Sandbox:Shakiba
Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[1]
Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory cytokines.[1]
Cytokines Involved in Cytokine Storm
- Cytokines are small proteins that are released for cell signaling.[1]
- Cytokines types and their actions include:[1]
- 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 chemoattractants
- Recruitment of leukocytes
- Colony-stimulating factors
- Induction of hematopoietic progenitor cell proliferation and differentiation
- Tumor necrosis factor (TNF)
- Interferons (INFs)
Pathogenesis of Cytokine Storm
- Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory cytokines.[1]
- During sepsis, cytokine storm may be the cause of tissue or organ injury.[2]
- Cytokine storm causes inflammation, which in the beginning of the disease is local and later spreads around by the systemic circulation. This is followed by repair and restoration of tissues, organs and their functions. However, in severe or some inflammations, the repair is with fibrosis which may lead to permanent dysfunction of organs.[1]
- 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:[1]
- In the early stages of the infection (minutes to hours), cytokines such as TNF and IL-1, and chemokines such as IL-8 and MCP-1 (CCL2) increase.
- Then, an increase in IL-6 is followed.
- Later, IL-10 (anti-inflammatory cytokine) increases.
- Proinflammatory cytokines that have a role in ARDS include:[3][4][5][6]
- IL-1β
- IL-6
- IL-8 (CXCL8)
- CCL-2 (MCP-1)
- CCL-3 (Macrophage inflammatory protein-1A)
- CCL-5
- IFNγ -induced protein 10 (IP-10, CXCL10)
- Granulocytemacrophage colony-stimulating factor (GM-CSF)
- Cytokine storm (dysregulated and excessive release of cytokines) has been associated with ARDS in SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV) infections.[7]
There have been reports on an association between cytokine storm and severity of COVID-19 infection and COVID-19-associated-ARDS.
Significant increase in pro-inflammatory cytokines (such as IL-6), reduction in CD+8 T cells, suppressed Th1 antiviral responses and increase in IL-10 (a Th2 cytokine) have been reported to be associated with severe COVID-19 infection. (kupalli) Therefore, it has been suggested that the pathogenesis of severe COVID-19 infection may be due to cytokine storm and suppressed Th1 antiviral responses. (kupalli)
High levels of expression of IL-1B, IFN-γ , IP-10, and monocyte hemoattractant protein 1 (MCP-1) have been detected in patients with COVID-19.These inflammatory cytokines may activate the Thelper type 1 (Th1) cell response.47 Th1 activation is a key event in the activation of specific immunity.48The serum levels of IL-2R and IL-6 in patients with COVID-19 are positively correlated with the severity of the disease (i.e., critically ill patients > severely ill patients > ordinary patients).49ther studies have found that, compared with COVID-19 patients from general wards, patients in the intensive care unit (ICU) display increased serum levels of granulocyte colony-stimulating factor, IP-10, MCP-1, macrophage inflammatory protein-1A, and TNF-α. The above studies suggest that the cytokine storm is positively correlated with disease severity.47
In contrast to SARS infection, patients with COVID-19 infection have high levels of IL-4 and IL-10 (secreted by Th2 cells), which are antiinflammatory cytokines.
| Cytokines Involved in COVID-19-Associated-Cytokine Storm | ||
|---|---|---|
| Proinflammatory | Interferones |
|
| Interleukines |
| |
| Chemokines |
| |
| Colony-stimulating
factors |
| |
| Tumor necrosis
factor |
| |
| Anti-inflammatory | Interleukines |
|
Overview
COVID-19-Associated Hematologic Findings
LeukocytosisIncrease in C-reactive protein (CRP)Increase in procalcitoninIncrease in ferritinIncrease in aspartate aminotransferase (AST)Increase in alanine aminotransferase (ALT)Increase in lactate dehydrogenase (LDH)Increase in monocyte volume distribution width (MDW)Increase in total bilirubinIncrease in creatinineIncrease in cardiac troponinsDecrease in albuminIncrease in interleukin-6 (IL-6)Thrombocytosis
Pathophysiology and Causes
CRP is an acute phase reactant that increases in conditions with inflammation.[8]In sepsis, the activation and adherence of monocytes increase procalcitonin, therefore procalcitonin in a biomarker for sepsis and septic shock.[9]ALT is produced by liver cells and is increased in liver conditions.[8]LDH is expressed in almost all cells and an increase in LDH could be seen in damage to any of the cell types.[8]Bilirubin is produced by liver cells and increases in liver and biliary conditions.[8]Creatinin is produced in the liver and excreted by the kidneys; creatinine increases when there is decrease in glomerular filtration rate.[8]Increase in cardiac troponins are used for diagnosing myocardial infarction and acute coronary syndrome .[8]Albumin may be decreased in many conditions such as sepsis, renal disease or malnutrition.[8]
Epidemiology
Leukocytosis is seen in 11.4% of patients with severe COVID-19 infection compared to 4.8% of patients with non-severe infection.[10][11]Increase in CRP is seen in 81.5% of patients with severe COVID-19 infection compared to 56.4% of patients with non-severe infection.[10][11]Increase in procalcitonin is seen in 13.7% of patients with severe COVID-19 infection compared to 3.7% of patients with non-severe infection.[10][11]Increase in AST is seen in 39.4% of patients with severe COVID-19 infection compared to 18.2% of patients with non-severe infection.[10][11]Increase in ALT is seen in 28.1% of patients with severe COVID-19 infection compared to 19.8% of patients with non-severe infection.[10][11]Increase in LDH is seen in 58.1% of patients with severe COVID-19 infection compared to 37.2% of patients with non-severe infection.[10][11]MDW was found to be increased in all patients with COVID-19 infection, particularly in those with the worst conditions.[11]Increase in total bilirubin is seen in 13.3% of patients with severe COVID-19 infection compared to 9.9% of patients with non-severe infection.[10][11]Increase in creatinine is seen in 4.3% of patients with severe COVID-19 infection compared to 1% of patients with non-severe infection.[10][11]Thrombocytosis has been reported in 4% of patients with COVID-19 infection.[12]
Clinical Significance
Laboratory findings in COVID-19 infection may indicate clinical abnormalities, including:
In patients with COVID-19 infection, leukocytosis may be an indication of a bacterial infection or superinfection.[11]In patients with COVID-19 infection, increase in CRP may be an indication of severe viral infection or sepsis and viremia.[11]In patients with COVID-19 infection, increase in procalcitonin may be an indication of bacterial infection or superinfection.[11]There have been different reports regarding the association of increase in ferritin with death in COVID-19 infection; for example, there has been a report that increase in ferritin is associated with acute respiratory distress syndrome (ARDS) but not death[13], while another one reports an association between increase in ferritin and death in COVID-19 infection[14]In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.[11]In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.[11]In patients with COVID-19 infection, increase in LDH may indicate injury to the lungs or multi-system damage.[11]In patients with COVID-19 infection, increase in total bilirubin may indicate injury to the liver.[11]In patients with COVID-19 infection, increase in creatinine may indicate injury to the kidneys.[11]In patients with COVID-19 infection, increase in cardiac troponins may indicate cardiac injury.[11]In patients with COVID-19 infection, decrease in albumin may indicate liver function abnormality.[11]Increase in IL-6 has been reported to be associated with death in COVID-19 infection.[13]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG (2012). "Into the eye of the cytokine storm". Microbiol Mol Biol Rev. 76 (1): 16–32. doi:10.1128/MMBR.05015-11. PMC 3294426. PMID 22390970.
- ↑ Chousterman BG, Swirski FK, Weber GF (2017). "Cytokine storm and sepsis disease pathogenesis". Semin Immunopathol. 39 (5): 517–528. doi:10.1007/s00281-017-0639-8. PMID 28555385.
- ↑ Jiang Y, Xu J, Zhou C, Wu Z, Zhong S, Liu J; et al. (2005). "Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome". Am J Respir Crit Care Med. 171 (8): 850–7. doi:10.1164/rccm.200407-857OC. PMID 15657466.
- ↑ Cameron MJ, Bermejo-Martin JF, Danesh A, Muller MP, Kelvin DJ (2008). "Human immunopathogenesis of severe acute respiratory syndrome (SARS)". Virus Res. 133 (1): 13–9. doi:10.1016/j.virusres.2007.02.014. PMC 7114310 Check
|pmc=value (help). PMID 17374415. - ↑ Reghunathan R, Jayapal M, Hsu LY, Chng HH, Tai D, Leung BP; et al. (2005). "Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome". BMC Immunol. 6: 2. doi:10.1186/1471-2172-6-2. PMC 546205. PMID 15655079.
- ↑ Ye Q, Wang B, Mao J (2020). "The pathogenesis and treatment of the `Cytokine Storm' in COVID-19". J Infect. 80 (6): 607–613. doi:10.1016/j.jinf.2020.03.037. PMC 7194613 Check
|pmc=value (help). PMID 32283152 Check|pmid=value (help). - ↑ Channappanavar R, Perlman S (2017). "Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology". Semin Immunopathol. 39 (5): 529–539. doi:10.1007/s00281-017-0629-x. PMC 7079893 Check
|pmc=value (help). PMID 28466096. - ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 Frater JL, Zini G, d'Onofrio G, Rogers HJ (2020). "COVID-19 and the clinical hematology laboratory". Int J Lab Hematol. 42 Suppl 1: 11–18. doi:10.1111/ijlh.13229. PMC 7264622 Check
|pmc=value (help). PMID 32311826 Check|pmid=value (help). - ↑ Meisner M (2014). "Update on procalcitonin measurements". Ann Lab Med. 34 (4): 263–73. doi:10.3343/alm.2014.34.4.263. PMC 4071182. PMID 24982830.
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7
- ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 Lippi G, Plebani M (2020). "The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks". Clin Chem Lab Med. 58 (7): 1063–1069. doi:10.1515/cclm-2020-0240. PMID 32191623 Check
|pmid=value (help). - ↑ Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y; et al. (2020). "Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study". Lancet. 395 (10223): 507–513. doi:10.1016/S0140-6736(20)30211-7. PMC 7135076 Check
|pmc=value (help). PMID 32007143 Check|pmid=value (help). - ↑ 13.0 13.1 Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S; et al. (2020). "Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China". JAMA Intern Med. doi:10.1001/jamainternmed.2020.0994. PMC 7070509 Check
|pmc=value (help). PMID 32167524 Check|pmid=value (help). - ↑ Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z; et al. (2020). "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study". Lancet. 395 (10229): 1054–1062. doi:10.1016/S0140-6736(20)30566-3. PMC 7270627 Check
|pmc=value (help). PMID 32171076 Check|pmid=value (help).