SARS-CoV-2, the virus that causes COVID-19, continues to baffle even the most knowledgeable infectious disease experts. One perplexing concern is the increasing number of younger individuals, between the ages of 20 and 60, who contract COVID-19 and develop serious illness requiring intensive care treatment. Even more disconcerting is that some of these patients do not have a known underlying medical condition that would predispose them to greater risk.

One phenomenon that may play a role in COVID-19 is cytokine release syndrome (CRS), also known as cytokine storm. CRS has been described as an acute systemic inflammatory syndrome, or an excessive immune response, characterized by fever and multiple organ dysfunction (Porter & Maloney, 2019). It has been experienced by patients undergoing immune-based cancer treatments such as chimeric antigen receptor (CAR)-T cell therapy and may also occur after treatment with a therapeutic antibody (i.e. blinatumomab) or following haploidentical allogeneic hematopoietic cell transplantation. A CRS-like syndrome that develops after a severe viral infection is often referred to as a cytokine storm rather than CRS. Researchers postulate that a type of cytokine storm contributed to the high mortality rates associated with prior viral epidemics such as the 1918 H1N1 Spanish flu, 1957 H2N2 Asian influenza, the 1968 H3N2 Hong Kong influenza, the 2009 H1N1 pandemic influenza, and the avian flus that occurred between 1997 and 2014 caused by several different virus strains H5N1, H7N9, and H10N8 (Liu, Zhou & Yang, 2016).

Pathology of the Storm (Liu, Zhou & Yang, 2016)

The pathology of the cytokine storm is not fully understood however a great deal has been learned. Viruses typically attack the respiratory epithelial cells which trigger a cytokine response. Pattern recognition receptors (PRRs) of the immune cells recognize the virus and signal release of the pro-inflammatory cytokines such as interferon gamma (IFN-g), tumor necrosis factors (TNFs), interleukins (ILs), and chemokines (Liu, Zhou & Yang, 2016). IFN-g activates macrophages which produce IL-6, TNF-α, and IL-10.

Macrophages are the main cells recruited to the alveolar space initially in response to viral infection. They increase cytokine production and attract additional immune cells to the affected area such as T-helper cells CD4 and CD8 which work to combat the virus. Additional pathways associated with PRRs are triggered including cyclooxygenase (COX)-2 and c-Jun N-terminal kinase (JNK). Once the virus is cleared, the immune pathways shut down.

In a cytokine storm however, this process does not stop as it normally should. The inflammatory cytokines go into overdrive and can leak into the circulation causing systemic cytokine storms and ultimately multi-organ dysfunction. IL-6 is associated with vascular leakage, coagulation cascades, disseminated intravascular coagulation (DIC), and cardiomyopathy (Porter & Maloney, 2019). IFN-g may induce fever, chills, headache, dizziness, and fatigue while TNF-α can lead to fever, malaise, vascular leakage, cardiomyopathy and lung injury. Genetics may be one factor which could explain why some individuals develop only mild symptoms while other young, healthy patients become extremely ill.

Laboratory Findings

Early data from patients with severe COVID-19 show laboratory findings consistent with cytokine storm such as elevated inflammatory markers (i.e. D-dimer, ferritin) and increased proinflammatory cytokines, both of which have been associated with critical and life-threatening illness (McIntosh, 2020). Mehta et al. (2020) states that patients with COVID-19 exhibit clinical features similar to secondary hemophagocytic lymphohistiocytosis (sHLH), another aggressive and lethal syndrome of excessive immune activity which is commonly triggered by viral infections and develops in some sepsis patients. The symptoms include fever, cytopenias, high ferritin levels and acute respiratory distress syndrome (ARDS) (Mehta et al., 2020). Clinicians should consider screening patients with severe COVID-19 for hyperinflammation markers such as increasing ferritin, decreasing platelet counts, or erythrocyte sedimentation rate, to distinguish patients that could benefit from immunosuppression therapy (Mehta et al., 2020).

Potential Treatment Strategies

We have no magic bullet. It could be at least a year, possibly longer, before an effective vaccine is developed, tested and approved for use against COVID-19. Until then, several immunomodulatory therapies have potential to treat patients with the infection who are experiencing a cytokine storm:

• Corticosteroids: while not typically recommended to treat COVID-19 lung injury, immunosuppression with corticosteroids may be useful in treating hyperinflammation (Mehta et al., 2020).
• Selective cytokine blockade such as anakinra or tocilizumab:
  • Anakinra, a recombinant human IL-1 receptor antagonist, currently used to treat rheumatoid arthritis, is undergoing clinical trials to reduce hyperinflammation and respiratory distress in COVID-19 patients.
  • Tocilizumab, an IL-6 receptor blocking indicated to treat CRS, has been approved in China to treat COVID-19 pneumonia and elevated IL-6 (Mehta et al., 2020).
• Intravenous immunoglobulin:
  • Concentrated globulin prepared from pooled human plasma has been used to treat SARS-CoV-1 (classic SARS) and the 2009 H1N1 pandemic influenza (Liu, Zhou & Yang, 2016). Convalescent plasma collected from recovered COVID-19 patients is being studied as a potential treatment.
• Janus kinase (JAK1/JAK2) inhibitors may impact inflammation and virus entry into the cell in COVID-19 patients (Mehta et al., 2020).

It appears that an individual’s response to an infection is determined by both viral virulence and host resistance (Liu, Zhou & Yang, 2016). Prior experience with viral epidemics found immunomodulator treatments coupled with antiviral agents could be effective in treating severe illness. However, until randomized controlled trials are conducted to prove the efficacy of the therapies outlined above, clinicians should continue to follow the latest Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronarvirus Disease 2019 (COVID-19) when providing care at the bedside.
 

References
 
Liu, Q., Zhou, Y. & Yang, Z. (2016). The cytokine storm of severe influenza and development of immunomodulatory therapy. Cellular and Molecular Immunology. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711683/
 
McIntosh, K. (2020). Coronavirus disease 2019 (COVID-19). UpToDate. Retrieved from https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19
 
Mehta, P., McAuley, D.F., Brown, M., Sanchez, E. Tattersall, R.S., & Manson, J. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. Retrieved from https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext
 
Porter, D.L. & Maloney, D. G. (2019). Cytokine release syndrome (CRS). UpToDate. Retrieved from https://www.uptodate.com/contents/cytokine-release-syndrome-crs? 

Yuen, K., Ye, Z., Fung, S., Chan, C., & Jin, D. (2020). SARS-CoV-2 and COVID-19: The most important research questions. Cell and Bioscience. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074995/