- Chronotherapy involves administering anti-inflammatory drugs in a certain time frame
- The cytokine storm, associated with COVID-19, was found to be the most harmful between 4:00 pm and midnight
- Treatment to prevent inflammation should be provided during that time
- Anti-inflammatory treatments should not be performed between midnight and 4 am, as the virus is not very active during that time
- IL-6 receptors, which cause inflammation, are at their peak at 5 am and 7 pm
- IL-10 is known to mediate the cytokine storms and is at its peak during the time the cytokine storm is most harmful
- IL-6 --> pro-inflammatory
- IL-10 --> anti-inflammatory
- The lungs play a role in inflammation based on their intrinsic circadian clock



COVID-19 associated ARDS and chronotherapy (relating to the cytokine storm)

Aged garlic extract increased IL-10 In peripheral blood monocytes by inhibiting TNF-a and IL-6, which are inflammatory cytokines that play a key role in the pathogenesis of SARS-CoV-2. 

Aged garlic extract effects on  IL-10 and the pathogenesis of SARS-CoV-2  

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. 

Smith College

University of California, Berkeley

Michigan State University

- 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

Mehta, Puja et al. “COVID-19: consider cytokine storm syndromes and immunosuppression.” Lancet (London, England) vol. 395,10229 (2020): 1033-1034. doi:10.1016/S0140-6736(20)30628-0
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270045/

COVID-19: consider cytokine storm syndromes and immunosuppression

- 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

Acute Respiratory Distress Syndrome (ARDS) in COVID-19

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

Cytokine Release Syndrome and 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.  

Learn Before

Related

Learn After