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Revision as of 16:41, 24 July 2020

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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 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 pro-inflammatory cytokines. Cytokine storm (dysregulated and excessive release of cytokines) has 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 growing number of patients however, 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 storm is 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

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

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]

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 storm (dysregulated and excessive release of cytokines) has 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

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

Echocardiography or Ultrasound

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.

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:^[27]
  - Systemic use of corticosteroid is not recommended by WHO based on evidence from patients with MERS and ARDS.
  - Currently in U.K. there is an ongoing trial (RECOVERY Trial) that Suggest Systemic low dose Dexamethasone decreases mortality by one third.
- Azithromycin: ^[28]
- Remdesivir:^[29]
- Tocilizumab:^[30]^[31]^[32]^[33]
  - 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.
- Etoposide:^[34]
  - Etoposide is used for suppressing cytokine release in hemophagocytic lymphohistiocytosis.
  - In patients with severe disease, etoposide can inhibit overwhelming inflammation.
- Ruxolitinib:^[35]
  - 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.

Surgery

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

Primary Prevention

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

Secondary Prevention

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

References

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[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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[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.

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[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.

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@@ Line 226: / Line 226: @@
 **[[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>
 *** Systemic use of [[corticosteroid]] is not recommended by [[World Health Organization|WHO]] based on evidence from patients with [[Middle East respiratory syndrome coronavirus infection|MERS]] and [[Acute respiratory distress syndrome|ARDS]].
+***Currently in U.K. there is an ongoing trial ([https://www.recoverytrial.net/ RECOVERY] Trial) that Suggest Systemic low dose [[Dexamethasone]] decreases mortality by one third.
+**[[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>
+***
+**[[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>
+***
 **[[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.