The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has highlighted various complications associated with viral infections, one of the most severe being the cytokine storm. This hyperactive immune response is associated with high rates of complications and fatal outcomes.  Understanding the phases of viral infection, acute inflammation, and the cytokine storm is crucial for developing effective treatments targeting specific steps¹.

The initial phase of COVID-19 begins with the viral infection itself. SARS-CoV-2 primarily targets the respiratory system, invading host cells through the ACE2 receptor. During this stage, the virus replicates actively, inducing the body's initial immune response to combat the infection by producing interferons and other cytokines ². As the disease progresses, the body enters the acute inflammation phase characterized by an amplified response to resist the virus. Key players in this response include macrophages, neutrophils, and dendritic cells, which release pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α ^2,3. This inflammatory response is essential for controlling the virus, but can cause tissue damage if unregulated. In some cases, the inflammatory response spirals into a cytokine storm, characterized by an excessive and uncontrolled release of pro-inflammatory cytokines. This escalation triggers widespread inflammation and severe tissue damage, potentially leading to critical conditions like acute respiratory distress syndrome (ARDS), multi-organ failure, and death⁴.

The pathogenesis of cytokine storms involves several mechanisms. One pivotal factor is the overactivation of the immune system, resulting in the excessive production of cytokines, which are central to the progression of the cytokine storm⁵. These molecules exhibit both pro-inflammatory and anti-inflammatory effects, and the trans-signaling pathway has been a critical target for therapeutic strategies over classical signaling pathways. In addition, emerging research suggests that the gut microbiota imbalance may affect immune response during COVID-19, affecting cytokine production and contributing to the disease's complexity ⁶.

Managing cytokine storms in COVID-19 patients involves several strategies. One approach uses cytokine inhibitors, such as IL-6 receptor antagonists (e.g., tocilizumab or sarilumab) and IL-1 receptor inhibitors (e.g., anakinra)⁷ to suppress the excessive inflammatory response and improve patient outcomes. Another treatment strategy includes corticosteroids, which have effectively reduced mortality in severe COVID-19 cases by modulating the immune response. Additionally, therapies targeting specific cytokine pathways, such as TNF-α inhibitors and JAK inhibitors, are being explored for their potential to mitigate cytokine storms.

Cytokine storm poses a significant challenge in treating severe COVID-19 cases. Understanding the phases of viral infection, acute inflammation, and the mechanisms driving cytokine storm is vital for advancing therapeutic approaches. Our ‘Cytokine storm in COVID-19’ poster offers essential insights into the various key players and the timeline associated with this condition. Ongoing research and clinical trials remain crucial for enhancing treatment strategies and improving outcomes for patients.

References

1.    Fajgenbaum, D. C., June, C. H. Cytokine Storm.  N. Engl. J. Med.   383, 2255-2273 (2020).

2.    Montazersaheb, S., Hosseiniyan Khatibi, S. M., Hejazi, M. S. et al. COVID-19 infection: an overview on cytokine storm and related interventions.  Virol. J.   19, 92 (2022).

3.    Zanza, C., Romenskaya, T., Manetti, A. C., Franceschi, F., La Russa, R., Bertozzi, G., Maiese, A., Savioli, G., Volonnino, G., Longhitano, Y. Cytokine Storm in COVID-19: Immunopathogenesis and Therapy.  Medicina (Kaunas)   58, 144 (2022).

4.    Castelli, V., Cimini, A., Ferri, C. Cytokine Storm in COVID-19: "When You Come Out of the Storm, You Won't Be the Same Person Who Walked in".  Front. Immunol.   11, 2132 (2020).

5.    Zhang, C., Wu, Z., Li, J. W., Zhao, H., Wang, G. Q. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality.  Int. J. Antimicrob. Agents   55, 105954 (2020).

6.    Liu, Y., Kuang, D., Li, D., Yang, J., Yan, J., Xia, Y., Zhang, F., Cao, H. Roles of the gut microbiota in severe SARS-CoV-2 infection.  Cytokine Growth Factor Rev.   63, 98-107 (2022).

7.    Arcani, R., Correard, F., Suchon, P. et al. Tocilizumab versus anakinra in COVID-19: results from propensity score matching.  Front. Immunol.   14, 1185716 (2023).