Cytokines and COVID-19: friends or foes?

ABSTRACT

The cytokine storm following sepsis has been proven to be an important mechanism for triggering acute respiratory distress syndrome, which is a fatal uncontrolled systemic inflammation characterized by high concentrations of pro-inflammatory cytokines and chemokines, secreted by immune effector cells. The cytokine storm also occurs in the recently emerged novel coronavirus disease (COVID-19). Therefore, cytokines which usually help the immune system to fight infections are potentially harmful in the course of COVID-19 infections. Therefore, avoiding or mitigating the cytokine storm may be a key treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Commentary

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the novel coronavirus disease (COVID-19), was reported in late 2019 in China.¹ This virus, which has a similar phylogenetic classification to SARS-CoV, triggers a cytokine storm in the pulmonary tissue by releasing various pro-inflammatory mediators, including interleukin-2 (IL-2), IL-6, IL-7, granulocyte colony-stimulating factor (GCSF), human interferon-inducible protein 10 (IP-10 or CXCL10), monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein 1 alpha (MIP-1α), and tumor necrosis factor-alpha (TNFα). This cytokine storm can potentially lead to severe clinical phenotypes such as tissue hypoxia, acute respiratory distress syndrome (ARDS), and even death in affected patients. Cytokines, which usually act to help the immune system to fight infections, are potentially harmful in fighting COVID-19. Therefore, mitigating the cytokine storm and avoiding secondary infections may be a key approach for the treatment of SARS-CoV-2.^2–4

Generally speaking, T helper (Th) cells are key players in the adaptive immune response triggered following viral infections. After recognition of the virus by antigen presenting cells (APCs) such as dendritic cells (DCs) or other types, these cells secret cytokines and generate a microenvironment that directs the T cell responses. While Th1 cells primarily regulate the adaptive immune response by cytokine production, the role of cytotoxic T-lymphocytes (CTLs), also known as CD8⁺ T cells, is the specific killing of virus-infected cells.⁵ Proinflammatory cytokines produced by Th cells are regulated via the NF-κB signaling pathway. IL-17, produced by Th17 cells, plays a critical role in the recruitment and rapid influx of monocytes and neutrophils to the site of infection. IL17 can also exacerbate inflammation by activation of other downstream cytokine and chemokine cascades, e.g. IL-1, IL-6, IL-8, IL-21, TNF-α, and MCP-1.^6,7 In viral infections, Th cells and CTLs may balance each other between fighting the pathogens and suppressing the development of autoimmunity or overwhelming inflammation. Additionally, the production of virus-specific antibodies is mediated by CD4⁺ T cells which activate the T-cell dependent B cells.⁵ According to evidence, major alterations in several serum cytokines have been observed in patients with SARS-CoV-2 infection. Although the plasma levels of IL-5, IL-12p70, eotaxin, and RANTES in these patients were similar to healthy cases, the plasma levels of IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1α, and TNF-α were higher in severe COVID-19 patients, compared to those with moderate illness, suggesting that an overproduction of inflammatory chemokines and cytokines could result in impaired lung function (Figure 1).⁸ In the COVID-19 patients, depletion of CD8⁺ T cells does not affect viral replication. However, CD4⁺ T cell depletion has been shown to be related to decreased pulmonary recruitment of lymphocytes, and lower production of cytokines and antibodies. These processes lead to severe pneumonitis mediated by the immune system and delayed clearance of SARS-CoV from the lungs.⁹

Figure 1.

Immune response and pathogenesis of against SARS-CoV-2 (Figure is made with biorender).

The cytokine release syndrome (CRS) plays a critical role in severe COVID-19 patients. Several studies have recommended the identification and treatment of hyperinflammation in order to reduce mortality and hasten recovery. Some existing and approved therapies with proven efficacy and safety profiles can be used to manage this condition. The current strategies for the management of COVID-19 patients are generally supportive approaches. ARDS appears to be the pathological event that is common between the three known coronavirus diseases, such as SARS-CoV-2, SARS-CoV and MERS-CoV infections,¹⁰ and respiratory failure due to ARDS was the most important cause of mortality in these patients.¹¹ The cytokine storm following sepsis has been proven to be an important mechanism for triggering ARDS, which is a fatal uncontrolled systemic inflammation characterized by high concentrations of pro-inflammatory cytokines e.g. IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, etc. and chemokines e.g. CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc. These were also secreted by immune effector cells in SARS-CoV infection.^12–14 Similarly, patients with severe MERS-CoV infection showed higher serum levels of IL-6, IFN-α, and CCL5, CXCL8, CXCL-10 compared to those with a mild to moderate illness.¹⁵ Similar to SARS-CoV and MERS-CoV infection, the cytokine storm in SARS-CoV-2 infection triggers a violent assault to the body caused by an excessive activation of the immune system, leading to ARDS and multi-organ failure, and finally causing death in severely affected individuals.^10,16

Although corticosteroids are not routinely recommended, immunosuppressive agents are likely to be effective in hyperinflammation syndromes. The data from a phase 3 randomized controlled trial using IL-1 receptor blockade (anakinra) in the management of sepsis were re-analyzed, and an increased survival benefit in patients with hyperinflammation, without excessive side effects was reported.^17,18 Furthermore, in a multi-center, randomized controlled trial in China, the beneficial effects of tocilizumab administration (IL-6 receptor blockade, licensed for cytokine release syndrome) (Figure 2), were established in COVID-19 patients with pneumonia and elevated IL-6 (ChiCTR2000029765).¹⁹ Inhibitors of Janus kinase (JAK) have been shown to beneficially affect both inflammation and mechanisms of cellular viral entry in SARS-CoV-2 infection.²⁰

Figure 2.

Tocilizumab is an immunosuppressive drug, for the treatment of COVID-19 patients. It is a humanized monoclonal antibody against the IL-6 R and inhibits intracellular signaling in cells that express GP130 (Figure is made with biorender).

These findings have highlighted the importance of screening approaches using laboratory tests (e.g., increased ferritin, decreased platelet counts, or erythrocyte sedimentation rate) to measure hyperinflammation in all patients with severe COVID-19.²¹ By identifying those patients who require immunosuppressive strategies, clinicians may improve the treatment outcome and decrease the mortality rate. In these cases, IL-6, IL-1, or TNF blockades may also be effective. Recently, in various clinical centers, the use of mesenchymal stromal/stem cells (MSCs) has been reported in the management of patients with severe COVID-19 infection. Because lung damage is a major obstacle to recovery in severe patients, MSCs may help repair the damage caused by viral infection through the production of various growth factors and immunosuppressive agents.²²

In conclusion, the cytokine release syndrome occurs in a majority of patients with severe COVID-19, which is also an important cause of death. IL-6 and JAK are the key molecules involved in the cytokine release syndrome and antagonists of these molecules may be worth considering as effective drugs to save patients’ lives.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.