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{{AE}} {{SHA}}
{{AE}} {{SHA}}


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  '''


*  
*  
*<s>Cytokine storms have been identified as key players in acute respiratory distress syndrome (ARDS) and multiple organ failure . (3 in ye)</s>
*<s>In SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV), cytokine storms have been associated with acute respiratory distress syndrome (ARDS). (2 in kuppali)</s>
*<s>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)</s>


===<s>Proinflammatory Cytokines and Chemokines</s>===
'''Tumor necrosis factor'''  


*<s>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)</s>
*  
**<s>High levels of  proinflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF))</s>
**<s>High levels of chemokines (C-C motif chemokine ligand (CCL)-2, CCL-3, and CCL- 5)</s>
**<s>Low levels of antiviral factors interferons (IFNs)</s>


*<s>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) </s>
*  
*
*
*
*
*<s>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  </s>
*<s>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  </s>


*<s>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  </s>
=== Pathogenesis of ARDS by Cytokine Storm ===
*<s>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</s>
 
*<s>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  </s>
*In SARS coronavirus (SARS-CoV) and MERS coronavirus (MERS-CoV), cytokine storms have been associated with acute respiratory distress syndrome (ARDS). (2 in kuppali)
*<s>In addition, IFN-α/β or mononuclear macrophage-derivedproinflammatory cytokines induce the apoptosis of T cells, whichfurther hinders viral clearance.  </s>
*The pathogenesis of SARS or MERS  infection may be related to a excessive or dysregulated cytokine release.
*<s>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.  </s>
*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.
*<s>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.  </s>
*Proinflammatory cytokines that have a role in ARDS include:44–4
*<s>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</s>
**Proinflammatory cytokines (IL-6, IL-8, IL-1β, granulocytemacrophage colony-stimulating factor, and reactive oxygen species)
*<s>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  </s>
**Proinflammatory chemokines (such as CCL2, CCL-5, IFNγ -induced protein10 (IP-10), and CCL3)
*<s>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  </s>
 
* 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  


=== <s>Anti-inflammatory Cytokines</s> ===
===== Anti-inflammatory Cytokines =====


*<s>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</s>
* 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.


{| class="wikitable"
|+
! colspan="3" |Cytokines Involved in COVID-19-Associated-Cytokine Storm
|-
| rowspan="5" |'''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
|}




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==<s>Overview</s>==


== Overview ==
==<s>COVID-19-Associated Hematologic Findings</s>==


==COVID-19-Associated Hematologic Findings ==
*<s>[[Leukocytosis]]</s>
*<s>Increase in [[C-reactive protein|C-reactive protein (CRP)]]</s>
*<s>Increase in [[procalcitonin]]</s>
*<s>Increase in [[ferritin]]</s>
*<s>Increase in [[Aspartate aminotransferase|aspartate aminotransferase (AST)]]</s>
*<s>Increase in [[Alanine aminotransferase|alanine aminotransferase (ALT)]]</s>
*<s>Increase in [[Lactate dehydrogenase|lactate dehydrogenase (LDH)]]</s>
*<s>Increase in monocyte volume distribution width (MDW)</s>
*<s>Increase in total [[bilirubin]]</s>
*<s>Increase in creatinine</s>
*<s>Increase in cardiac [[Troponin|troponins]]</s>
*<s>Decrease in [[albumin]]</s>
*<s>Increase in [[Interleukin-6|interleukin-6 (IL-6)]]</s>
*<s>[[Thrombocytosis]]</s>


*[[Leukocytosis]]
==<s>Pathophysiology and Causes</s>==
* Increase in [[C-reactive protein|C-reactive protein (CRP)]]
* Increase in [[procalcitonin]]
* Increase in [[ferritin]]
* Increase in [[Aspartate aminotransferase|aspartate aminotransferase (AST)]]
* Increase in [[Alanine aminotransferase|alanine aminotransferase (ALT)]]
* Increase in [[Lactate dehydrogenase|lactate dehydrogenase (LDH)]]
* Increase in monocyte volume distribution width (MDW)
* Increase in total [[bilirubin]]
* Increase in creatinine
* Increase in cardiac [[Troponin|troponins]]
* Decrease in [[albumin]]
* Increase in [[Interleukin-6|interleukin-6 (IL-6)]]
*[[Thrombocytosis]]


== Pathophysiology and Causes ==
*<s>CRP is an [[Acute phase protein|acute phase reactant]] that increases in conditions with inflammation.<ref name="pmid32311826">{{cite journal| author=Frater JL, Zini G, d'Onofrio G, Rogers HJ| title=COVID-19 and the clinical hematology laboratory. | journal=Int J Lab Hematol | year= 2020 | volume= 42 Suppl 1 | issue=  | pages= 11-18 | pmid=32311826 | doi=10.1111/ijlh.13229 | pmc=7264622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32311826  }} </ref></s>
*<s>In [[sepsis]], the activation and adherence of [[Monocyte|monocytes]] increase [[procalcitonin]], therefore [[procalcitonin]] in a biomarker for sepsis and septic shock.<ref name="pmid24982830">{{cite journal| author=Meisner M| title=Update on procalcitonin measurements. | journal=Ann Lab Med | year= 2014 | volume= 34 | issue= 4 | pages= 263-73 | pmid=24982830 | doi=10.3343/alm.2014.34.4.263 | pmc=4071182 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24982830  }} </ref></s>
*<s>[[Alanine transaminase|ALT]] is produced by liver cells and is increased in liver conditions.<ref name="pmid32311826" /></s>
*<s>[[Lactate dehydrogenase|LDH]] is expressed in almost all cells and an increase in [[LDH]] could be seen in damage to any of the cell types.<ref name="pmid32311826" /></s>
*<s>[[Bilirubin]]  is produced by liver cells and increases in liver and biliary conditions.<ref name="pmid32311826" /></s>
*<s>Creatinin is produced in the liver and excreted by the kidneys; [[creatinine]] increases when there is decrease in [[glomerular filtration rate]].<ref name="pmid32311826" /></s>
*<s>Increase in cardiac [[Troponin|troponins]] are used for diagnosing myocardial infarction and [[Acute coronary syndromes|acute coronary syndrome]] .<ref name="pmid32311826" /></s>
*<s>[[Albumin]] may be decreased in many conditions such as [[sepsis]], renal disease or [[malnutrition]].<ref name="pmid32311826" /></s>


* CRP is an [[Acute phase protein|acute phase reactant]] that increases in conditions with inflammation.<ref name="pmid32311826">{{cite journal| author=Frater JL, Zini G, d'Onofrio G, Rogers HJ| title=COVID-19 and the clinical hematology laboratory. | journal=Int J Lab Hematol | year= 2020 | volume= 42 Suppl 1 | issue=  | pages= 11-18 | pmid=32311826 | doi=10.1111/ijlh.13229 | pmc=7264622 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32311826  }} </ref>
==<s>Epidemiology</s>==
* In [[sepsis]], the activation and adherence of [[Monocyte|monocytes]] increase [[procalcitonin]], therefore [[procalcitonin]] in a biomarker for sepsis and septic shock.<ref name="pmid24982830">{{cite journal| author=Meisner M| title=Update on procalcitonin measurements. | journal=Ann Lab Med | year= 2014 | volume= 34 | issue= 4 | pages= 263-73 | pmid=24982830 | doi=10.3343/alm.2014.34.4.263 | pmc=4071182 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24982830  }} </ref>
* [[Alanine transaminase|ALT]] is produced by liver cells and is increased in liver conditions.<ref name="pmid32311826" />
*[[Lactate dehydrogenase|LDH]] is expressed in almost all cells and an increase in [[LDH]] could be seen in damage to any of the cell types.<ref name="pmid32311826" />
*[[Bilirubin]]  is produced by liver cells and increases in liver and biliary conditions.<ref name="pmid32311826" />
* Creatinin is produced in the liver and excreted by the kidneys; [[creatinine]] increases when there is decrease in [[glomerular filtration rate]].<ref name="pmid32311826" />
* Increase in cardiac [[Troponin|troponins]] are used for diagnosing myocardial infarction and [[Acute coronary syndromes|acute coronary syndrome]] .<ref name="pmid32311826" />
* [[Albumin]] may be decreased in many conditions such as [[sepsis]], renal disease or [[malnutrition]].<ref name="pmid32311826" />


== Epidemiology ==
*<s>[[Leukocytosis]] is seen in 11.4% of patients with severe [[COVID-19]] infection compared to 4.8% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623">{{cite journal| author=Lippi G, Plebani M| title=The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks. | journal=Clin Chem Lab Med | year= 2020 | volume= 58 | issue= 7 | pages= 1063-1069 | pmid=32191623 | doi=10.1515/cclm-2020-0240 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32191623  }} </ref></s>
*<s>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.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>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.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>Increase in [[Aspartate transaminase|AST]] is seen in 39.4% of patients with severe [[COVID-19]] infection compared to 18.2% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>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.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>Increase in [[Lactate dehydrogenase|LDH]] is seen in 58.1% of patients with severe [[COVID-19]] infection compared to 37.2% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>MDW was found to be increased in all patients with COVID-19 infection, particularly in those with the worst conditions.<ref name="pmid32191623" /></s>
*<s>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.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>Increase in [[creatinine]] is seen in 4.3% of patients with severe [[COVID-19]] infection compared to 1% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623" /></s>
*<s>[[Thrombocytosis]] has been reported in 4% of patients with [[COVID-19]] infection.<ref name="pmid32007143">{{cite journal| author=Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y | display-authors=etal| title=Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. | journal=Lancet | year= 2020 | volume= 395 | issue= 10223 | pages= 507-513 | pmid=32007143 | doi=10.1016/S0140-6736(20)30211-7 | pmc=7135076 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32007143  }} </ref></s>


* [[Leukocytosis]] is seen in 11.4% of patients with severe [[COVID-19]] infection compared to 4.8% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623">{{cite journal| author=Lippi G, Plebani M| title=The critical role of laboratory medicine during coronavirus disease 2019 (COVID-19) and other viral outbreaks. | journal=Clin Chem Lab Med | year= 2020 | volume= 58 | issue= 7 | pages= 1063-1069 | pmid=32191623 | doi=10.1515/cclm-2020-0240 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32191623  }} </ref>
==<s>Clinical Significance</s>==
* 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.<ref name="pmid32109013" /><ref name="pmid32191623" />
<s>Laboratory findings in [[COVID-19]] infection may indicate clinical abnormalities, including:</s>
* 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.<ref name="pmid32109013" /><ref name="pmid32191623" />
* Increase in [[Aspartate transaminase|AST]] is seen in 39.4% of patients with severe [[COVID-19]] infection compared to 18.2% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623" />
* 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.<ref name="pmid32109013" /><ref name="pmid32191623" />
* Increase in [[Lactate dehydrogenase|LDH]] is seen in 58.1% of patients with severe [[COVID-19]] infection compared to 37.2% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623" />
* MDW was found to be increased in all patients with COVID-19 infection, particularly in those with the worst conditions.<ref name="pmid32191623" />
* 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.<ref name="pmid32109013" /><ref name="pmid32191623" />
* Increase in [[creatinine]] is seen in 4.3% of patients with severe [[COVID-19]] infection compared to 1% of patients with non-severe infection.<ref name="pmid32109013" /><ref name="pmid32191623" />
*[[Thrombocytosis]] has been reported in 4% of patients with [[COVID-19]] infection.<ref name="pmid32007143">{{cite journal| author=Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y | display-authors=etal| title=Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. | journal=Lancet | year= 2020 | volume= 395 | issue= 10223 | pages= 507-513 | pmid=32007143 | doi=10.1016/S0140-6736(20)30211-7 | pmc=7135076 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32007143  }} </ref>


== Clinical Significance ==
*<s>In patients with [[COVID-19]] infection, leukocytosis may be an indication of a bacterial infection or superinfection.<ref name="pmid32191623" /></s>
Laboratory findings in [[COVID-19]] infection may indicate clinical abnormalities, including:
*<s>In patients with [[COVID-19]] infection, increase in [[CRP]] may be an indication of severe viral infection or [[sepsis]] and [[viremia]].<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, increase in [[procalcitonin]] may be an indication of bacterial infection or [[superinfection]].<ref name="pmid32191623" /></s>
*<s>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|acute respiratory distress syndrome (ARDS)]] but not death<ref name="pmid32167524">{{cite journal| author=Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S | display-authors=etal| title=Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. | journal=JAMA Intern Med | year= 2020 | volume=  | issue=  | pages=  | pmid=32167524 | doi=10.1001/jamainternmed.2020.0994 | pmc=7070509 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32167524  }} </ref>, while another one reports an association between increase in [[ferritin]] and death in COVID-19 infection<ref name="pmid32171076">{{cite journal| author=Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z | display-authors=etal| title=Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. | journal=Lancet | year= 2020 | volume= 395 | issue= 10229 | pages= 1054-1062 | pmid=32171076 | doi=10.1016/S0140-6736(20)30566-3 | pmc=7270627 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32171076  }} </ref></s>
*<s>In patients with [[COVID-19]] infection, increase in [[aminotransferases]] may indicate injury to the [[liver]] or multi-system damage.<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, increase in [[aminotransferases]] may indicate injury to the liver or multi-system damage.<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, increase in [[Lactate dehydrogenase|LDH]] may indicate injury to the lungs or multi-system damage.<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, increase in total bilirubin may indicate injury to the liver.<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, increase in [[creatinine]] may indicate injury to the kidneys.<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, increase in cardiac troponins may indicate cardiac injury.<ref name="pmid32191623" /></s>
*<s>In patients with [[COVID-19]] infection, decrease in [[albumin]] may indicate liver function abnormality.<ref name="pmid32191623" /></s>
*<s>Increase in [[IL-6]] has been reported to be associated with death in  [[COVID-19]] infection.<ref name="pmid32167524" /></s>


* In patients with [[COVID-19]] infection, leukocytosis may be an indication of a bacterial infection or superinfection.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in [[CRP]] may be an indication of severe viral infection or [[sepsis]] and [[viremia]].<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in [[procalcitonin]] may be an indication of bacterial infection or [[superinfection]].<ref name="pmid32191623" />
* 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|acute respiratory distress syndrome (ARDS)]] but not death<ref name="pmid32167524">{{cite journal| author=Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S | display-authors=etal| title=Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. | journal=JAMA Intern Med | year= 2020 | volume=  | issue=  | pages=  | pmid=32167524 | doi=10.1001/jamainternmed.2020.0994 | pmc=7070509 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32167524  }} </ref>, while another one reports an association between increase in [[ferritin]] and death in COVID-19 infection<ref name="pmid32171076">{{cite journal| author=Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z | display-authors=etal| title=Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. | journal=Lancet | year= 2020 | volume= 395 | issue= 10229 | pages= 1054-1062 | pmid=32171076 | doi=10.1016/S0140-6736(20)30566-3 | pmc=7270627 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32171076  }} </ref>
* In patients with [[COVID-19]] infection, increase in [[aminotransferases]] may indicate injury to the [[liver]] or multi-system damage.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in [[aminotransferases]] may indicate injury to the liver or multi-system damage.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in [[Lactate dehydrogenase|LDH]] may indicate injury to the lungs or multi-system damage.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in total bilirubin may indicate injury to the liver.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in [[creatinine]] may indicate injury to the kidneys.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, increase in cardiac troponins may indicate cardiac injury.<ref name="pmid32191623" />
* In patients with [[COVID-19]] infection, decrease in [[albumin]] may indicate liver function abnormality.<ref name="pmid32191623" />
* Increase in [[IL-6]] has been reported to be associated with death in  [[COVID-19]] infection.<ref name="pmid32167524" />




Revision as of 06:39, 11 July 2020

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




Overview

COVID-19-Associated Hematologic Findings

Pathophysiology and Causes

Epidemiology

  • Leukocytosis is seen in 11.4% of patients with severe COVID-19 infection compared to 4.8% of patients with non-severe infection.[3][4]
  • 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.[3][4]
  • 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.[3][4]
  • 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.[3][4]
  • 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.[3][4]
  • 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.[3][4]
  • MDW was found to be increased in all patients with COVID-19 infection, particularly in those with the worst conditions.[4]
  • 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.[3][4]
  • Increase in creatinine is seen in 4.3% of patients with severe COVID-19 infection compared to 1% of patients with non-severe infection.[3][4]
  • Thrombocytosis has been reported in 4% of patients with COVID-19 infection.[5]

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.[4]
  • In patients with COVID-19 infection, increase in CRP may be an indication of severe viral infection or sepsis and viremia.[4]
  • In patients with COVID-19 infection, increase in procalcitonin may be an indication of bacterial infection or superinfection.[4]
  • 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[6], while another one reports an association between increase in ferritin and death in COVID-19 infection[7]
  • In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.[4]
  • In patients with COVID-19 infection, increase in aminotransferases may indicate injury to the liver or multi-system damage.[4]
  • In patients with COVID-19 infection, increase in LDH may indicate injury to the lungs or multi-system damage.[4]
  • In patients with COVID-19 infection, increase in total bilirubin may indicate injury to the liver.[4]
  • In patients with COVID-19 infection, increase in creatinine may indicate injury to the kidneys.[4]
  • In patients with COVID-19 infection, increase in cardiac troponins may indicate cardiac injury.[4]
  • In patients with COVID-19 infection, decrease in albumin may indicate liver function abnormality.[4]
  • Increase in IL-6 has been reported to be associated with death in COVID-19 infection.[6]


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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).
  2. ↑ 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.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 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).
  5. ↑ 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).
  6. ↑ 6.0 6.1 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).
  7. ↑ 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).


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