Storm warning – The critical role of cytokines in severe COVID-19
COVID-19, a novel viral pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread and become a worldwide pandemic. Whereas most people with SARS-CoV-2 infections are either asymptomatic or show mild to moderate symptoms, about 15-20% of the patients progress to severe pneumonia, with around 5% developing acute respiratory distress syndrome (ARDS). The leading cause of death associated with COVID-19 is respiratory failure, followed by septic shock, heart failure, hemorrhage and renal failure1. Serological tests indicate that inflammatory cytokine storm response is associated with COVID-19 severity and mortality.2,3 Thus, enhancing our understanding of the biological function of cytokines and the underlying mechanisms of the cytokine storm response in some COVID-19 patients is key to developing effective treatment strategies and reducing the mortality rate.
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What are cytokines?
Cytokines are a group of low-molecular-weight extracellular signaling proteins produced by various immune cells including macrophages, lymphocytes and mast cells, as well as other cell types such as endothelial cells (cells that form the interior lining of blood and lymph vessels). There are several classes of cytokines in the human body including interleukins (IL), interferons (IFN), lymphokines, chemokines, and tumor necrosis factors (TNF). Cytokines act as immune modulators in our bodies by binding to cell surface receptors responsible for regulating various biological functions including cell proliferation and innate and acquired immune responses, as well as pro- and anti-inflammatory actions.4
During viral infections, cytokines stimulate our immune system to eliminate pathogens, remove destroyed cells and repair injured tissue. In this way, cytokines help our body fight pathogens. However, when unbalanced or overproduced they can also have severe adverse effects.
The potentially deadly cytokine storm
Cytokine storm syndrome (CSS) or cytokine release syndrome (CRS) is a systemic inﬂammatory response commonly caused by viral infections. It is characterized by a large number of cells releasing excessive amounts of pro-inﬂammatory cytokines. This uncontrolled inflammatory process can cause septic shock, multi-organ damage and even eventually organ failure.5
In the case of COVID-19, SARS-CoV-2 enters host cells, replicates and releases progeny viruses via a process called pyroptosis (programmed cell death triggered by inflammation), which activates our innate and adaptive immune systems. The viral infection triggers epithelial cells and alveolar macrophages in the lungs to produce a large number of various inflammatory cytokines and chemokines, as shown in Figure 1. These cytokines attract monocytes, macrophages and T cells to the infection site that produce more inflammatory cytokines, forming a feedback loop. Aggregation of T-cells in the lungs also causes a decrease in the blood levels of lymphocytes (i.e., lymphopenia) in severe COVID-19 patients.2,3
The initial activation of immune cells triggers either a functional or dysfunctional immune response. During a functional immune response, cytotoxic T cells (CD8+) directly attack the infected cells, while neutralizing antibodies bind the virus and initiate cell death (apoptosis). Then, the lung alveolar macrophages clean up neutralized viruses and engulf the apoptotic cells, a process called phagocytosis. In most cases, infections are resolved through this process, the level of inflammatory cytokines recedes, and patients recover.
In some cases, however, a dysfunctional immune response attracts additional immune cells to the lungs. This results in overproduction of the inflammatory cytokines, leading to a cytokine storm. During a cytokine storm, an increase in vascular permeability allows ﬂuid and blood cells to move into the lung alveoli, resulting in pulmonary edema, ARDS, and even respiratory failure. When these extra cytokines circulate to other organs, they can also cause systemic inflammation such as sepsis and disseminated intravascular coagulation, tissue damage, and eventually multi-organ failure.6
Lymphopenia and elevated cytokine profiles exhibit a positive correlation with virus titers and disease severity.7 Thus, such serological measurements could help physicians effectively identify patients who are susceptible to CSS and provide timely intervention. However, more studies are needed to fully define the role of cytokines and the associated pathophysiological mechanism of the host immune response in severe COVID-19.
Therapeutic strategies to weather the cytokine storm
Currently, there are no approved drugs for managing CSS in severe COVID-19 cases. Although corticosteroids are commonly used to inhibit inflammation, such drugs are not recommended for COVID-19 patients and may actually worsen associated lung injuries.8 Alternative immunosuppressant strategies targeting several cytokines and their receptors are under investigation, including those that target the IL-6-mediated pathway.
SARS-CoV-2 infection activates immune cells and releases IL-6 and other inflammatory cytokines. As shown in Figure 2, IL-6 then binds to the soluble IL-6 receptor (sIL-6R) forming a complex with another protein, gp130 dimer, on the surface of endothelial cells. This triggers the release of cytokines from endothelial cells, which in turn attract immune cells to the infection site and produce more cytokines resulting in a cytokine storm.10 IL-6 receptor-antagonists bind to the IL-6 receptors and block their interaction with IL-6 as well as the subsequent biological events.
A clinical trial of tocilizumab, an anti-IL-6 receptor antibody approved for treating CSS associated with some cases of CAR-T cell therapy, has been initiated in patients with COVID-19 in China.9 Initial results from 21 severe patients treated with tocilizumab are promising. Body temperature returned to normal on the first day of treatment in all patients. 75% of patients required less oxygen support, and all patients were eventually discharged.10 Tocilizumab recently received US FDA approval for a Phase III trial.11 Sarilumab, another anti-IL6R antibody, has also been tested.12
Although excessive IL-6 can cause CSS in COVID-19 patients, IL-6 also plays an important role in their recovery by supporting lung repair and remodeling. As such, timing of anti-IL-6R agent administration could also be a critical factor affecting patient outcomes.13
While cytokines constitute an important host defense system and modulate immune responses, they may also contribute to the development of severe cases of COVID-19 and even lead to death. Therefore, development of therapies to effectively control the cytokine storm is a key research focus necessary to reduce COVID-19 mortality.
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- Clinical characteristics of 82 death cases with COVID-19 medRxiv (2020) 1-30, 2020 https://www.medrxiv.org/
- Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497–506
- Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients - https://doi.org/10.1016/j.ebiom.2020.102763
- Cytokine Milieu in Infectious Disease: A Sword or a Boon? Journal of Interferon & Cytokine Research (2020), 40(1), 24-32
- Constitutive Inﬂammatory Cytokine Storm: A Major Threat to Human Health Journal of Interferon & Cytokine Research (2020), 40(1), 19-23
- The trinity of COVID-19: immunity, inflammation and intervention Nature Reviews Immunology (2020) Ahead of Print https://www.nature.com/articles/s41577-020-0311-8#rightslink
- Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020).
- Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020; 395: 473-475
- Effective treatment of severe COVID-19 patients with tocilizumab https://www.pnas.org/content/early/2020/04/27/2005615117
- The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease Autoimmunity Reviews (2020) Ahead of Print https://www.sciencedirect.com/science/article/pii/S1568997220300926
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