Introduction- COVID-19 and Global Health Impact:
One of the most pressing global health issues that humanity has encountered since World War II is the COVID-19 pandemic. With the exception of Antarctica, the virus has spread to every continent since it first appeared in Asia in 2020. Medical professionals and researchers were investigating the underlying mechanism regarding how this virus dilapidated the human systems in such a short period, while countries were rushing to slow the spread of the virus by testing and treating patients, conducting contact tracing, restricting travel, quarantining citizens, and taking all possible small steps to help contain the virus.
Understanding Cytokine Storm Syndrome (CSS):
Cytokine Storm Syndrome is thought and studied to be a possible mechanism leading to hyperinflammation that later leads to rapid liver damage, but the entire mechanism is not fully understood.
It is recommended that laboratory trends be used to check for hyperinflammation in all individuals with severe COVID-19. Chinese hospitals close to the outbreak’s epicenter provided the first indications that severe COVID-19 cases exhibited a cytokine storm. Guangdong physicians discovered that IL-6 was also an early indicator of a cytokine storm-like illness in research involving 11 patients. A different team discovered a variety of molecular markers for a cytokine storm after examining 150 cases in Wuhan. Cytokine storms are a frequent side effect of respiratory illnesses brought on by coronaviruses, including SARS and MERS, in addition to COVID-19 and the flu. Additionally, they are linked to non-communicable illnesses like pancreatitis and multiple sclerosis.
Early Evidence of Cytokine Storm in COVID-19:
Although the general idea of an excessive or uncontrollable release of proinflammatory cytokines is widely recognized, the term “cytokine storm” and the biological effects of cytokine overproduction are not well defined. Despite this, the cytokine storm has drawn the attention of both the scientific community and the general public. Numerous infectious and noninfectious disorders are linked to cytokine storms. The phrase entered the mainstream media primarily as a result of its widespread use in relation to avian H5N1 influenza virus infection. Although the idea of an excessive or uncontrollable release of proinflammatory cytokines is widely recognized, there isn’t a precise definition of what a cytokine storm is. Furthermore, there is no good understanding of the molecular events that precipitate a cytokine storm.
Immunopathogenesis and Cytokine Cascade:
Cytokine Storm is defined as a deadly burst of cytokines causing hyperinflammation that can be triggered by a variety of factors, such as infections and certain drugs. A subset of COVID-19 patients is experiencing a cytokine storm. Inflammation is the first line of defense caused due to invading pathogens or damaged and infected cells.
- ACE2 Receptor and Viral Entry
- Role of Pattern Recognition Receptors (PRRs)
- Inflammatory Cytokines (IL-6, TNF-α, IL-1, IL-12)
- Acute Phase Response and Hepatic Involvement
Talking about COVID-19, the receptors of the virus are ACE2 receptors found in organs like the lungs, heart, kidneys, etc. When the virus is internalized, the Pattern Recognition Receptors, PRRs, recognize the virus, and then the innate system, after recognizing the inflammatory stimuli, inflammatory response is generated. Presenting Cells and other cells, like stromal cells, release proinflammatory cytokines like IL-1, IL-6, IL-12, and TNF-α. TNF and IL-1 stimulate endothelial cells and macrophages to secrete chemokines that increase the affinity of integrins for ligands, attracting more immune cells. TNF acts on mononuclear phagocytes to stimulate the secretion of IL1, leading to inflammation. In severe inflammation, TNF is produced in large amounts and causes clinical and physiological abnormalities. TNF acts on hepatocytes to increase the synthesis of serum proteins like serum amyloid A and fibrinogen. The increase in hepatocyte-derived plasma protein induced by TNF and IL-6 constitutes an acute phase response to inflammatory stimuli. Reactive oxygen species and other mediators that are released seriously harm tissue. When the system fails to dampen the macrophages, there occurs abnormal Toll-like receptor signaling leading to over inflammation and then causes damage to lung tissue, termed Acute Lung Injury (ALI). It is not fully understood why some people are more prone to cytokine storming. ALI can progress to acute respiratory distress syndrome (ARDS), whereby there is severe alveolar and capillary damage leading to lung consolidation and fibrosis, even organization of pneumonia.
Regarding what is being done to resolve this pandemic, in addition to study of the antiviral therapies for targeting the host response with a variety of anti-inflammatory drugs and adjunct approaches in a range of acute severe infections including treatment with monoclonal antibodies (MAbs), plasma exchange, the experts are focusing in how to combat the Cytokine Storm Syndrome associated with COVID-19. A subset of COVID-19 patients is experiencing elevated Cytokine profiles and ARDS.
The complete immune response to the infection is not fully elucidated, but the immune response is broadly studied as a mild state and a severe state. In a mild state, inflammatory cytokines are produced by the body to combat the infection. In this stage, it can be beneficial to use an inflammatory treatment to stimulate an immune response. In the severe cases, hyperinflammation and high cytokine levels are experienced. In this stage, patients experience ARDS, which is found to be the leading cause of death. Cases have been observed due to extreme inflammation whereby high cytokines are released, causing systemic manifestations like Myocarditis in patients, even though there is no sign of viral load in the heart.
Cytokine Profiling and Biomarkers:
During the study, the cytokine profile was also observed in a spectrum of people ranging from non-infected individuals to patients with severe cases. The levels of IL-16, IL-10, TNF-α, and IL-2R are elevated in patients with severe cases. Cytokine level was also studied in the Pneumonic patients who were under ICU treatment and non-ICU treatment. It was observed that the levels of IL-7, G-CSF, TP-10, MCP-1, and MIP-1α were elevated in pneumonic patients under ICU treatment.
Increased ferritin (mean 1297·6 ng/ml in non-survivors vs. 614·0 ng/ml in survivors; p<0·001) and IL-6 (p<0·0001) were predictors of death in a recent retrospective, multicenter study of 150 confirmed COVID-19 cases in Wuhan, China, indicating that mortality may be caused by virally driven hyper-inflammatory response. All patients with severe COVID-19 should be screened for hyperinflammation using laboratory trends (e.g., increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate) and the HScore11 table to identify the subgroup of patients for whom immunosuppression could improve mortality.
Since the study of large sample sizes and the study of time kinetics of expression level of cytokine is not fully lucid, enough studies and research are necessary to develop the treatment strategy.
References:
- Fagone, P., Ciurleo, R., Lombardo, S. D., Iacobello, C., Palermo, C. I., Shoenfeld, Y., Bendtzen, K., Bramanti, P., & Nicoletti, F. (2020). Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies. Autoimmunity reviews, 19(7), 102571. https://doi.org/10.1016/j.autrev.2020.102571
- Hu, B., Huang, S., & Yin, L. (2021). The cytokine storm and COVID-19. Journal of medical virology, 93(1), 250–256. https://doi.org/10.1002/jmv.26232
- Yap SH, Moshage HJ, Hazenberg BP, Roelofs HM, Bijzet J, Limburg PC, Aarden LA, van Rijswijk MH. Tumor necrosis factor (TNF) inhibits interleukin (IL)-1 and/or IL-6 stimulated synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes. Biochim Biophys Acta. 1991 Feb 19;1091(3):405-8. doi: 10.1016/0167-4889(91)90207-e