP-10, [[CXCL10]])
-**[[Granulocyte macrophage colony stimulating factor|Granulocytemacrophage colony-stimulating factor (GM-CSF)]]
+**[[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>
+*[[Cytokine storm]]<nowiki/>s (dysregulated and excessive release of [[Cytokine|cytokines]]) have 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>
-*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, [[Interferon|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 anti-inflammatory [[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><ref name="pmid32361250" /><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><ref name="pmid31986264" /><ref name="pmid32388462" />
-*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"
-{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
 |+
-!colspan="9" style="background: #4479BA; text-align: center;" |{{fontcolor|#000|'''Most 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>
+!colspan="9" style="background: #4479BA; text-align: center;" |{{fontcolor|#FFFFFF|'''Some of The Cytokines Involved in COVID-19-Associated-Cytokine Storm'''}}
 |-
-| rowspan="5" style="padding: 5px 5px; background: #4479BA;" align="center" |{{fontcolor|#000|'''Proinflammatory'''}}
+| rowspan="5" style="padding: 5px 5px; background: #4479BA;" align="center" |{{fontcolor|#FFFFFF|'''Proinflammatory'''}}
-|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Interferones'''
+|style="padding: 5px 5px; background: #4479BA; color: #FFFFFF" align="center" |'''Interferones'''
 |style="padding: 5px 5px; background: #DCDCDC;" align="left" |
-* IFN-γ
+*[[Interferon|IFN]]-γ
 |-
-|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Interleukines'''
+|style="padding: 5px 5px; background: #4479BA; color: #FFFFFF" align="center" |'''Interleukines'''
-|style="padding: 5px 5px; background: #DCDCDC;" align="left" |
+|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: #4479BA; color: #FFFFFF" align="center" |'''Chemokines'''
 |style="padding: 5px 5px; background: #DCDCDC;" align="left" |
-*CCL-2 (MCP-1)
+*CCL-2 ([[MCP-1|MCP]]-1)
-* CCL-3 (Macrophage inflammatory protein-1A)
+* CCL-3 ([[Macrophage inflammatory protein]]-1A)
 * CCL-5
-* IL-8 (CXCL8)
+*[[IL-8]] (CXCL8)
-* IP-10 (CXCL10)
+* IP-10 ([[CXCL10]])
 |-
-|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Colony-stimulating'''
+|style="padding: 5px 5px; background: #4479BA; color: #FFFFFF" align="center" |'''Colony-stimulating'''
 '''factors  '''
 |style="padding: 5px 5px; background: #DCDCDC;" align="left" |
-* GM-CSF
+*[[Granulocyte macrophage colony stimulating factor|GM-CSF]]
 |-
-|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Tumor necrosis'''
+|style="padding: 5px 5px; background: #4479BA; color: #FFFFFF" align="center" |'''Tumor necrosis'''
 '''factor  '''
 |style="padding: 5px 5px; background: #DCDCDC;" align="left" |
-* TNF-α
+*[[TNF-α]]
 |-
-|style="padding: 5px 5px; background: #4479BA;" align="center" |{{fontcolor|#000|'''Anti-inflammatory'''}}
+|style="padding: 5px 5px; background: #4479BA;" align="center" |{{fontcolor|#FFFFFF|'''Anti-inflammatory'''}}
-|style="padding: 5px 5px; background: #4479BA;" align="center" |'''Interleukines'''
+|style="padding: 5px 5px; background: #4479BA; color: #FFFFFF" align="center" |'''Interleukines'''
 |style="padding: 5px 5px; background: #DCDCDC;" align="left" |
-*IL-4
+*[[Interleukin 4|IL-4]]
-* IL-10
+*[[Interleukin 10|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.
+* [[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.
+==Differentiating COVID-19 cytokine storm from other Diseases==
+*The most appropriate marker of [[cytokine storm]] is an increase in [[IL-6]] level.
+*Following is a list of diseases that can cause an increase in [[Interleukin 6|IL-6]] level and cytokine storm :<ref name="Magro2020">{{cite journal|last1=Magro|first1=Giuseppe|title=Cytokine Storm: Is it the only major death factor in COVID-19 patients? Coagulation role|journal=Medical Hypotheses|volume=142|year=2020|pages=109829|issn=03069877|doi=10.1016/j.mehy.2020.109829}}</ref>
+**[[Rheumatoid arthritis|Rheumatoid Arthritis]]
+**[[Sepsis]]
+**[[Graft versus host disease]]
+**[[Acute respiratory distress syndrome|ARDS]]
+**[[Avian Influenza]]
+**[[Systemic inflammatory response syndrome]]
+**[[Systemic Juvenile Idiopathic Arthritis]]
+** [[Castleman's disease]]
+** [[Hemophagocytic lymphohistiocytosis]]
 ==Epidemiology and Demographics==
-* Estimation of an accurate number of severe acute inflammation is hard due to the lack of a global system to define the severity of the disease.
+* Estimation of an accurate number of severe acute [[inflammation]] cases is hard due to the lack of a global system to define the severity of the disease.
-* Below is a comparison of different studies on the cytokine level of IL-6 in healthy and severely infected individuals:
+* Below is a comparison of different studies on the [[cytokine]] level of [[Interleukin 6|IL-6]] in healthy and severely infected individuals:
 {| class="wikitable"
@@ Line 133: / Line 148: @@
 |-
 ! style="background: #4479BA; color: #FFFFFF; " align="center" |Report
-! style="background: #4479BA; color: #FFFFFF; " align="center" |Total population(IL-6 level pg/ml)
+! style="background: #4479BA; color: #FFFFFF; " align="center" |Total population(IL-6 level range pg/ml)
-! style="background: #4479BA; color: #FFFFFF; " align="center" |Severe infection (IL-6 level pg/ml)
+! style="background: #4479BA; color: #FFFFFF; " align="center" |Severe infection (IL-6 level range pg/ml)
 |-
 | style="background: #DCDCDC; " |Zhou et al<ref name="ZhouYu2020">{{cite journal|last1=Zhou|first1=Fei|last2=Yu|first2=Ting|last3=Du|first3=Ronghui|last4=Fan|first4=Guohui|last5=Liu|first5=Ying|last6=Liu|first6=Zhibo|last7=Xiang|first7=Jie|last8=Wang|first8=Yeming|last9=Song|first9=Bin|last10=Gu|first10=Xiaoying|last11=Guan|first11=Lulu|last12=Wei|first12=Yuan|last13=Li|first13=Hui|last14=Wu|first14=Xudong|last15=Xu|first15=Jiuyang|last16=Tu|first16=Shengjin|last17=Zhang|first17=Yi|last18=Chen|first18=Hua|last19=Cao|first19=Bin|title=Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study|journal=The Lancet|volume=395|issue=10229|year=2020|pages=1054–1062|issn=01406736|doi=10.1016/S0140-6736(20)30566-3}}</ref>
@@ Line 150: / Line 165: @@
 |-
 |}
+*For more information about [[COVID-19]] epidemiology and demographics please click [[COVID-19 epidemiology and demographics|here]].
 ==Risk Factors==
-There are no established risk factors for COVID-19-associated cytokine storm.
+* There are no established risk factors for [[COVID-19|COVID-19-]]<nowiki/>associated [[cytokine storm]].
 ==Screening==
-There is insufficient evidence to recommend routine screening for COVID-19 related cytokine storm.
+* 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 [[Interferon|interferons]], [[Interleukin|interleukins]], [[Tumor necrosis factors|TNF]], [[Chemokine|chemokines]] and several other mediators.
-* Cytokine storm has no definition. It denotes a hyperactive immune response characterized by release of [[Interferon|interferons]], [[Interleukin|interleukins]], [[Tumor necrosis factors|TNF]], [[Chemokine|chemokines]] and several other mediators. Since  SARS-Cov-1, cytokine elevation was associated with various adverse features.<ref name="CalfeeDelucchi2014">{{cite journal|last1=Calfee|first1=Carolyn S|last2=Delucchi|first2=Kevin|last3=Parsons|first3=Polly E|last4=Thompson|first4=B Taylor|last5=Ware|first5=Lorraine B|last6=Matthay|first6=Michael A|title=Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials|journal=The Lancet Respiratory Medicine|volume=2|issue=8|year=2014|pages=611–620|issn=22132600|doi=10.1016/S2213-2600(14)70097-9}}</ref><ref name="FamousDelucchi2017">{{cite journal|last1=Famous|first1=Katie R.|last2=Delucchi|first2=Kevin|last3=Ware|first3=Lorraine B.|last4=Kangelaris|first4=Kirsten N.|last5=Liu|first5=Kathleen D.|last6=Thompson|first6=B. Taylor|last7=Calfee|first7=Carolyn S.|title=Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy|journal=American Journal of Respiratory and Critical Care Medicine|volume=195|issue=3|year=2017|pages=331–338|issn=1073-449X|doi=10.1164/rccm.201603-0645OC}}</ref>
+*Since SARS-Cov-1, [[cytokine]] elevation was associated with various adverse features.<ref name="CalfeeDelucchi2014">{{cite journal|last1=Calfee|first1=Carolyn S|last2=Delucchi|first2=Kevin|last3=Parsons|first3=Polly E|last4=Thompson|first4=B Taylor|last5=Ware|first5=Lorraine B|last6=Matthay|first6=Michael A|title=Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials|journal=The Lancet Respiratory Medicine|volume=2|issue=8|year=2014|pages=611–620|issn=22132600|doi=10.1016/S2213-2600(14)70097-9}}</ref><ref name="FamousDelucchi2017">{{cite journal|last1=Famous|first1=Katie R.|last2=Delucchi|first2=Kevin|last3=Ware|first3=Lorraine B.|last4=Kangelaris|first4=Kirsten N.|last5=Liu|first5=Kathleen D.|last6=Thompson|first6=B. Taylor|last7=Calfee|first7=Carolyn S.|title=Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy|journal=American Journal of Respiratory and Critical Care Medicine|volume=195|issue=3|year=2017|pages=331–338|issn=1073-449X|doi=10.1164/rccm.201603-0645OC}}</ref>
-* The characteristic of this phenomena could be considered as an indicator of adverse clinical outcomes such as ARDs, shock and ARF.<ref name="SinhaDelucchi2018">{{cite journal|last1=Sinha|first1=Pratik|last2=Delucchi|first2=Kevin L.|last3=Thompson|first3=B. Taylor|last4=McAuley|first4=Daniel F.|last5=Matthay|first5=Michael A.|last6=Calfee|first6=Carolyn S.|title=Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study|journal=Intensive Care Medicine|volume=44|issue=11|year=2018|pages=1859–1869|issn=0342-4642|doi=10.1007/s00134-018-5378-3}}</ref>
+* The characteristic of this phenomena could be considered as an indicator of adverse clinical outcomes such as [[COVID-19-associated acute respiratory distress syndrome|ARDS]], [[shock]] and [[COVID-19-associated acute kidney injury|ARF]].<ref name="SinhaDelucchi2018">{{cite journal|last1=Sinha|first1=Pratik|last2=Delucchi|first2=Kevin L.|last3=Thompson|first3=B. Taylor|last4=McAuley|first4=Daniel F.|last5=Matthay|first5=Michael A.|last6=Calfee|first6=Carolyn S.|title=Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study|journal=Intensive Care Medicine|volume=44|issue=11|year=2018|pages=1859–1869|issn=0342-4642|doi=10.1007/s00134-018-5378-3}}</ref>
+*Hyper [[immunity]] caused by [[cytokine storm]] leading to multi-organ failure in [[COVID-19]] is not fully proved yet, but from previous viral [[Epidemic|epidemics]], it is highly suggested to be considered as a reason to this outcome.
+*For more information about [[COVID-19]] natural history,complication and prognosis please click [[COVID-19 natural history, complications and prognosis|here]].
 ==Diagnosis==
 ===Diagnostic Study of Choice===
-The most important cytokines that increase are :<ref name="SchultzArnold1990">{{cite journal|last1=Schultz|first1=Duane R.|last2=Arnold|first2=Patricia I.|title=Properties of four acute phase proteins: C-reactive protein, serum amyloid a protein, α1-acid glycoprotein, and fibrinogen|journal=Seminars in Arthritis and Rheumatism|volume=20|issue=3|year=1990|pages=129–147|issn=00490172|doi=10.1016/0049-0172(90)90055-K}}</ref>
+The most important [[Cytokine|cytokines]] that increase are :<ref name="SchultzArnold1990">{{cite journal|last1=Schultz|first1=Duane R.|last2=Arnold|first2=Patricia I.|title=Properties of four acute phase proteins: C-reactive protein, serum amyloid a protein, α1-acid glycoprotein, and fibrinogen|journal=Seminars in Arthritis and Rheumatism|volume=20|issue=3|year=1990|pages=129–147|issn=00490172|doi=10.1016/0049-0172(90)90055-K}}</ref>
 * [[Interleukin 6|IL-6]]
 * [[IFN|IFNɤ]]
 * [[C-reactive protein|CRP]]
+The suggested strategy is to measure the so-called [[cytokines]].
 ===History and Symptoms===
+* [[COVID-19]] infected individuals who go through more adverse clinical manifestations, such as [[COVID-19-associated acute respiratory distress syndrome|ARDS]] and high inflammatory states, are more likely to undergo [[cytokine]] elevation.
-* [[COVID-19]] infected individuals who go through more adverse clinical manifestations, such as [[Acute respiratory distress syndrome|ARDS]] and high inflammatory states, are more likely to undergo [[cytokine]] elevation.
+* For [[COVID-19]] associated history and symptoms click [[COVID-19 history and symptoms|here]].
-*For COVID-19 associated history and symptoms click [[COVID-19 history and symptoms|here]].
 ===Physical Examination===
 * For COVID-19 Physical examination click [[COVID-19 physical examination|here]].
 ===Laboratory Findings===
+* According to many reviews, [[Interleukin 6|Interleukin-6]] is the best indicator of the [[cytokine storm]].
+*[[Interleukin 6|IL-6]] concentration has been reported by many studies and is believed to be at a maximal cut of 80 pg/ml in a severe form of the disease.
+*Patients with higher levels of [[Interleukin 6|IL-6]] are at a greater chance of severe disease.<ref name="ZhangWang2020">{{cite journal|last1=Zhang|first1=Yongxi|last2=Wang|first2=Fan|last3=Cao|first3=Qian|last4=Zheng|first4=Ruiying|last5=Chen|first5=Xiaoping|last6=Ma|first6=Zhiyong|last7=Song|first7=Shihui|last8=Chen|first8=Tielong|last9=Luo|first9=Mingqi|last10=Liang|first10=Ke|last11=Gao|first11=Shicheng|last12=Cheng|first12=Zhenshun|last13=Xiong|first13=Yong|last14=Wang|first14=Hongling|last15=Zhao|first15=Qiu|last16=Deng|first16=Liping|last17=Xiao|first17=Yu|last18=Xing|first18=Yuanyuan|last19=Mo|first19=Pingzheng|title=Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China|journal=Clinical Infectious Diseases|year=2020|issn=1058-4838|doi=10.1093/cid/ciaa270}}</ref>
-* According to many reviews so far, Interleukin-6 is the best indicator of the cytokine storm.
-* IL-6 concentration has been reported by many studies and is believed to be at a maximal cut of 80 pg/ml in a severe form of the disease.
-*Patients with higher levels of IL-6 are at a greater chance of severe disease.<ref name="ZhangWang2020">{{cite journal|last1=Zhang|first1=Yongxi|last2=Wang|first2=Fan|last3=Cao|first3=Qian|last4=Zheng|first4=Ruiying|last5=Chen|first5=Xiaoping|last6=Ma|first6=Zhiyong|last7=Song|first7=Shihui|last8=Chen|first8=Tielong|last9=Luo|first9=Mingqi|last10=Liang|first10=Ke|last11=Gao|first11=Shicheng|last12=Cheng|first12=Zhenshun|last13=Xiong|first13=Yong|last14=Wang|first14=Hongling|last15=Zhao|first15=Qiu|last16=Deng|first16=Liping|last17=Xiao|first17=Yu|last18=Xing|first18=Yuanyuan|last19=Mo|first19=Pingzheng|title=Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China|journal=Clinical Infectious Diseases|year=2020|issn=1058-4838|doi=10.1093/cid/ciaa270}}</ref>
 ===Electrocardiogram===
-There are no ECG findings regarding COVID-19-associated Cytokine storm.
+* There are no [[The electrocardiogram|ECG]] findings regarding COVID-19-associated Cytokine storm.
 ===X-ray===
-There are no x-ray findings regarding COVID-19-associated Cytokine storm.
+* COVID-19 associated cytokine storm leads to Acute respiratory distress syndrome(ARDS).
+*X-ray Findings related to COVID-19 ARDS are:
+**Ground-glass opacification and consolidation
+**Early findings on the [[chest radiograph]] include normal or diffuse alveolar opacities (consolidation), which are often bilateral and which obscure the pulmonary vascular markings.
+** Later, these opacities progress to more extensive consolidation that is diffuse, and they are often asymmetrical.
+[[File:Covid-19-rapidly-progressive-acute-respiratory-distress-syndrome-ards.jpg|center|250px|thumbnail|Bilateral alveolar consolidation with panlobar change, with typical radiological findings of ARDS.<ref> name="urlCOVID-19 - rapidly progressive acute respiratory distress syndrome (ARDS) | Radiology Case | Radiopaedia.org">{{cite web |url=https://radiopaedia.org/cases/covid-19-rapidly-progressive-acute-respiratory-distress-syndrome-ards?lang=us |title=COVID-19 - rapidly progressive acute respiratory distress syndrome (ARDS) &#124; Radiology Case &#124; Radiopaedia.org |format= |work= |accessdate=}}</ref>]]
 ===Echocardiography or Ultrasound===
-There are no echocardiography or ultrasound findings regarding the COVID-19-associated Cytokine storm.
+* There are no [[echocardiography]] or ultrasound findings regarding the [[COVID-19]]-associated [[cytokine storm]].
 ===CT scan===
-There are no CT scan findings regarding the COVID-19-associated Cytokine storm.
+* COVID-19 associated cytokine storm Leads to ARDS.
+*Multifocal ground glass opacity would be found at both lungs.
+[[File:Covid-19-pneumonia-45.jpg|center|250px|thumbnail|Multifocal ground glass, mainly in the periphery of both lungs.<ref> name="urlCOVID-19 pneumonia | Radiology Case | Radiopaedia.org">{{cite web |url=https://radiopaedia.org/cases/covid-19-pneumonia-45?lang=us |title=COVID-19 pneumonia &#124; Radiology Case &#124; Radiopaedia.org |format= |work= |accessdate=}}</ref>]]
 ===MRI===
-There are no MRI findings regarding the COVID-19-associated Cytokine storm.
+* There are no [[Magnetic resonance imaging|MRI]] findings regarding the [[COVID-19]]-associated [[cytokine storm]].
 ===Other Imaging Findings===
-There are no other imaging findings regarding the COVID-19-associated Cytokine storm.
+* There are no other imaging findings regarding the [[COVID-19]]-associated [[cytokine storm]].
 ==Treatment==
 ===Medical Therapy===
 * Currently, no proven treatment has been suggested.
 * Potential therapies for reducing inflammation are:
-**[[Corticosteroids]]:<ref name="HuangWang20202">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref>
+**[[Corticosteroids]]:<ref name="HuangWang20202">{{cite journal|last1=Huang|first1=Chaolin|last2=Wang|first2=Yeming|last3=Li|first3=Xingwang|last4=Ren|first4=Lili|last5=Zhao|first5=Jianping|last6=Hu|first6=Yi|last7=Zhang|first7=Li|last8=Fan|first8=Guohui|last9=Xu|first9=Jiuyang|last10=Gu|first10=Xiaoying|last11=Cheng|first11=Zhenshun|last12=Yu|first12=Ting|last13=Xia|first13=Jiaan|last14=Wei|first14=Yuan|last15=Wu|first15=Wenjuan|last16=Xie|first16=Xuelei|last17=Yin|first17=Wen|last18=Li|first18=Hui|last19=Liu|first19=Min|last20=Xiao|first20=Yan|last21=Gao|first21=Hong|last22=Guo|first22=Li|last23=Xie|first23=Jungang|last24=Wang|first24=Guangfa|last25=Jiang|first25=Rongmeng|last26=Gao|first26=Zhancheng|last27=Jin|first27=Qi|last28=Wang|first28=Jianwei|last29=Cao|first29=Bin|title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China|journal=The Lancet|volume=395|issue=10223|year=2020|pages=497–506|issn=01406736|doi=10.1016/S0140-6736(20)30183-5}}</ref><ref name="HorbyLim2020">{{cite journal|last1=Horby|first1=Peter|last2=Lim|first2=Wei Shen|last3=Emberson|first3=Jonathan|last4=Mafham|first4=Marion|last5=Bell|first5=Jennifer|last6=Linsell|first6=Louise|last7=Staplin|first7=Natalie|last8=Brightling|first8=Christopher|last9=Ustianowski|first9=Andrew|last10=Elmahi|first10=Einas|last11=Prudon|first11=Benjamin|last12=Green|first12=Christopher|last13=Felton|first13=Timothy|last14=Chadwick|first14=David|last15=Rege|first15=Kanchan|last16=Fegan|first16=Christopher|last17=Chappell|first17=Lucy C|last18=Faust|first18=Saul N|last19=Jaki|first19=Thomas|last20=Jeffery|first20=Katie|last21=Montgomery|first21=Alan|last22=Rowan|first22=Kathryn|last23=Juszczak|first23=Edmund|last24=Baillie|first24=J Kenneth|last25=Haynes|first25=Richard|last26=Landray|first26=Martin J|year=2020|doi=10.1101/2020.06.22.20137273}}</ref>
-*** Systemic use of [[corticosteroid]] is not recommended by WHO based on evidence from patients with MERS and ARDS.
+***Currently in the U.K. there is an ongoing trial ([https://www.recoverytrial.net/ RECOVERY] Trial) that Suggest Systemic low dose [[Dexamethasone]] decreases mortality by one third.
-** Tocilizumab:<ref name="LeLi2018">{{cite journal|last1=Le|first1=Robert Q.|last2=Li|first2=Liang|last3=Yuan|first3=Weishi|last4=Shord|first4=Stacy S.|last5=Nie|first5=Lei|last6=Habtemariam|first6=Bahru A.|last7=Przepiorka|first7=Donna|last8=Farrell|first8=Ann T.|last9=Pazdur|first9=Richard|title=FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome|journal=The Oncologist|volume=23|issue=8|year=2018|pages=943–947|issn=1083-7159|doi=10.1634/theoncologist.2018-0028}}</ref><ref name="XuTang2014">{{cite journal|last1=Xu|first1=Xiao-Jun|last2=Tang|first2=Yong-Min|title=Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells|journal=Cancer Letters|volume=343|issue=2|year=2014|pages=172–178|issn=03043835|doi=10.1016/j.canlet.2013.10.004}}</ref><ref name="pmid32456769">{{cite journal| author=Campins L, Boixeda R, Perez-Cordon L, Aranega R, Lopera C, Force L| title=Early tocilizumab treatment could improve survival among COVID-19 patients. | journal=Clin Exp Rheumatol | year= 2020 | volume= 38 | issue= 3 | pages= 578 | pmid=32456769 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32456769  }}</ref><ref name="MorenaMilazzo2020">{{cite journal|last1=Morena|first1=Valentina|last2=Milazzo|first2=Laura|last3=Oreni|first3=Letizia|last4=Bestetti|first4=Giovanna|last5=Fossali|first5=Tommaso|last6=Bassoli|first6=Cinzia|last7=Torre|first7=Alessandro|last8=Cossu|first8=Maria Vittoria|last9=Minari|first9=Caterina|last10=Ballone|first10=Elisabetta|last11=Perotti|first11=Andrea|last12=Mileto|first12=Davide|last13=Niero|first13=Fosca|last14=Merli|first14=Stefania|last15=Foschi|first15=Antonella|last16=Vimercati|first16=Stefania|last17=Rizzardini|first17=Giuliano|last18=Sollima|first18=Salvatore|last19=Bradanini|first19=Lucia|last20=Galimberti|first20=Laura|last21=Colombo|first21=Riccardo|last22=Micheli|first22=Valeria|last23=Negri|first23=Cristina|last24=Ridolfo|first24=Anna Lisa|last25=Meroni|first25=Luca|last26=Galli|first26=Massimo|last27=Antinori|first27=Spinello|last28=Corbellino|first28=Mario|title=Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy|journal=European Journal of Internal Medicine|volume=76|year=2020|pages=36–42|issn=09536205|doi=10.1016/j.ejim.2020.05.011}}</ref>
+***[[Dexamethasone]] administered as an oral (liquid or tablets) or intravenous preparation. In pregnancy or breastfeeding women, [[prednisolone]] (or intravenous hydrocortisone) should be used.
-*** Toclizumab is an FDA approved drug used for [[cytokine]] release syndrome after Chimeric Antigen Receptor infusion, which cause cytokine release storm.
+***The suggested dosage is 6 mg once daily for 10 days
-*** It is an [[Interleukin 6|IL-6]] Receptor [[antibody]], which is effective in similar clinical manifestations.
+**[[Azithromycin]]: <ref name="BleyzacGoutelle2020">{{cite journal|last1=Bleyzac|first1=Nathalie|last2=Goutelle|first2=Sylvain|last3=Bourguignon|first3=Laurent|last4=Tod|first4=Michel|title=Azithromycin for COVID-19: More Than Just an Antimicrobial?|journal=Clinical Drug Investigation|volume=40|issue=8|year=2020|pages=683–686|issn=1173-2563|doi=10.1007/s40261-020-00933-3}}</ref>
-***In some off label studies, it has been shown that tocolizumab can cause improvement in patients.
+***[[Azithromycin]] Have shown anti inflammatory effects against [[Ebola]], [[respiratory syncytial virus]] and [[Influenza, avian|Influenza H1N1]].
+***[[Azithromycin]] 500mg by mouth (or [[nasogastric tube]]) or intravenously once daily for 10 days is recommended.
+****
+**[[COVID-19 future or investigational therapies|Remdesivir]]:<ref name="BeigelTomashek2020">{{cite journal|last1=Beigel|first1=John H.|last2=Tomashek|first2=Kay M.|last3=Dodd|first3=Lori E.|last4=Mehta|first4=Aneesh K.|last5=Zingman|first5=Barry S.|last6=Kalil|first6=Andre C.|last7=Hohmann|first7=Elizabeth|last8=Chu|first8=Helen Y.|last9=Luetkemeyer|first9=Annie|last10=Kline|first10=Susan|last11=Lopez de Castilla|first11=Diego|last12=Finberg|first12=Robert W.|last13=Dierberg|first13=Kerry|last14=Tapson|first14=Victor|last15=Hsieh|first15=Lanny|last16=Patterson|first16=Thomas F.|last17=Paredes|first17=Roger|last18=Sweeney|first18=Daniel A.|last19=Short|first19=William R.|last20=Touloumi|first20=Giota|last21=Lye|first21=David Chien|last22=Ohmagari|first22=Norio|last23=Oh|first23=Myoung-don|last24=Ruiz-Palacios|first24=Guillermo M.|last25=Benfield|first25=Thomas|last26=Fätkenheuer|first26=Gerd|last27=Kortepeter|first27=Mark G.|last28=Atmar|first28=Robert L.|last29=Creech|first29=C. Buddy|last30=Lundgren|first30=Jens|last31=Babiker|first31=Abdel G.|last32=Pett|first32=Sarah|last33=Neaton|first33=James D.|last34=Burgess|first34=Timothy H.|last35=Bonnett|first35=Tyler|last36=Green|first36=Michelle|last37=Makowski|first37=Mat|last38=Osinusi|first38=Anu|last39=Nayak|first39=Seema|last40=Lane|first40=H. Clifford|title=Remdesivir for the Treatment of Covid-19 — Preliminary Report|journal=New England Journal of Medicine|year=2020|issn=0028-4793|doi=10.1056/NEJMoa2007764}}</ref><ref name="BeigelTomashek20202">{{cite journal|last1=Beigel|first1=John H.|last2=Tomashek|first2=Kay M.|last3=Dodd|first3=Lori E.|last4=Mehta|first4=Aneesh K.|last5=Zingman|first5=Barry S.|last6=Kalil|first6=Andre C.|last7=Hohmann|first7=Elizabeth|last8=Chu|first8=Helen Y.|last9=Luetkemeyer|first9=Annie|last10=Kline|first10=Susan|last11=Lopez de Castilla|first11=Diego|last12=Finberg|first12=Robert W.|last13=Dierberg|first13=Kerry|last14=Tapson|first14=Victor|last15=Hsieh|first15=Lanny|last16=Patterson|first16=Thomas F.|last17=Paredes|first17=Roger|last18=Sweeney|first18=Daniel A.|last19=Short|first19=William R.|last20=Touloumi|first20=Giota|last21=Lye|first21=David Chien|last22=Ohmagari|first22=Norio|last23=Oh|first23=Myoung-don|last24=Ruiz-Palacios|first24=Guillermo M.|last25=Benfield|first25=Thomas|last26=Fätkenheuer|first26=Gerd|last27=Kortepeter|first27=Mark G.|last28=Atmar|first28=Robert L.|last29=Creech|first29=C. Buddy|last30=Lundgren|first30=Jens|last31=Babiker|first31=Abdel G.|last32=Pett|first32=Sarah|last33=Neaton|first33=James D.|last34=Burgess|first34=Timothy H.|last35=Bonnett|first35=Tyler|last36=Green|first36=Michelle|last37=Makowski|first37=Mat|last38=Osinusi|first38=Anu|last39=Nayak|first39=Seema|last40=Lane|first40=H. Clifford|title=Remdesivir for the Treatment of Covid-19 — Preliminary Report|journal=New England Journal of Medicine|year=2020|issn=0028-4793|doi=10.1056/NEJMoa2007764}}</ref>
+***In a first [[COVID-19]] treatment EMA’s human medicines committee (CHMP) recommended [[remdesivir]] for EU authorization in a preliminary report.
+***A total of 1063 patients underwent randomization in the [[remdesivir]] [[double-blind]], [[Placebo-controlled trials|placebo-controlled trial]].
+***[[Intravenous]] [[remdesivir]] used in adult hospitalized [[COVID-19]] patients in a [[double-blind]], [[Randomized controlled trial|randomized]], [[Placebo-controlled trials|placebo-controlled trial]].
+*** Dosage of [[remdesivir]] is 200 mg loading dose on day 1, which is followed by 100 mg daily for up to 9 additional days or a placebo for up to 10 days in the random trail.
+***Preferred regimen in [[pediatric]] population who are weighing 3.5 kg to less than 40kg: [[Remdesivir]] injection, 100 mg, [[lyophilized]] powder which includes a single loading dose of [[remdesivir]] 5 mg/kg on Day 1 followed by [[remdesivir]] 2.5 mg/kg once daily from Day 2
+***
+**[[Tocilizumab]]:<ref name="LeLi2018">{{cite journal|last1=Le|first1=Robert Q.|last2=Li|first2=Liang|last3=Yuan|first3=Weishi|last4=Shord|first4=Stacy S.|last5=Nie|first5=Lei|last6=Habtemariam|first6=Bahru A.|last7=Przepiorka|first7=Donna|last8=Farrell|first8=Ann T.|last9=Pazdur|first9=Richard|title=FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell‐Induced Severe or Life‐Threatening Cytokine Release Syndrome|journal=The Oncologist|volume=23|issue=8|year=2018|pages=943–947|issn=1083-7159|doi=10.1634/theoncologist.2018-0028}}</ref><ref name="XuTang2014">{{cite journal|last1=Xu|first1=Xiao-Jun|last2=Tang|first2=Yong-Min|title=Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells|journal=Cancer Letters|volume=343|issue=2|year=2014|pages=172–178|issn=03043835|doi=10.1016/j.canlet.2013.10.004}}</ref><ref name="pmid32456769">{{cite journal| author=Campins L, Boixeda R, Perez-Cordon L, Aranega R, Lopera C, Force L| title=Early tocilizumab treatment could improve survival among COVID-19 patients. | journal=Clin Exp Rheumatol | year= 2020 | volume= 38 | issue= 3 | pages= 578 | pmid=32456769 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32456769  }}</ref><ref name="MorenaMilazzo2020">{{cite journal|last1=Morena|first1=Valentina|last2=Milazzo|first2=Laura|last3=Oreni|first3=Letizia|last4=Bestetti|first4=Giovanna|last5=Fossali|first5=Tommaso|last6=Bassoli|first6=Cinzia|last7=Torre|first7=Alessandro|last8=Cossu|first8=Maria Vittoria|last9=Minari|first9=Caterina|last10=Ballone|first10=Elisabetta|last11=Perotti|first11=Andrea|last12=Mileto|first12=Davide|last13=Niero|first13=Fosca|last14=Merli|first14=Stefania|last15=Foschi|first15=Antonella|last16=Vimercati|first16=Stefania|last17=Rizzardini|first17=Giuliano|last18=Sollima|first18=Salvatore|last19=Bradanini|first19=Lucia|last20=Galimberti|first20=Laura|last21=Colombo|first21=Riccardo|last22=Micheli|first22=Valeria|last23=Negri|first23=Cristina|last24=Ridolfo|first24=Anna Lisa|last25=Meroni|first25=Luca|last26=Galli|first26=Massimo|last27=Antinori|first27=Spinello|last28=Corbellino|first28=Mario|title=Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy|journal=European Journal of Internal Medicine|volume=76|year=2020|pages=36–42|issn=09536205|doi=10.1016/j.ejim.2020.05.011}}</ref>
+***[[Tocilizumab]] is an [[Food and Drug Administration|FDA]] approved drug used for [[cytokine]] release syndrome after chimeric [[antigen]] receptor [[infusion]], which cause [[cytokine]] release storm.
+*** It is an [[Interleukin 6|IL-6]] receptor [[antibody]], which is effective in similar clinical manifestations.
+***In some off label studies, it has been shown that [[tocilizumab]] can cause improvement in patients.
+***intravenous infusion with the dose determined by body weight
+**** 8 mg/kg (maximum: 800 mg/dose) as a single dose; may repeat dose in 8 to 12 hours if signs/symptoms worsen or do not improve.
+**** 8 mg/kg (maximum: 800 mg/dose) every 12 hours for 2 doses.
+**** 8 mg/kg as a single dose.
+**** 4 to 8 mg/kg (usual dose: 400 mg/dose; maximum: 800 mg/dose) as a single dose; may repeat dose in ≥12 hours in patients who remain [[febrile]] within 24 hours of initial dose.
 **[[Etoposide]]:<ref name="La Rosée2015">{{cite journal|last1=La Rosée|first1=Paul|title=Treatment of hemophagocytic lymphohistiocytosis in adults|journal=Hematology|volume=2015|issue=1|year=2015|pages=190–196|issn=1520-4391|doi=10.1182/asheducation-2015.1.190}}</ref>
-***[[Etoposide]] is used for suppressing cytokine release in [[hemophagocytic lymphohistiocytosis]].
+***[[Etoposide]] is used for suppressing [[cytokine]] release in [[hemophagocytic lymphohistiocytosis]].
 ***In patients with severe disease, etoposide can inhibit overwhelming inflammation.
+***the suggested dosage is [[Etoposide]] 150 mg/m2 daily days 1 and 4
 **[[Ruxolitinib]]:<ref name="CaoWei2020">{{cite journal|last1=Cao|first1=Yang|last2=Wei|first2=Jia|last3=Zou|first3=Liang|last4=Jiang|first4=Tiebin|last5=Wang|first5=Gaoxiang|last6=Chen|first6=Liting|last7=Huang|first7=Liang|last8=Meng|first8=Fankai|last9=Huang|first9=Lifang|last10=Wang|first10=Na|last11=Zhou|first11=Xiaoxi|last12=Luo|first12=Hui|last13=Mao|first13=Zekai|last14=Chen|first14=Xing|last15=Xie|first15=Jungang|last16=Liu|first16=Jing|last17=Cheng|first17=Hui|last18=Zhao|first18=Jianping|last19=Huang|first19=Gang|last20=Wang|first20=Wei|last21=Zhou|first21=Jianfeng|title=Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial|journal=Journal of Allergy and Clinical Immunology|volume=146|issue=1|year=2020|pages=137–146.e3|issn=00916749|doi=10.1016/j.jaci.2020.05.019}}</ref>
-***Jack1/2 inhibitor
+***Jack1/2 [[inhibitor]].
 ***It is used in [[hemophagocytic lymphohistiocytosis]].
-***In a prospective randomized trial, it was shown that it reduces the levels of seven [[Cytokine|cytokines]] compared to the control group, and resulted in faster improvement in patients with severe infection.
+***In a prospective [[randomized trial]], it was shown that it reduces the levels of seven [[Cytokine|cytokines]] compared to the control group, and resulted in faster improvement in patients with severe [[infection]].
-**
+***the suggested dose is 5 mg twice daily.<ref name="La RoséeBremer2020">{{cite journal|last1=La Rosée|first1=F.|last2=Bremer|first2=H. C.|last3=Gehrke|first3=I.|last4=Kehr|first4=A.|last5=Hochhaus|first5=A.|last6=Birndt|first6=S.|last7=Fellhauer|first7=M.|last8=Henkes|first8=M.|last9=Kumle|first9=B.|last10=Russo|first10=S. G.|last11=La Rosée|first11=P.|title=The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation|journal=Leukemia|volume=34|issue=7|year=2020|pages=1805–1815|issn=0887-6924|doi=10.1038/s41375-020-0891-0}}</ref>
+**[[Lopinavir]]-[[Ritonavir]]:<ref>{{cite journal|title=A Trial of Lopinavir–Ritonavir in Covid-19|journal=New England Journal of Medicine|volume=382|issue=21|year=2020|pages=e68|issn=0028-4793|doi=10.1056/NEJMc2008043}}</ref>
+***[[Lopinavir]] 400 mg every 12 hours for ten days
+***[[Ritonavir]] 100 mg every 12 hours for ten days
 ===Surgery===
-Surgical intervention is not recommended for the management of COVID-19-associated cytokine storm.
+* 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.
+* Since there is no vaccine for COVID-19 there are plenty of primary prevention suggested from CDC such as:<ref>{{Cite web|url=https://www.cdc.gov/coronavirus/2019-ncov/index.html|title=|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
+** Hand washing every 10 minutes.
+** Using alcoholic hand sanitizer.
+** Self [[quarantine]] for two weeks if [[symptomatic]].
+* To view the primary prevention measures of COVID-19, click [[COVID-19 primary prevention|here]].
 ===Secondary Prevention===
-There are no established measures for the secondary prevention of COVID-19-associated cytokine storm.
+* [[World Health Organization|WHO]] recommends home care for patients with suspected [[COVID-19]] who present with mild symptoms:<ref>{{cite web |url=https://www.who.int/publications/i/item/home-care-for-patients-with-suspected-novel-coronavirus-(ncov)-infection-presenting-with-mild-symptoms-and-management-of-contacts |title=Home care for patients with COVID-19 presenting with mild symptoms and management of their contacts |format= |work= |accessdate=}}</ref>
+** Family members of an infected patient are better to wear masks.
+** Using separate bathroom and bedroom by the infected person.
+** Using [[antipyretics]] and analgesics for [[fever]], [[myalgias]], and [[headaches]]
+* To view the secondary prevention measures of COVID-19, click [[COVID-19 secondary prevention|here]].
 ==References==
 {{reflist|2}}
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