- 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

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.  

COVID-19-Associated Hyperinflammation

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



Smith College

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 

New treatment strategies in addition to antiviral therapy has potential to significantly improve clinical outcome. One of those new potential treatments is immunomodulatory therapy. Immunomodulatory agents for the reduction of cytokine storms combined with antiviral agents could aid in the treatment process. 

- Corticosteroids
- Chloroquine
- Tocilizumab
- Proposed Doses for COVID-19 Immunomodulatory Therapy 

Immunomodulatory Therapy for the Reduction of Cytokine Storms and COVID-19 Treatment

The inflammatory mediators associated with the cytokine storm in COVID-19 leads the increased permeability of the lungs.  This allows for SARS-CoV-2 and the inflammatory mediators to enter the bloodstream and migrate from the lungs to the intestine.  SARS-CoV-2 can decrease ACE2 expression and alter the gut microbiota which can alter normal immune responses.  Additionally, the inflammatory mediators can weaken the integrity of the gut, allowing for microbes and their metabolites to leak out.  This can cause microbial dysbriosis which may contribute to why diarrhea is a common symptom of COVID-19.  

Gut-Lung Axis of COVID-19

Cytokines are inflammatory proteins that play a crucial role in an inflammatory response. But a response that is too strong is characterised as a "cytokine storm", which can also be harmful for the patient. It was previously thought that a cytokine storm was responsible for a severe immune response to COVID-19, but researchers compared several cytokine levels of patients with COVID-19 to patients with other diseases and found no increase in cytokine concentration. This indicates to the fact that severe COVID-19 immune responses are not liked to a cytokine storm. 
The cytokines that were tested were TNF-alpha, IL-6 and IL-8. It was found that the concentration of these cytokines in COVID-19 patients was significantly less elevated.

COVID-19 Cytokine Storm may not exist

Downstream Inflammatory Pathogenesis of Cytokine Storms in COVID-19

The increased production of cytokines is a result of many mechnisms, for example:

- CD14+CD16+ monocytes are triggered by activated pathogenic T helper cells to release IL-6 (a major component of the development of the cytokine storm)
- An increase in a subpopulation of CD14+IL-1β+ monocytes may increase IL-1β levels
- Th17 cells that produce IL-17 go on to recruit more monocytes/macrophages and neutrophils, which then triggers other cytokine cascades 
- Monocytes/macrophages may produce additional inflammatory cytokines
- Eosinophils can may release a large amount of cytokines, including IL-6 

Potential Mechanisms of SARS-CoV-2-induced Cytokine Storm 

- Obesity as a risk factor for cytokine storm onset
- Cytokine Storm as a risk factor for obese patient morbidity/mortality

Cytokine Storm and Obesity Relationship in COVID-19

- The target location of COVID-19 is the lung 
- The etiology attribute is "damp and toxin plague"
- The QPD concoction has 16 herbs that are lung-specific, making it a great treatment for respiratory illnesses like COVID-19. Studies have shown that it has the ability to reduce the cytokine storm triggered by SARS-CoV-2 infection.
- The aim of TCM is the holistic balance of Ying and Yang in the body., which strengthenes the body to fight infection 

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