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The Cytokine Storm

The COVID-19 pandemic caused by severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2) is often compared to two other serious viruses we have seen in the past, SARS-CoV, and MERS-CoV, and is actually 79% genomically similar to SARS-CoV.1 This respiratory condition is known for its effects on the lungs, however, it can affect other organs in the body as well. The virus enters bodily cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptors. These receptors are found not only on lung cells, but on the heart, kidney, and gut cells as well.1

Angela Nguyen

One of the physiological reactions to COVID-19 is the inflammatory reaction referred to as the cytokine storm. This storm entails the overwhelming release of pro-inflammatory cytokines including IL-2, IL-6, IL-7, IL-10, G-CSF (granulocyte-colony stimulating factor), IP10 (inducible protein 10), MCP1 (monocyte chemoattractant protein 1), MIP1A (macrophage inflammatory protein 1-α), and TNFα2,3 sending the immune system into overdrive and the body into a hyper-inflammatory state. This cytokine storm leads T cell death, resulting in acute lung injury and acute respiratory distress,1,2  making respiratory failure the leading cause of death for those suffering from COVID-19.3 Although further research is necessary to understand exactly why this extreme reaction occurs, one of the hypotheses for this reaction is cell pyroptosis. Rapid replication of the virus within the cell can cause apoptosis, or cell death, resulting in the flood of inflammatory markers.1 Another theory is that the body’s natural reaction to the spike proteins on the virus can also encourage an inflammatory accumulation of macrophages in the lungs.1 In autopsy, alveolar damage in the lungs shows infiltration with monocytes and macrophages. This, along with the presence of virus inclusion bodies and lack of lymphocytes suggests a cytokine storm induced by alveolar macrophages, epithelial cells, and endothelial cells rather than activated T lymphocytes.2

Another notable reaction to COVID-19 is an impaired immune system and lymphocytopenia. The lymphatic system is an important part of our defense system. Primary lymphatic tissues allow us to develop important immune cells like B and T cells, while secondary tissues allow our bodies to respond to invaders. Patients with this virus had low levels of T cells and natural killer cells, with levels plummeting even lower as the severity of their condition worsened.2 In addition, secondary lymphoid tissues like the spleen and lymph nodes showed atrophy and necrosis.2

Treatment of COVID-19 is also an area that needs continued research. Typically, corticosteroids are not suggested due to a risk of secondary infection and increased lung injury.3 Hydrocortisone was used in the treatment of SARS, and was associated with increased viral load and delayed viral clearance.1 However, with the severe inflammatory response, immunosuppression seen with corticosteroid use might reduce inflammation enough to prevent multi-organ dysfunction.2 One of the most talked about treatments is Chloroquine. This drug is typically used to treat malaria and other rheumatic diseases. Chloroquine prevents the virus from entering cells by interfering with the ACE2 receptors, and altering the cellular pH necessary for the virus to fuse.1 Other drug therapies focus on controlling or reducing the cytokine storm. Tocilizumab is a drug targeted at controlling the inflammatory marker, IL-6, and is in the COVID-19 treatment guideline in China and Italy.1 Anakinra is yet another drug, this one focused on the cytokine IL-1.

Although many different medications have been tested in the treatment of COVID-19, there is still the question of when is the best time to administer the drug, which medication is the best, who should the medication be given to, and is it too much of a risk for those who are immunocompromised? Research in the treatment of COVID-19 is still in progress, but the overall consensus is a need for controlled modulation of the immune system without the risk of secondary infection or delay in virus elimination.


  1. Sarzi-Puttini P, Giorgi V, Sirotti S, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?. Clin Exp Rheumatol. 2020;38(2):337-342.
  2. Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393. doi:10.1016/j.clim.2020.108393

3. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0

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