Sandbox:Shakiba

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

Some Differential Diagnosis of Asperger Syndrome (Modified Table from The Investigation and Differential Diagnosis of Asperger Syndrome in Adults)
	Asperger Syndrome	Schizoid Personality Disorder	Schizotypal Personality Disorder	Avoidant Personality Disorder	Social Phobia	Obsessive Personality Disorder	Obsessive-compulsive disorder (OCD)	Attention deficit–hyperactivity disorder (ADHD)
Abnormal social interaction	+	+	+	+	+	+	+	+
Abnormal verbal communication	+	+	+	-	-	-	-	-
Abnormal facial expression/gestures/prosody	+	+	+	+	+/-	-	-	+/-
Abnormal eye contact	+	+	+/-	+	+/-	-	-	+/-
Abnormal theory of mind	+	+/-	+/-	+/-	+/-	+/-	-	+/-
Abnormal empathy	+	+/-	+/-	-	-	+/-	-	+/-
Abnormal interests/rituals/compulsions	+	+/-	+/-	-	-	+	+	-
Abnormal attention	+/-	-	-	-	-	-	-	+
Abnormal psychomotor function	+	-	+/-	-	-	-	-	+/-
Abnormal self-injurious behavior	+/-	+/-	+/-	-	-	-	-	+/-
Abnormal psychotic manifestations	+/-	-	+/-	-	-	-	-	-
Abnormal social interaction in childhood	+	+/-	+/-	+/-	-	-	-	+
Abnormal biographical stress factors	-	+	+/-	+	+/-	+	+/-	+/-

Cytokine Storm

Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory cytokines.

Cytokines Involved in Cytokine Storm

• Cytokines are small proteins that are released for cell signaling.
• Cytokines types and their actions include:
  • 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) 
    • Activation of T cells (cytotoxic)

Pathogenesis of Cytokine Storm

• Cytokine storm is an immune reaction that is characterized by dysregulated and excessive release of proinflammatory cytokines.
• During sepsis, cytokine storm may be the cause of tissue or organ injury.

• 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.
• 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:
  • 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:
  • 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.
• There have been reports on an association between cytokine storm and severity of COVID-19 infection and COVID-19-associated-ARDS.

• 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:
  • 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 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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