Sandbox:Shakiba

Associate Editor(s)-in-Chief: Shakiba Hassanzadeh, MD[1]

Cytokine storms have been identified as key players in acute respiratory distress syndrome (ARDS) and multiple organ failure . (3 in ye)

Types of Cytokines

Interferons  

Interleukins  

Chemokines  

Colony-stimulating factors  

Tumor necrosis factor  

Pathogenesis of ARDS by Cytokine Storm

• In SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV), cytokine storms have been associated with acute respiratory distress syndrome (ARDS). (2 in kuppali)
• The pathogenesis of SARS or MERS infection may be related to a excessive or dysregulated cytokine release.
• In the early stages of SARS-CoV and MERS-CoV infection, there is delayed release of cytokines and chemokines. (36) However, later during the infection there is rapid release of cytokines and chemokines which attract neutrophils and monocytes. This excessive infiltration of neutrophils and monocytes in the lung causes lung damage.
• Proinflammatory cytokines that have a role in ARDS include:44–4
  • Proinflammatory cytokines (IL-6, IL-8, IL-1β, granulocytemacrophage colony-stimulating factor, and reactive oxygen species)
  • Proinflammatory chemokines (such as CCL2, CCL-5, IFNγ -induced protein10 (IP-10), and CCL3)

• IFN-I or IFN-α/β play an important role in antiviral immune defense. 35,36

• The IFN-α/β receptors on the surface of accumulated macrophages receive activating signals, this results in more production of chemokines by these cells which in turn results in further accumulation of macrophages. More proinflammatory cytokines are produced and therefore the infection becomes more severe.

• IFN-α/β or proinflammatory cytokines produced by macrophages induce T-cell apoptosis , which delays the antiviral defense process.
• Rapid cytokine increase induces apoptosis in lung cells, which causes vascular leakage and alveolar edema, resulting in hypoxia .

COVID-19 and Cytokine Storm

Proinflammatory Cytokines

• 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 patientswith 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.48
• The 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).49  
• ther 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

Anti-inflammatory Cytokines

• 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	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

COVID-19-Associated Hematologic Findings

• Leukocytosis
• Increase in C-reactive protein (CRP)
• Increase in procalcitonin
• Increase in ferritin
• Increase in aspartate aminotransferase (AST)
• Increase in alanine aminotransferase (ALT)
• Increase in lactate dehydrogenase (LDH)
• Increase in monocyte volume distribution width (MDW)
• Increase in total bilirubin
• Increase in creatinine
• Increase in cardiac troponins
• Decrease in albumin
• Increase in interleukin-6 (IL-6)
• Thrombocytosis

Pathophysiology and Causes

• CRP is an acute phase reactant that increases in conditions with inflammation.
• In sepsis, the activation and adherence of monocytes increase procalcitonin, therefore procalcitonin in a biomarker for sepsis and septic shock.
• ALT is produced by liver cells and is increased in liver conditions.
• LDH is expressed in almost all cells and an increase in LDH could be seen in damage to any of the cell types.
• Bilirubin  is produced by liver cells and increases in liver and biliary conditions.
• Creatinin is produced in the liver and excreted by the kidneys; creatinine increases when there is decrease in glomerular filtration rate.
• Increase in cardiac troponins are used for diagnosing myocardial infarction and acute coronary syndrome .
• Albumin may be decreased in many conditions such as sepsis, renal disease or malnutrition.

Epidemiology

• Leukocytosis is seen in 11.4% of patients with severe COVID-19 infection compared to 4.8% of patients with non-severe infection.
• 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.
• 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.
• 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.
• 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.
• 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.
• MDW was found to be increased in all patients with COVID-19 infection, particularly in those with the worst conditions.
• 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.
• Increase in creatinine is seen in 4.3% of patients with severe COVID-19 infection compared to 1% of patients with non-severe infection.
• Thrombocytosis has been reported in 4% of patients with COVID-19 infection.

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.
• In patients with COVID-19 infection, increase in CRP may be an indication of severe viral infection or sepsis and viremia.
• In patients with COVID-19 infection, increase in procalcitonin may be an indication of bacterial infection or superinfection.
• 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, while another one reports an association between increase in ferritin and death in COVID-19 infection
• In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.
• In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.
• In patients with COVID-19 infection, increase in LDH may indicate injury to the lungs or multi-system damage.
• In patients with COVID-19 infection, increase in total bilirubin may indicate injury to the liver.
• In patients with COVID-19 infection, increase in creatinine may indicate injury to the kidneys.
• In patients with COVID-19 infection, increase in cardiac troponins may indicate cardiac injury.
• In patients with COVID-19 infection, decrease in albumin may indicate liver function abnormality.
• Increase in IL-6 has been reported to be associated with death in COVID-19 infection.

References

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