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)
• In SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV), cytokine storms have been associated with acute respiratory distress syndrome (ARDS). (2 in kuppali)
• 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)

Proinflammatory Cytokines and Chemokines

• In SARS-CoV infection, in the early stages of the disease,there is delayed release of cytokines and chemokines. However, later during the infection release of the following occurs: (28 ta 20 in ye)
  • High levels of proinflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF))
  • High levels of chemokines (C-C motif chemokine ligand (CCL)-2, CCL-3, and CCL- 5)
  • Low levels of antiviral factors interferons (IFNs)

• In MERS-CoV infection there is delayed but high level of proinflammatory cytokine and chemokine release as well.(21-22 in ye) These are due to increased neutorphils and monocytes in the lung and blood of of MERS-CoV patients which suggests their contribution to lung injury in this infection. (24-25 ye) This has also been seen in SARS CoV infection. (27ta 34 in ye) 
• t is now known that several proinflammatory cytokines (IL-6, IL-8, IL-1β, granulocytemacrophage colony-stimulating factor, and reactive oxygen species) and chemokines (such as CCL2, CCL-5, IFNγ -induced protein10 (IP-10), and CCL3) all contribute to the occurrence ofARDS.44–4  
• hese results support such points of view that, following SARS-CoV infection, high virus titers and dysregulationof cytokine/chemokine response cause an inflammatory cytokinestorm. The inflammatory cytokine storm is accompanied by immunopathological changes in the lungs  

• The production of IFN-I or IFN-α/β is the key natural immune defense response against viral infections, and IFN-I is the key molecule that plays an antiviral role in the early stages of viral infection.35,36 Delayed release of IFNs in the early stages of SARS-CoV and MERS-CoV infection hinders the body’s antiviral response.36 Afterward, the rapidly increased cytokines and chemokines attract many inflammatory cells, such as neutrophils and monocytes, resulting in excessive infiltration of the inflammatory cells into lung tissue and thus lung injury. It appears from these studies that dysregulated and/or exaggerated cytokine nd chemokine responses by SARS-CoV-infected or MERS-CoVinfected cells could play an important role in pathogenesis of SARS or MERS  
• IFN-I or IFN-α/β is the key natural immune defense response against viral infections, and IFN-I is the key molecule that plays an antiviral role in the early stages of viral infection.35,36
• The ccumulated mononuclear macrophages receive activating signals hrough the IFN-α/β receptors on their surface and produce more onocyte chemoattractants (such as CCL2, CCL7, and CCL12), resulting in the further accumulation of mononuclear macrophages.These mononuclear macrophages produce elevated levels of proinflammatory cytokines (TNF, IL-6, IL1-β, and inducible nitric oxidesynthase), thereby increasing the severity of the disease  
• In addition, IFN-α/β or mononuclear macrophage-derivedproinflammatory cytokines induce the apoptosis of T cells, whichfurther hinders viral clearance.  
• Another consequence of rapid viral replication and vigorous proinflammatory cytokine/chemokineresponse is the induction of apoptosis in lung epithelial and endothelial cells. IFN-αβ and IFN-γ induce inflammatory cell infiltration through mechanisms involving Fas–Fas ligand (FasL) or TRAIL–death receptor 5 (DR5) and cause the apoptosis of airwayand alveolar epithelial cells.39–41 Apoptosis of endothelial cells andepithelial cells damages the pulmonary microvascular and alveolar epithelial cell barriers and causes vascular leakage and alveolar edema, eventually leading to hypoxia in the body. Therefore,inflammatory mediators play a key role in the pathogenesis ofARDS.  
• 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

• However, unlike SARS patients, patients with COVID-19 also have elevated levels of Th2 cellsecreted cytokines (such as IL-4 and IL-10), which inhibit the inflammatory response

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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