Cytokines are a collection of many proteins produced by cells, with the function of transmitting information between cells to activate the body's natural immune responses. There are 3 groups of cytokines in the human body: interleukin, interferon and TNF.
In the body, cytokines play an important role in coordination. As soon as a pathogen invades, the immune system will be mobilized, cytokines will "notify" T lymphocytes and migratory macrophages. move to the site of infection. The original cytokines in turn activate these cells causing them to produce more cytokines. Under normal conditions, this activation loop is controlled by a negative feedback mechanism. In some situations, the activation is out of control, cytokines are produced and released massively, causing a cytokine storm in the body, causing harm to the body.
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Cytokine storm (as known as Cytokine Release Syndrome - CRS) is the phenomenon of excessive release of cytokines by the immune system when one or more agents invade the body, leading to to systemic inflammatory reactions. The mechanism of cytokine storm is as follows:
1. When an agent (such as a virus, bacteria, chemical toxin, etc.) enters the body, it will be detected by the immune barrier and destroyed.
2. If the invading agent is too massive and strong, the immune system uses a series of cells such as B lymphocytes, T lymphocytes, macrophages, monocytes, eosinophils,... to destroy destroys "intruders" and at the same time produces cytokines that cause inflammatory reactions.
3. If the "intruder" is too stubborn, immune cells will produce cytokines to trigger the immune system to produce more white blood cells, while also stimulating those same white blood cells. produce more cytokines. The above process takes place continuously, leading to cytokine release syndrome - CRS, also known as cytokine storm.
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CYTOKINE STORM IN TREATMENT OF COVID PATIENTS
As of early June 2021, the number of confirmed deaths due to the new pneumonia virus, COVID-19, has surpassed 3.7 million, while more than 172 million people worldwide are infected. Patients infected with the SARS-CoV-2 virus (positive for Covid-19) initially had only mild symptoms such as fever, cough, difficulty breathing, and muscle aches, but their body condition rapidly deteriorated (multiple organ failure), acute respiratory failure, neurotoxicity,...) and lead to death within a short period of time.
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Although the link between the cytokine storm and lung damage during SARS-Cov2 infection remains unclear, it is currently believed that high levels of cytokines promote the relentless destruction of capillaries. lung. Pulmonary complications are thought to result from disruption of the vascular barrier, leading to tissue edema, fluid accumulation in the lungs, and intense inflammatory cell infiltration that ultimately manifests as ARDS.
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Indeed, Dr. Mukesh Kumar, a virologist and immunologist at Atlanta University, Georgia, USA, after experiments infecting SARS-CoV-2 on animal cells, affirmed, "In COVID-19, most cells Cells die from cytokine storms. The cytokine storm has irreversibly destroyed the lung parenchyma”; “The amount of cytokines in SARS-CoV-2 infection is about 50 times higher than in Zika or West Nile virus infection,” Dr. Max Konig, Johns Hopkins University, also had a similar opinion.
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MECHANISM OF IMPACT
Cytokine release syndrome (CRS) or cytokine storm has been associated with a variety of infectious and non-infectious diseases over the past decades, including influenza and SARS-CoV (Tisoncik et al., 2012; Shimabukuro- Vornhagen et al., 2018). However, the exact signaling pathways leading to CRS remain to be determined (Lukan, 2020).
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Several mechanisms have been proposed to explain CRS and the dynamics of viral and immune responses to SARS-CoV-2. One hypothesis is that SARS-CoV-2 infects macrophages, CD4+ T cells, and CD8+ T cells, in addition to alveolar epithelial cells (Davanzo et al, 2020; Grant et al. 2021), thereby inducing the production of several inflammatory cytokines (mainly IL-6) and also attenuating the immune response mediated by macrophages and T cells.
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According to another study, the immune system is overstimulated, cytokines flood the blood, like a storm, cytokines seen in the blood such as IL1-β, IL1RA, IL7, IL8, IL9, IL10, basic FGF2, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1α, MIP1β, PDGFB, TNFα, and VEGFA... cause inflammatory reactions, blood clotting, lymphopenia, and mononuclear cell infiltration of organs.
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LIỆU PHÁP ĐẶC TRỊ
Experience in treating SARS and MERS shows that reducing viral load through interventions at the early stages of the disease and controlling inflammatory responses through immunomodulators that inhibit these responses Inflammatory responses caused by cytokines/chemokines are effective solutions to improve the prognosis of diseases caused by human coronavirus (HCoV) infection. Autopsy results of COVID-19 patients in China have reinforced the above argument.
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The approach to evaluating a patient with cytokine storm should achieve the following three main goals: identify the underlying disorder (and rule out disorders that may mimic the cytokine storm), determine severity, and determine the clinical trajectory. All cases of suspected cytokine storm should undergo a complete work-up for infection, as well as laboratory assessment of liver and kidney function. Acute-phase inflammation biomarkers, such as CRP and ferritin, and blood counts should be measured, as they correlate with disease activity. Additionally, cytokine profiles can be useful in determining trends from baseline values.
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Potential treatment interventions for the "cytokine storm" are continuing to be researched and clinically tested with the hope that in the near future there will be more specific treatment solutions for critically ill patients. due to COVID-19 infection. Below are specific “cytokine storm” medications that target IL-6 and other forms of immunosuppression that have been tested in the treatment of COVID-19:
1. Tocilizumab
Tocilizumab is a humanized monoclonal antibody directed against the IL-6 receptor. It was first used in the treatment of hematological tumors with Chimeric antigen receptor T-cell (CAR-T) immunotherapy to prevent CRS produced during treatment without affecting efficacy. anti-tumor treatment results. Since then, it has been recommended as a first-line treatment for severe CRS associated with CAR-T therapy.
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Most studies of Tocilizumab have been conducted in patients who are already critically ill or have severe disease, so it is unknown whether there is a greater benefit if it is given earlier in therapy, before patients reach critical illness. severe or critical condition or not. In the newly released seventh edition of the China CDC guidelines, tocilizumab was included as an experimental therapy. Fortunately, a recent initial study in Italy reported that the application of tocilizumab was able to reduce serum CRP, ferritin and fibrinogen levels to normal levels and was therefore strongly associated with clinical improvement.
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2. Hydroxychloroquine và chloroquine
Chloroquine and Hydroxychloroquine are widely used to prevent and treat malaria and are also an important aspect in the management of autoimmune diseases. These two drugs have recognized anti-inflammatory and immunomodulatory effects. Hydroxychloroquine and chloroquine can inhibit viral entry by adjusting pH values, affecting the activity of glycosyltransferases or glycosyl modifying enzymes in host cells, interfering with the correct glycosylation of ACE2 and Prevents the binding of the virus to ACE2 - SARS-CoV-2 enters cells. Other research has suggested that hydroxychloroquine may also prevent SARS-CoV-2 from binding to gangliosides, which in turn may inhibit virion exposure to the ACE-2 receptor. Overall, hydroxychloroquine/chloroquine has the potential to affect several cellular pathways and thus may have several mechanisms of action against SARS-CoV-2.
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Unfortunately, the effectiveness of these drugs in treating COVID-19 has never been conclusive, and the potential risk of heart disease caused by these drugs has made the Food and Drug Administration The United States withdrew its emergency use authorization (EUA) for COVID-19 treatment and the WHO also suspended its trials because of the failure of pharmacological treatments to reduce mortality.
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3. Baricitinib
Clathrin-mediated endocytosis (CME) is important for viral entry into lung cells, and numb-associated kinase (NAK) is involved in this process. Baricitinib is a tyrosine protein kinase inhibitor, which can inhibit NAK, thereby limiting systemic inflammatory response and cytokine production through inhibition of the canonical JAK-STAT pathway. It can also prevent the assembly of viral particles in cells by inhibiting protein kinases. Because interferon transcription is mediated by the JAK-STAT pathway, Baricitinib has been proposed as a possible treatment for patients with moderate COVID-19 who have CRS and require hospital care. institute. There is preliminary clinical evidence that oral Baricitinib may be beneficial in the treatment of COVID-19, especially respiratory function when administered at a dose of 4mg in combination with high-dose corticosteroids. The long-term effects of baricitinib on COVID-19 will need to be confirmed by future studies.
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4. Anakinra
Anakinra is an interleukin-1 receptor antagonist that interferes with the action of IL-1α and IL-1β and is used for autoinflammatory disorders. Recent studies have shown that coronavirus regulates the activation of the NLRP3 inflammasome by inducing IL-1β maturation and secretion. Anakinra has been shown to be effective in patients with cytokine storm syndrome, and further studies have suggested that high-dose anakinra is a safe alternative for treating cytokine release syndrome in COVID-19 cause. It should also be noted that previous studies have shown that IL-1 inhibition can also cause endothelial dysfunction and affect blood coagulation. A recent case report described a reduction in serum inflammatory markers and clinical improvement in a patient with COVID-19 myocarditis after treatment with anakinra. Further clinical studies are underway to confirm the effectiveness and safety of anakinra and other interleukin-1 inhibitors in the treatment of COVID-19.
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5. Glucocorticoid
Glucocorticoids, widely used in the treatment of SARS and MERS, inhibit immune cell activation and cytokine production. However, glucocorticoids also suppress the immune response and the immune system's ability to eliminate viruses. An early study evaluated the use of corticosteroids in COVID-19 and other infectious diseases, and found no evidence that corticosteroids were beneficial. Notably, glucocorticoids were widely used in large quantities for emergency treatment during the SARS epidemic in 2003, leading to the development of femoral head necrosis and pulmonary dysfunction.
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6. Intravenous immunoglobulin
Intravenous immune globulin (IVIG) uses synthetic IgG to carry out its immunomodulatory function. IVIG regulates immune activity through several mechanisms, including blocking the production of proinflammatory cytokines and inhibiting pathogenic Th1 and Th17 differentiation. IVIG has been widely used to treat autoimmune and chronic inflammatory diseases, and is used as an immunotherapeutic agent in cases of hyperinflammatory states caused by infection. Interestingly, although most currently available preparations of IVIG were collected from patients long before the COVID-19 pandemic, it has been found that these preparations may contain antibodies against SARS-CoV-2 antigens, possibly due to cross-reactivity with other coronaviruses. A study by Yun after 28 days. Other studies also report that high-dose IVIG (2gr/kg or 0.3-0.5g/kg) may play an important role in recovery. However, Aljaberi reported that a group of COVID-19 patients treated with high-dose IVIG and hydroxychloroquine had a higher mortality rate, although the reason for this is unclear.
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CONCLUSION
In summary, SARS-CoV-2 induces an excessive and prolonged cytokine/chemokine response in some infected individuals, known as a cytokine storm. The cytokine storm causes ARDS or multi-organ dysfunction, leading to death. Timely control of the cytokine storm in the early stages through measures such as immunomodulation and cytokine antagonism, as well as reducing inflammatory cell infiltration in the lungs, is the key to improving treatment success rates. and reduce the mortality rate of patients with COVID-19.
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Summary and editing: Hai Anh – Phacogen Institute of Technology;
(Biotechnology Engineer - Hanoi University of Science and Technology)
Referral:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919105/
https://jlb.onlinelibrary.wiley.com/doi/10.1002/JLB.3COVA0820-410RRR
https://www.medicalnewstoday.com/articles/cytokine-release-syndrome
