The cytokine storm was the major cause of death for SARS-CoV-2 virus infection because of excessive inflammatory reactions in the body of severely ill COVID-19 patients. The question is what is the relationship between cytokine storms and coronavirus infections. Let's understand the connection between them.
Understanding the Connection Between Cytokine Storm and COVID-19
The outbreak of the coronavirus disease 2019, also known as COVID-19, has drastically affected the human population - approximately 219 million people have been infected with the SARS-CoV-2 virus and around 4.5 million deaths have been reported so far. Unfortunately, this life-threatening disease is worsening due to newly emerging variants of SARS-CoV-2, challenging the global medical health system to develop new COVID-19 detection protocols and treatment modalities to prevent fatal pneumonia associated with acute respiratory distress syndrome (ARDS).
Current medical studies from China revealed that high levels of certain proinflammatory mediators, such as cytokines and chemokines, have been observed in severe cases of SARS-CoV-2 infection (Wang et al., 2020). The progression of COVID-19 usually starts with some mild symptoms after 5–6 days, which can lead to severe cases if not treated properly. It should be noted that the unusual rise in pro-inflammatory cytokines levels has only been observed in the severe cases of SARS-CoV-2 infection, not in mild states (Melo et al., 2021). Medical professionals and scientists have now been using cytokine ELISA kits to detect the association of the “cytokine storm” with severe cases of COVID-19.
Cytokine Release
In general, cytokines are soluble, pro-inflammatory glycoproteins that are released by a variety of innate and adaptive immune cells, like T and B-cells, dendritic cells, neutrophils, natural killer cells (NK-cells), and macrophage, in response to bacterial or viral infections. Upon their release, they carry out various functions, from regulating the cell signaling pathways to initiating immune and inflammatory responses. Mild cytokine release in response to infection may result in nausea, depression, rash, arthralgia, elevated local temperature, and other flu-like symptoms (Wang et al., 2020).
There are a variety of pro-inflammatory and anti-inflammatory cytokines, including interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), and colony-stimulating factors (CSFs). Each type of cytokine with its sub-types perform specific functions.
- Interferons (IFNs) possess an anti-proliferative effect, interfere with viral replication, and regulate the immune response.
- Interleukins (ILs) possess both pro and anti-inflammatory effects and regulate the activation and differentiation of immune cells.
- Tumor necrosis factors (TNFs) are a major type of proinflammatory cytokines and play a central role in viral disease by activating the cytotoxic T-cells. They also have a prominent role during a cytokine storm.
- Colony-stimulating factors (CSFs) act on stem cells and promote cell growth and differentiation of various types of immune cells such as monocytes, dendritic cells, and neutrophils.
Cytokine Storm
Cytokine storm is a serious condition in which the body’s immune system becomes hyperactive by drugs, infection, or other stimuli, leading to the excessive release of pro-inflammatory cytokines by immune cells. The high level of cytokines (chemokines, IFNs, ILs, CSFs, TNFs) in the circulation causes acute respiratory distress syndrome (ARDS), vascular damage, endothelial dysfunction, and dysregulation of the metabolic and paracrine system, ultimately leading to death in many severe COVID-19 cases. This condition has mainly been observed in critical cases of COVID-19 patients admitted into intensive care units (ICUs). In medical terms, it is also referred to as cytokine release syndrome (CRS) or hypercytokinemia, which has a high morbidity and mortality rate (Hojyo et al., 2020; Qin et al., 2020).
In 1993, the “cytokine storm” term was first used to describe the graft-vs.-host disease. The term was later extended to other conditions such as sepsis, autoimmune disorders, hemophagocytic lymphohistiocytosis, cancers, and infectious diseases (Ferrara, Abhyankar, & Gilliland, 1993).
Association of COVID-19 with Cytokine Storm
Association of the cytokine storm with COVID-19 was first reported by Professor Bin Cao's team in January 2020. They revealed that the cytokine storm was the major cause of death for SARS-CoV-2 virus infection because of excessive inflammatory reactions in the body of severely ill COVID-19 patients (Huang et al., 2020). After the publication of the first report, several studies were conducted to further elaborate the association of cytokine storm with COVID-19 and how this mechanism takes place in patients with severe COVID-19 pneumonia. Overall, several studies have found the cytokine storm to be directly linked with lung injury, multiple organs failure, and severe COVID-19 (Mangalmurti & Hunter, 2020).
Action Mechanism of Cytokine Storm
When inside the body, the SARS-CoV-2 virus directly binds to specific receptors known as ACE2 (angiotensin-converting enzyme-2) present on the type-2 alveolar cells and other various tissues. After binding to its corresponding receptor, it enters inside the cells and takes control of the cell’s machinery to start replication. Viruses replicate rapidly and ultimately burst out of cells to infect other neighboring cells.
On the other hand, the alveolar epithelial cells, blood circulating monocytes, and alveolar macrophages become activated through binding to pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). Activation of innate immune cells releases not only a robust amount of chemokines and cytokines, but also triggers a cascade of inflammatory pathways against the invading virus. The inflammatory pathways regulate the expressions and transcription of anti-viral proteins (pro-inflammatory cytokines). Increased production of cytokines attracts more immune cells, specifically monocytes and T-cells, to the site of infection, which results in killing the infected alveolar cells as well as causing lung inflammation and edema (Yang et al., 2021).
Clinical studies have highlighted that 70% of COVID-19 deaths are due to ARDS, which is associated with cytokine storms. The serum of hospitalized patients with critical COVID-19 condition had higher plasma levels of IL-2, IL-6, IL-7, IL-10, IP10 G-CSF (granulocyte colony-stimulating factor), TNF-α, CXCL10 (CXC-chemokine ligand 10), MCP1, and MIP1α (macrophage inflammatory protein 1 alpha) (Hojyo et al., 2020).
Determination of Cytokines Profile in COVID-19 Patient Samples
Current advancements in COVID-19 research has made it easier for scientists and medical professionals to detect and study the onset of cytokine storm in severe cases of COVID-19 through cytokine ELISA kits. Cytokine ELISA kits are easy-to-use, cost-effective, rapid detection tools that accurately measure the levels of specific proinflammatory cytokines (e.g. IL-1α & 1β, IL-2, IL-3, γGMCSF, IL-4, IL-6, IL-10, IL-12p70, IL-17, TNFα, MCP-1, MIP-1α) in biological samples, such as serum or plasma, under certain pathological and physiological conditions. Cytokine ELISA kits offer valuable insight into the fluctuations linked with severe COVID-19 and other different disease states.
REFERENCES
Ferrara, J.M., Abhyankar, S., & Gilliland, D. (1993). Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Paper presented at the Transplantation proceedings.
Hojyo, S., Uchida, M., Tanaka, K., Hasebe, R., Tanaka, Y., Murakami, M., & Hirano, T. (2020). How COVID-19 induces cytokine storm with high mortality. Inflammation and regeneration, 40(1), 1-7. https://dx.doi.org/10.1186%2Fs41232-020-00146-3
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., . . . Gu, X. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497-506. https://doi.org/10.1016/S0140-6736(20)30183-5
Mangalmurti, N., & Hunter, C.A. (2020). Cytokine storms: understanding COVID-19. Immunity. https://doi.org/10.1016/j.immuni.2020.06.017
Melo, A.K.G., Milby, K.M., Caparroz, A.L.M., Pinto, A.C.P., Santos, R.R., Rocha, A.P., ...Vieira, R.M. (2021). Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis. PloS one, 16(6), e0253894. https://doi.org/10.1371/journal.pone.0253894
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., . . . Wang, W. (2020). Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clinical infectious diseases, 71(15), 762-768. https://doi.org/10.1093/cid/ciaa248
Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., . . . Xiong, Y. (2020). Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama, 323(11), 1061-1069. https://doi.org/10.1001/jama.2020.1585
Yang, L., Xie, X., Tu, Z., Fu, J., Xu, D., & Zhou, Y. (2021). The signal pathways and treatment of cytokine storm in COVID-19. Signal transduction and targeted therapy, 6(1), 1-20. https://doi.org/10.1038/s41392-021-00744-8.
Wang, J., Jiang, M., Chen, X., & Montaner, L.J. (2020). Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: Review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. Journal of Leukocyte Biology 108(1), 17– 41. https://doi.org/10.1002/JLB.3COVR0520-272R.