Biomarkers of cytokine storm syndrome and status in COVID-19

Treatments for cytokine storm syndrome and potential utility in COVID-19

SARS-CoV-2 is known to activate mast cells in affected patients, along with other immune cells including monocytes/macrophages, neutrophils, T cells, killer cells, and resident tissue epithelial and endothelial cells. These various groups cells have been thought to induce the "cytokine storm syndrome" that is experienced by COVID-19 patients. However, since mast cells are well-expressed throughout the body (including the CNS) and are involved in certain neuroinflammatory diseases, it is hypothesized that their activation by SARS-CoV-2 upregulates certain neuroinflammatory responses, which may result in some of the other symptoms observed in COVID-19 patients, including ischemic stroke.

Mast Cell Activation in COVID-19 Patients

Although the leading cause of mortality from COVID-19 is acute respiratory distress syndrome (ARDS), new data demonstrates the potential of cytokine storm syndrome in patients with severe COVID-19. 

Severe COVID-19 patients should have hyperinflammation screenings for laboratory markers, including increased levels of ferritin, decreased platelet counts, or erythrocyte sedimation rate. The HScore table should be applied when deciding potential therapy options and in the consideration of immunosuppression to reduce inflammation and improve mortalitly. 

- Biomarkers of cytokine storm syndrome and status in COVID-19
- Treatments for cytokine storm syndrome and potential utility in COVID-19

Hamilton College

Smith College

The term "cytokine storm syndromes (CSS)" encompasses many different inflammatory causes of disease (i.e., CSS represents various inflammatory etiologies). Regardless, the final results are shared: systematic inflammation, hemodynamic instability, multiple organ dysfunction, and potential death. Optimal treatment varies between different syndromes, making identification of the specific syndrome critical for effective treatment.

Cytokine storm syndromes are common in diseases such as systemic junvenile idiopathic arthrisits (JIA), adult onset Still’s disease, systemic lupus erythematosus, and many more. 

Cytokine storm syndromes represent various inflammatory etiologies

Cytokine Release Syndrome (CRS), or Cytokine Storm Syndrome (CSS) is a life-threatening inflammatory condition most commonly associated with immunotherapies, though also triggered by other factors (drugs, infection, etc.). In the case of COVID-19, this syndrome should not be used interchangeably with "cytokine storm (CS)" (they have a shared phenotype), and the distinctions are important to clarify. 
- both CRS/CSS and CS are illustrated by sharp significant increases in the circulation of different pro-inflammatory cytokines
- CRS/CSS (when resulting from immunotherapy) has delayed symptomatology (days to weeks)
- immediate onset CRS/CSS = CS


Clarifications: Cytokine Release/Storm Syndrome vs Cytokine Storms.

- Acute Respiratory Distress Syndrome (ARDS)
- Cytokine Release/Storm Syndrome 
- Multi-Organ failure 
- Multisystem Inflammatory Syndromes (MIS)
- Secondary Haemophagocytic Lymphiohistocytosis
- Vascular Hyperpemeability 



Downstream Inflammatory Pathogenesis of Cytokine Storms in COVID-19

Henderson, L. A., Canna, S. W., Schulert, G. S., Volpi, S., Lee, P. Y., Kernan, K. F., ... & Hoyt, K. J. (2020). On the alert for cytokine storm: Immunopathology in COVID‐19. Arthritis & Rheumatology. https://onlinelibrary.wiley.com/doi/full/10.1002/art.41285

On the Alert for Cytokine Storms: Immunopathology in COVID-19

COVID-19 cytokine storms refer to the overproduction of pro-inflammatory stimuli (antigens, superantigens, adjuvants, allergens, pro-inflammatory cytokines) and/or the inadequate regulation of inflammation following severe/critical SARS-CoV-2 infection. Current evidence suggests that this chemical overproduction can have dangerous repercussions, with ties to more severe clinical outcomes. 

- Cytokine storms increase the risk of vascular hyper-permeability, acute respiratory distress syndrome (ARDS), multi-organ failure, and consequently, patient mortality 
- Cytokine storm syndromes are disorders that represent various inflammatory etiologies
- Immunomodulatory therapy for the reduction of cytokine storms could aid in the treatment process


 Cytokine Storms in COVID-19 

Cytokine Release Syndrome and COVID-19

- A severe inflammatory response that presents as a fever, nausea, and swelling
- Has been observed in tandem with COVID-19 pulmonary symptoms
- Involves overproduction of cytokines (key proteins in the immune system)
- Immunosuppression can be helpful in calming the immune system and mitigating this extreme immune response

Secondary Haemophagocytic Lymphiohistocytosis and COVID-19

- Eight children with the recent onset hyperinflammatory shock were chosen for the study (symptoms similar to Kawasaki disease)
- 4 children came from families with exposure to COVID-19
- 7 children presented with inflammation in both lungs
- All of the children tested negative for the virus
- 1 of the children was secluded due to having adenovirus and enterovirus
- 1 child had a coronary aneurysm
- Another child had an irregular heartbeat and faced a refractory shock; the child eventually died due to a stroke
- During the first day of the study, the children were intravenously given immunoglobulin and antibiotics
- 6 children were given aspirin
- After 4-6 days, all the children were discharged
- After discharge, two children tested positive for COVID-19, one of them being the child that died (post-mortem report) 
- Overall, 7/8 children survived


Hyperinflammatory shock in children with family exposure to COVID-19

MIS-C "is a condition where different body parts can become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs. This rampant inflammation has been recorded in multiple organ systems; yet, clinical research into the pathogenesis of the disease is insufficient. However, we know that many children with MIS-C were exposed or infected with SARS-CoV-2. Currently, the lack of a universal case definition of MIS-C has limited the number of cases that are accurately diagnosed and hampered with proper treatment of the disease. Further research into the clinical, epidemiological and immunological nature of MIS-C is desperately needed. MIS-C can be serious, even deadly, but most children who were diagnosed with this condition have gotten better with medical care."

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19

Cytokine storms increase risk of vascular hyperpermeability and multiorgan failure. When vascular permability is increased by pro inflammatory cytokines (and other factors), large amounts of fluid and blood cells enter the alveoli. This results in dyspnoea (difficulty of breathing) and even respiratory failure. When the high concentration of cytokines is not addressed, they can even lead to death. 

Vascular Hyperpemeability and Multi-organ failure in COVID-19

Secondary haemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome that leads to fatal hyper cytokinaemia with multiorgan failure. It is characterized by unremitting fever, hyperferritinaemia, and cytopenias. Pulmonary involvement (ARDS) also occurs in 50% of patients. A cytokine profile similar to sHLH is associated with COVID-19 severity, and it is suggested through data on patients with elevated ferritin that hyperinflammation from SARS- CoV-2 is connected to mortalitiy.  

Secondary haemophagocytic lymphohistiocytosis (sHLH) and COVID-19

There is strong evidence that COVID-19 patients diagnosed with Acute Respiratory Distress Syndrome (ARDS) can attribute this phenotype to the cytokine storms taking place in their immune system's response. 

Acute Respiratory Distress Syndrome (ARDS) in COVID-19

Hyperinflammatory syndromes result from elevated levels of inflammatory biomarkers, such as interleukin (IL)-6, and are sometimes developed in patients with severe COVID-19.  Some examples of hyperinflammatory syndromes are macrophage activation syndrome and cytokine release syndrome. Hyperinflammatory syndromes stem from cytokine storm syndromes and can lead to mortality and morbidity.  

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