Studies have shown that continuous elevated levels of cytokines can lead to multiple organ dysfunction and viral sepsis. As a result, regulation of cytokine levels may be critical in both treatment and prevention.

Clinical Implications of SARS-CoV-2-induced Elevated Cytokine Production 

Severe cases of COVID-19 tend to exhibit a “cytokine storm”, which is an extreme increase in certain inflammatory cytokines. While patients with non-severe COVID-19 have an upregulated level of some of the same cytokines, the amount and diversity of cytokines are much less than that of severe cases. 

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Patients with severe COVID-19 are known to exhibit uncontrolled pro-inflammatory responses to SARS-CoV-2. As a result, these patients have lymphopenia, lymphocyte activation and dysfunction, granulocyte and monocyte abnormalities, high cytokine levels, and elevated immunoglobulin G and total antibodies. 

The Immunopathology of COVID-19

Following SARS-CoV-2 infection of the lungs, host cells release pro-inflammatory cytokines and chemokines, as illustrated in the diagram below. Of the chemicals listed, the three notable cytokines are: 
- IL-1
- TNF- α
- IL-6


The relationship between coronaviruses and chemokines has been extensively studied in other coronaviruses including the SARS-CoV and MERS-CoV epidemics. Current data on SARS-CoV-2 also illustrates a very similar relationship. 

Pro-inflammatory Cytokine Production in COVID-19

Yang, Li, et al. “COVID-19: Immunopathogenesis and Immunotherapeutics.” Signal Transduction and Targeted Therapy, vol. 5, no. 1, 2020, doi:10.1038/s41392-020-00243-2.

https://www.nature.com/articles/s41392-020-00243-2

COVID-19: Immunopathogenesis and Immunotherapeutics

Decreased levels of lymphocytes, or lymphopenia, is a key indicator of severe COVID-19. While T cell and NK cell levels have been found to be significantly reduced, B cell count remains within a normal range. Because lymphopenia is so distinctive of COVID-19, it has been proposed as a tool to measure both the severity of COVID-19 and the prognosis of the patient. 

Lymphopenia 

Studies have shown that T cells are very active in response to SARS-CoV-2. As a result, patients with COVID-19 can show evidence of T cell exhaustion. In severe cases, apoptosis in CD8+ T cells is unusually frequent, also reducing functional diversity. 

Lymphocyte Activation and Dysfunction 


The relative number of neutrophils compared to lymphocytes is much higher in severe cases of COVID-19 than in non-severe cases. However, there is a decreased percentage of eosinophils (indicates parasitic infections), basophils (indicates allergic reactions), and monocytes in severe patients. A low monocyte count makes it difficult to fight off viral infections, and neutrophils aid in bacterial infections, not viral.

Abnormalities of Granulocytes and Monocytes 

While IgM and IgG are both SARS-CoV-2-specific antibodies, the level of IgG is more closely correlated with the severity of the disease and therefore can be used to evaluate severity and prognosis. However, a quicker test can be done on the total antibody level, in which higher levels are indicative of worse patient outcomes.

Increased Antibodies

Even though SARS-CoV-2 and SARS-CoV infection is initiated by similar innate and adaptive immune responses, there is no strong evidence that would indicate that lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities are associated with SARS-CoV, therefore making these abnormalities unique to SARS-CoV-2. 


Comparison with SARS-CoV-induced Immunopathology 


Increased Production of Cytokines in COVID-19 Patients 

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 (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.

Propolis led to the reduction of pro-inflammatory cytokines TNF-a, IL-6 and IL-1 beta.

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