Immune response and cytokine storm in SARS-CoV-2 infection: Risk factors,ways of control and treatment

Abstract

In 2020, a deadly pandemic caused by the SARS-COV-2 virus spread worldwide and killed many people. In some viral infections, in addition to the pathogenic role of the virus, impaired immune function leads to inflammation and further damage in internal tissues. For example, coronavirus in some patients prevents the stimulation of the acquired immune system. Therefore, innate immunity is over-stimulated to compensate, followed by the overproduction of inflammatory cytokines and cytokine storm. Various underlying factors such as age, gender, blood pressure, diabetes, and obesity affect cytokine storm. It seems that cytokine storm is one of the leading causes of death among COVID-19 patients, and providing that this storm is detected and controlled in time, it can reduce the mortality of COVID-19 patients. This article aims to investigate the immune system response to COVID-19, various factors associated with cytokine storm, and its treatment. In the current situation, in parallel with the progress made in the field of vaccination, it is necessary to carefully examine the various dimensions of the immune system in response to the COVID-19 virus to seek a suitable treatment strategy to save the lives of patients in intensive care units

Keywords

Immune response SARS-CoV-2 cytokine storm treatment

Corona virus-2 (SARS-CoV-2) characteristics

As of 20 April 2020, an epidemic of severe acute respiratory infection, the Corona Virus-2 (SARS-CoV-2), has infected 2.5 million people worldwide, killing more than 165,000.^1–5 Generally, studies have shown that more than 12% of COVID-19 virus transmissions occur before the clinical symptoms in infected individuals.^6–8 This virus is transmitted through coughing and sneezing via respiratory droplets.⁹ Also, studies could isolate SARS-CoV-2 from the patients’ feces, which indicates the possibility of fecal-oral transmission of this virus.¹⁰

COVID-19 is a crown-like RNA virus, approximately 60–140 nm in diameter, similar to MERS SARS viruses.^9,11 Angiotensin-converting enzyme 2 (ACE-2) is the primary receptor for the COVID-19 virus. Spike proteins (protein S) on the surface of SARS-CoV-2 bind to the ACE-2 receptors. The expression of ACE-2 receptors on the surface of alveolar epithelial type II cells of cardiac, renal, intestinal, and endothelial cells renders these organs the target of the SARS-CoV-2 virus. Following the virus’s entry and replication, the cell bursts, and the viruses are released. The viruses are detected by antigen-presenting cells (APCs) and delivered to cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells, stimulating innate and adaptive immunity and producing high levels of cytokines and chemokines.^12–14

COVID-19 manifestations and symptoms

The most common symptoms at the early onset of COVID-19 are fever, cough, myalgia, and headache. Nonetheless, less common symptoms include pharyngalgia, shortness of breath, diarrhea, chest pain, fear of cold, and sputum production. The virus also affects the body’s nervous system and causes gastrointestinal and neurological complications.^6,15–18 COVID-19 patients are categorized into mild and severe groups. Mild clinical symptoms and no severe pulmonary involvement were observed among the mild group, whereas the severe group developed respiratory distress and required mechanical respiration.

Moreover, shock and organ failure and the need for hospitalization in the ICU are observed in the severe group. Besides, in the studies performed among 135 hospitalized patients, it was found that 40 cases (29.6%) belonged to the severe group, whereas 95 cases (70.4%) belonged to the mild group. The mean age of all patients was 47 years, and 72 cases (53.3%) were male. Compared to mild patients, severe patients were significantly older (mean age 56 vs 44 years) and had underlying diseases such as diabetes, cardiovascular disease, hypertension, and malignancy.¹⁹

Immune response to COVID-19

Ideally, the immune system provides a suitable and balanced response, leading to resistance against invasive microorganisms and allows the host to survive the infection. In many infections, the coordinated production of inflammatory cytokines is a natural consequence of the innate and acquired responses to control the disease.²⁰ It appears that when the body is unable to respond to the virus appropriately, continuous inflammation due to the innate immunity and overproduction of proinflammatory cytokines leads to Adult Respiratory Distress Syndrome (ARDS) and extensive tissue damage.²¹ Typically, cytokines attempt to protect the host’s body, nonetheless, sometimes cause an imbalance in the immune system, which eventually leads to ARDS and several organs’ failure.²² Current knowledge about COVID-19 suggests that the immune system plays a vital role in determining the severity of the disease.²³

COVID-19 virus enters the cell via the enzyme ACE-2 and is sensed by toll-like receptor 7 (TLR7) in endosomes. Activation of TLR7 leads to the production of IFN-α, TNF-α, and the secretion of interleukins IL-12 and IL-6. This leads to the formation of CD8 + T cells and, through CD4 + helper T cells, to the formation of B cells and the production of antibodies. This adaptive immune response controls viral infection.^24–26,21 SARS-CoV-2 occupies ACE-2 receptors on the cell surface and reduces its expression, followed by an increase in angiotensin-2 (AngII). AngII type 1 angiotensin receptors can induce TNF‐α and soluble form of IL‐6Ra (Sil‐6Ra) (Soluble form of the IL-6 receptor) through breaking metalloprotease down. IL-6 binds to SIL-6R via (Glycoprotein) gp130 to form the compound IL‐6‐Sil‐6R, activating signal transducer and transcription activator 3 (STAT3) in non-immune cells. IL-6 not only binds to SIL-6R for cis‐signaling but can also bind to membrane‐bound IL‐6 receptor (MIL-6R) via gp130 for trans‐signaling. This can lead to pleiotropic effects on acquired and innate immune cells and thus cause cytokine storms.^22,27–29

Innate immunity and COVID-19

Inflammatory cytokines

Inflammatory cytokines such as IL-6, IL-8, IL-1β, TNF-α, IFNƔ-induced protein10 (IP-10), granulocyte-macrophage colony-stimulating factor (GM-CSF), and chemokines (CC motif) ligand 2 (CCL2), CCL-5, and CCL3 are usually produced by macrophages, mast cells, endothelial and epithelial cells during the innate immune response. In people with COVID-19, due to the dysfunctional acquired immunity, innate immunity causes a cytokine storm and the attraction of inflammatory cells such as neutrophils and monocytes into lung tissue, eventually leading to edema, reducing gas exchange in the alveoli, and leading to ARDS through overproduction of inflammatory cytokines.^21,30 Studies have shown that elevated IL-6 significantly affects the onset of cytokine storm.²² IL-6 plays a pleiotropic role in the immune system and is crucial for the formation of TH17 and follicular helper T cells. However, IL-6 can block cytotoxic CD8 + T cells by inhibiting IFN-Ɣ secretion. In addition, IL-6 can impair the cell-induced antiviral response in the cytokine storm by inducing the suppressor of cytokine signalin 3 (SOCS-3) and increasing PD-1 expression.^21,31 IL-6 is an essential target in cytokine release syndrome (CRS) subsequent to cell therapy and can lead to vascular leakage, complement and coagulation cascade activation, and CRS.³² Among the cytokines, IFN-γ causes fever, chills, headache, dizziness, and fatigue. TNF-α can cause acute influenza-like symptoms similar to IFN-γ, such as fever, general weakness and fatigue, vascular leakage, cardiomyopathy, lung injury, and acute-phase protein synthesis.^32–36

Macrophage activation syndrome and COVID-19

Clinical and laboratory characteristics of MAS include persistent fever, elevated ferritin levels, serum triglycerides, pancytopenia, fibrinolytic consumptive coagulopathy, and liver and spleen dysfunction. In addition, decreasing the number and activity of NK Cells increases the serum level of the soluble interleukin-2 receptor, soluble CD25 (Scd25), and Scd163. Besides, hemophagocytosis occurs, which means swallowing blood cells such as erythrocytes, leukocytes, platelets by phagocytes, and is a sign of MAS. MAS might also increase the serum level of C-Reactive Protein (CRP).^12,37

Macrophages and neutrophils in COVID-19

SARS-COV-2 infects CD169 + macrophages in the spleen and lymph nodes, causing damage to lymph tissues such as nodal atrophy, and depletion of lymph follicles. CD169 + macrophages also express high levels of FAS, which activate apoptosis-like cell death (ALCD) through FAS/FASL (Fas ligand) interactions. In the study of peripheral blood mononuclear cells, it was found that non-structural proteins (nsp9) and nsp10 of SARS are targeted by NKRF cells to produce IL-6, IL-8. As a result, neutrophils elicit an uncontrolled inflammatory response in the host.²²

Acquired immunity and COVID-19

Lymphopenia is a sign of a defective immune system and occurs in most COVID-19 patients, especially in severe cases. Therefore, it seems that neutrophils and leukocytes may play an important role in amplifying the cytokine storm in addition to other lymphocytes in COVID-19. The level of lymphocytes and subtypes of T cells that play an important role in modulating the immune response may vary depending on the type of virus. Total lymphocyte counts and T cell subsets are reduced in patients with SARS-CoV-2 infection. As a result, SARS-CoV-2 infection can lead to immune system dysfunction by affecting T cell subsets. The levels of helper T cells (CD3 +, CD4 +), cytotoxic suppressor T cells (CD3 +, CD8 +), and regulatory T cells (T-regs) are below normal in COVID-19 patients. T-regs are responsible for homeostasis and immune system regulation by controlling proliferation and proinflammatory function of CD + 4 T cells, CD + 8 cells, NK and B cells.³⁸ Studies have shown that SARS-COV-2 can activate apoptosis and the P53 signaling pathway, which is one of the reasons for the decrease in the number of lymphocytes in this patient. SARS-CoV-2 can rapidly induce the patient’s Th1 cells by secreting inflammatory cytokines such as (GM‐CSF) and IL-6. (GM-CSF) activates proinflammatory monocytes CD14 +, CD16 + to produce large amounts of IL-6, TNFα and tumor necrosis factor, and other cytokines. Membrane-linked immune receptors (e.g., FC and TOLL-LIKE receptors) might contribute to an unbalanced inflammatory response. Also, weak induction of INF-Ɣ may enhance cytokine production.²²

The role of B-cells and antibodies in COVID-19

Activation of extrafollicular B cells, expansion of antibody-secreting cells, and early production of neutralizing antibodies in high concentrations are among the changes in patients with SARS-COV-2. Besides, the number of peripheral blood mononuclear cells (PBMCs) and CD19 + B cells increases in these patients. Deficiency in the germinal center in spleen and lymph nodes has also been observed in these patients. One of the hallmarks of severe COVID-19 is the rapid proliferation of adipose stromal cells (ASC). Elevated ASC activates humoral immunity, which for unknown reasons, neutralizes antibody titers in several isotypes despite prolonging the course of the disease. Suggesting that the humoral immune response is not sufficient against this disease.³⁹ Antibodies participate in neutralization and perform numerous functions through their Fc receptors, including antibody-dependent cell-mediated phagocytosis (ADCP) perform antibody-dependent cell-mediated cytotoxicity (ADCC). These processes eliminate viruses, yet might also increase inflammatory factors. Anti-S1 and anti-receptor-binding domain (RBD) antibodies in hospitalized COVID-19 patients had higher ADCD but lower ADCP compared to outpatients with COVID-19. Higher ADCD caused higher systemic inflammation, while higher ADCP was associated with lower systemic inflammation.

Moreover, studies have shown that higher titers of SARS-CoV-2 neutralizing antibodies make the infection more severe. ADCC against S1- and RBD-coated target cells has also been significantly higher in hospitalized patients than in patients who are not hospitalized. In contrast, ADCP is elevated in patients who are not hospitalized. S1-specific antibodies significantly induce NK cell degranulation and intracellular cytokine production in hospitalized individuals compared to non-hospitalized individuals. In contrast, RBD-specific antibodies significantly induce ADCC in outpatients.⁴⁰

COVID-19 mechanisms to scape the immune system

COVID-19 virus has mechanisms to evade the immune system, which are described below:

Deficiencies in virus clearance

The impairment in the clearance of the virus is the main problem with COVID-19 infection. The virus has some strategies to resist. For instance, SARS-CoV and MERS-CoV can generate double-membrane vesicles without pattern recognition receptors (PRR) and proliferate within them.^12,41

Decrease in the level of Interferon type 1

The other element is the low level of interferon type 1, which is effective in the antiviral response of the immune system. Cellular proteins that detect cellular nucleic acid are produced through the stimulation of interferons. Detection of viral RNA by melanoma differentiation-associated protein 5 (MDA5) is essential for the antiviral responses. Therefore, MDA5 deficiency causes the spread of viral infections. The SARS-COV lateral protein, namely 4a, binds to double-stranded RNA. As a result, it blocks MDA5 function and induces the production of IFN.^42–46,12

Increase in extracellular neutrophils

Neutrophils eliminate harmful pathogens such as viruses, not only through phagocytosis, but also by forming neutrophil extracellular traps (NETS). NETosis is a type of programmed cell death that is distinct from apoptosis and necrosis. Viral RNA and proinflammatory cytokines might cause the formation of NETosis and NETs.^12,47

Pyroptosis

Pyroptosis is an inflammatory and caspase-dependent condition that is part of the antimicrobial response exploiting programmed cell death as a result of infection with intracellular pathogens. It is hypothesized that pyroptosis might also be involved in the pathogenesis of COVID-19 through the rupture of the plasma membrane and rapid diffusion of proinflammatory intracellular substances. Viral replication increases pyroptosis, which may lead to the release of inflammatory mediators. Impairment in iron metabolism is one of the reasons for the high level of free serum in the blood and is involved in inflammation. Recently, it has been reported that cell death due to iron, called ferroptosis, is involved in the pathogenesis of various diseases. In general, viral evasion mechanisms to prevent antiviral immunity associated with genetic or acquired defects in the host might interfere with virus clearance, resulting in MAS and overactivated immunity, leading to ARDS and multiple organ failure.^12,48–50

Risk factors for cytokine storm

Given the mechanisms by which the immune system reacts to COVID-19, and the behavior of the coronavirus against the immune system, one of the most crucial phenomenon in COVID-19 patients is the increase in the production of cytokines that may eventually lead to a cytokine storm. Studies have shown that cytokine storm is affected by various criteria such as old age, gender, diabetes, blood pressure, and obesity. Figure 1

Figure 1.

Factors predisposing to cytokine storm and various treatment methods.

Age

The mortality rate of COVID-19 is higher in the elderly than in the youngsters. One study revealed that 80% of COVID-19 mortality was in people over 65 years, and the disease tends to exacerbate in patients over 80 years of age with a higher incidence.⁵¹ The population of naÏve T cells decreases through aging, while memory T cells constitute an essential part of the T cell population, which means that the ability of the elderly’s immune system to respond to previous pathogens is more preserved than new pathogens. In contrast, large numbers of T cells in children can encounter and identify new pathogens. This may be one of the explanations for mild COVID-19 disease and a low mortality ratio in children compared to the elderly.²¹ Besides, aging reduces the proper function of the systemic and chronic responses of the immune system and leads to low degrees of pro-inflammatory responses, which is called inflammaging. Inflammation is affected by changes in the body during the aging process, such as decreased muscle tissue mass, increased body fat, and obesity. Sexual steroids are vital for modulating the function of the immune system. Testosterone and progesterone are generally anti-inflammatory and, therefore, suppress the inflammatory immune responses. While estrogens are pro-inflammatory at low concentrations, they are anti-inflammatory at high concentrations. Concentrations of sexual steroids rapidly decline in men and women after the first half of life. Thus, COVID-19 is usually mild or asymptomatic in young people with a healthy immune system. Nonetheless, the disease progresses to inflammation and cytokine storms in older adults.⁵¹

Gender

Studies have shown that the mortality rate of COVID-19 is higher in men than women. Perhaps because the rate of innate immune response in women is higher than men during viral infections.¹⁰ Genes related to the immune response on the X chromosome and differences in steroid hormone levels also make a difference. In general, men have a higher distribution of visceral adipose tissue, which is related to pro-inflammatory factors and cytokine storm. The tendency for adipose tissue inflammation in men is associated with the effects of androgens on immune cells. Thus, more prone to inflammation in obese men than in women, as well as the autonomic characteristics of male immune cells, which increase the risk of cytokine storm, are dependent on sexual hormones. Studies have shown that the enzyme gene (ACE2) is located on the X chromosome.

Furthermore, since women have two copies of the X chromosome in their bodies and men have only one copy, this enzyme might be regulated differently in men and women. In addition, Transmembrane protease, serine 2 (TMPSS2), is an endogen receptor target gene that its expression is increased by endogens. In general, TMPSS2 and ACE2 are different in men and women, which can affect the entry of the virus into the cell and the degree of pathogenicity of the virus.⁵¹

Blood group

According to a study, it was found that people with blood type A had higher levels of the ACE2 receptors, resulting in higher rates of SARS-COV-2 infection and mortality. However, it is not yet clear whether this mortality is due to an increased risk of a cytokine storm.⁵²

Metabolic disorders

Blood pressure

High blood pressure is not a single disease and is usually part of a metabolic syndrome that includes abdominal obesity, increased fasting blood sugar, dyslipidemia, and people with type 2 diabetes. Studies have shown that BMI (Body Mass Index) is higher in patients with acute SARS-COV-2 infection who have been transferred to hospital intensive care than other groups. A study of 5700 patients with COVID-19 in New York found that 57% of patients with COVID-19 had high blood pressure. In contrast, it was found that people with heart disease (coronary artery disease and heart failure) or respiratory disease (asthma or pulmonary obstruction) were observed in only 18% and 14% of people.⁵¹

Obesity

Samples from obese individuals have shown that the immune system’s response to adipose tissue is chronic and requires T, B, and NKC cells, which secrete cytokines and accumulate M1 proinflammatory macrophages. In addition, obesity and the western diet alter intestinal microbiota and increase intestinal permeability. This is associated with the transport of bacteria and lipopolysaccharides from the intestine to the blood and adipose tissue and the development of endotoxic metabolism, causing meta-inflammation. Meta-Inflammation through IL-6 and other pre-inflammatory factors somehow attenuate the immune system against SARS-COV-2. A study of 3615 patients in New York found that obese patients under 60 years old with a BMI between 30 and 34 were twice as likely to be admitted to the ICU as patients with a BMI of less than 30. The association between BMI and the risk of severe coronary heart disease has been shown to increase disease risk by 12% for every 1 unit increase in BMI. Collectively, these studies show that an increase in adipose tissue in obese people exacerbates COVID-19 infection. The effect of obesity depends on the amount of adipose tissue and reduces the capacity of the lungs and proper ventilation. Therefore, obesity exacerbates the inflammatory responses to SARS. In addition, obese people have symptoms of hyperleptinemia. Elevated leptin levels in these people worsens ARDS. Perhaps because leptin has a structure similar to IL-6, leptin receptor, OBR, which is part of the class 1 cytokine receptor and includes IL-6 receptor. Leptin acts as a potent inflammatory cytokine and stimulates the innate immune response by increasing monocytes, macrophages, neutrophils, and enhanced chemotaxis. Leptin also stimulates the production of IL-6 by epithelial cells in the human airways, thereby exacerbating inflammation. Eventually, leptin binds to the leptin receptors on human fibroblast cells, which increases the production of proinflammatory cytokines such as IL-6 and airway-involved chemokines such as IP-10, CC motif chemokine 11 (CCL11)/eotaxin, CCL2/monocyte chemoattractant protein 1 (MCP-1), ((CXC motif) ligand 8) CXCL8/IL-8, and CXCL10.⁵¹

Diabetes

Studies conducted in April 2020 on COVID-19 patients showed that diabetes had tripled the risk of requiring intensive care. It is not yet clear why diabetes exacerbates the condition of patients with COVID-19. Indirect evidence suggests that improving glycemic control plays a vital role in controlling patients with COVID-19. In a study conducted on 1300 hospitalized French patients with COVID-19 and type 2 diabetes, it was found that there was no association between the worsening of COVID-19 and diabetes in people who had been controlling their diabetes for a long time.⁵³ In general, studies have shown that an increase in the level of inflammatory cytokines has been observed in patients with COVID-19 with increased blood sugar levels. On the other hand, patients consuming hypoglycemic drugs such as metformin, insulin, or glitazones due to their anti-inflammatory and pleiotropic effects such as hypoglycemia, weight loss, insulin resistance, and inhibition of pathogenic mechanisms improve the condition of patients infected with SARS-COV-2.⁵⁴

AKR1B10 gene

Excessive expression of AKR1B10 gene is associated with increased expression of genes producing inflammatory cytokines and inflammatory response. Thus, AKR1B10 protein is a key protein in the production of inflammatory cytokines and inflammatory responses. Studies have shown that AKR1B10 protein is increased in the lungs of people with covid 19 by the production of inflammatory cytokines and ARDS and lymphopenia are associated⁵⁵

Treatment

It seems that cytokine storm is one of the leading causes of mortality in COVID-19 patients. Therefore, it is possible to reduce the mortality of patients by treating and controlling the cytokine storm. The followings are some of the treatments used to control the cytokine storm. Figure 1

Corticosteroids

It suppresses the immune system response, and studies have shown that consuming them delays the clearance of the virus, resulting in increased virus levels and mortality. It is mainly prescribed for patients with severe clinical conditions and coronavirus types such as SARS and MERS. In two studies, it was shown that the use of this drug not only was not beneficial for the patients but also increased the mortality in high doses. It is not yet known whether using this drug is beneficial for chronic patients with COVID-19.^38,53 For example, dexamethasone is a class of corticosteroids. In one study, 2104 patients with COVID-19 received dexamethasone, and 4321 received routine care. After less than 28 days, 482 people from the first group and 1110 people from the second group died. It was found that the difference in mortality between the two groups was related to the rate of ventilator use. In general, the mortality rate in patients who required mechanical ventilation and received dexamethasone was lower than in those who did not receive the drug.⁵⁶

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) can activate passive immunity and the anti-inflammatory process and regulate the immune system, increasing patient life expectancy. For example, the IgG molecule blocks cell-cell interactions with cell surface receptors such as CD95/CD95 ligands. Anti-idiotypic antibodies perform neutralization of autoantibodies under the supervision and control of T-regs while blocking the immune complexes to reduce the binding of receptors. To exert immunomodulation function after the combination of prednisolone with IVIG, the level of inflammatory cytokines and the virus decreases.^22,38

Janus Kinase Inhibitors

It can reduce inflammatory cytokines and also diminish the virus' ability to infect cells. (JAK) inhibitors can inhibit the production of IFN‐α, which helps the body fight the virus.²² As a result of interference with the JAK/STAT signaling pathway, JAK inhibitors have many effects on different types of molecules, including interleukins (IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL, IL-9, IL-10, IL-12, IL-15, IL-21, IL-23), IFN- (α, β, γ) and growth factors (GM-CSF, TGF-β (Transforming growth factor-beta), Erythropoietin, and thrombopoietin. JAK inhibitors are currently used to treat Rheumatoid Arthritis (RA) and Psoriatic Arthritis. Numerous proinflammatory cytokines involved in cytokine storm during the COVID-19 may be inhibited by JAK.³⁸

Antibodies

The utilization of plasma from patients undergoing the recovery after COVID-19 19, also known as inactive antibodies, is used to treat patients with advanced disease. This method uses the plasma of those who have survived COVID-19 infection. Antibodies that neutralize the virus are extracted in this method. These antibodies are available and active immediately after the injection, nonetheless only for a limited time. Anti-IL-6 monoclonal antibodies are the other beneficial choice of treatment. Moreover, another IL-17 inhibitor (squokinomab) (Novartis) was used as a specific treatment for severe patients with COVID-19 to control Th17 activation.³²

Interferons

The use of IFN leaves little impact on reducing the rate of virus replication in the early stages of the disease. Moreover, in case of delay in consuming this drug, it will not be helpful. The use of IFN-αβ receptor blockers or antagonists can be considered an approach to avoid excessive inflammatory reactions in the late stages of severe infection. Because SARS-CoV and MERS-CoV mainly infect the airway epithelium, the cells and IFN-γ stimulate the expression of antiviral genes. Therefore, IFN-γ may be an option in treating COVID-19 infection without over-stimulating the immune system.³²

Inhibition of oxidized phospholipids

Oxidized phospholipids cause acute lung damage by increasing the production of cytokines/chemokines from lung macrophages. Since the corona virus can cause acute lung damage and increase OxPL production in the lungs, OxPL suppression strategies using Eritoran (BOC Sciences) Or other similar compounds may be helpful in controlling COVID-19.³²

Sphingosine-1-phosphate receptor-1 agonist therapy

Signal transmission by the receptor Sphingosine-1-phosphate receptor-1 (S1P1) in the endothelial cells of mice infected with the influenza A virus is involved in the pathogenesis of inflammatory responses. S1P1 ligand reduces inflammatory cells, releases proinflammatory cytokines/chemokines, and reduces the mortality from influenza A virus. The S1P1 ligand may be used as a potential treatment for COVID-19-infected individuals to limit the cytokine response.³²

PD-1 checkpoint inhibitor

Generally, studies have shown that defective activity and loss of T-cells in patients with COVID-19 might be one of the causes of mortality, which can be prevented by prescribing PD-1 Checkpoint-Inhibitor(53).

Mesenchymal stem cells

MSCs are the source of immune system cells and can inhibit abnormal T lymphocytes, macrophages, and the secretion of inflammatory cytokines. MSC treatment significantly reduced mortality in patients with AR7 due to H7N9 without any side effects. Treatment with MSC can quickly reduce the symptoms of the disease without any side effects. Although side effects of MSC have been rarely reported, further investigations are required to confirm the safety and efficacy of this treatment.²²

Colchicine IL-6 antagonists

IL-6 receptors are expressed in almost all immune system cells, and IL-6 performs as a major player in the proliferation and differentiation of immune cells in healthy individuals.

Tocilizumab (TCZ) is a recombinant compound. The human IL-6 receptor ligand, which overlaps with IL-6, binds to its receptor and blocks the signaling.⁵⁷

Traditional Chinese medicine

Traditional Chinese medicine (TCM) plays a crucial role in the latest SARS epidemic. Several studies have represented that including TCM to the western drugs can shorten hospitalization, reduce symptoms, and mortality (in critically sick patients), as well as reducing the prevalence and adverse reactions in SARS. Compared to the control group (which used only Western medicine), a combination of TCM and western medicine showed benefits in reducing symptoms and preventing COVID-19. Artemisinin can be extracted from Artemisia annua and an antimalarial agent that is one of these drugs. Studies have shown that Artemisinin family extracts can control cell function and innate and acquired immunity, the anti-inflammatory process, as well as modulating the immune function. The Artemisinin family functions against infectious diseases and autoimmune diseases, and the Artemisinin family shows differences in immune regulation compared to hydroxychloroquine. The researchers concluded that artemisinin regulates the level of proteins such as the nucleotide-binding oligomerization domain (NOD), the leucine-rich repeat (LRR), and the pyrin domain, which include (Nod-like receptor protein 3) Pro 3 (NLRP3) and caspase 1 in macrophages. The post-treatment period has also observed decreases in proinflammatory cytokines such as IL-1β and IL-18.⁵³

Aspirin

Aspirin becomes a non-steroidal anti-inflammatory drug (NSAIDS). These drugs can inhibit the activity of the (cyclooxygenase) COX enzyme and prevent the formation of (prostaglandin)PGS. As a result, they prevent symptoms such as inflammation, fever, and pain.⁵⁸ Studies on 112,269 patients have shown that in patients with COVID 19 and hospitalized،

Aspirin on the first day of hospitalization reduces the risk of death. Patients over 60 years of age and people with underlying diseases are more affected by this drug.⁵⁹

Result

The corona virus appears to be different from other viruses, and the immune system cannot be controlled and eliminated as quickly as other viruses. One of the most important reasons for this is that in addition to the effects that the virus has directly on cells, it interferes with the immune system, causing the immune system to leave more damage to the body. One of the important events in infected people is the cytokine storm. This storm occurs due to the lack of specific immune stimulation and overstimulation of innate immunity, leading to damage to the body, organ failure, and death. It has also been found that underlying factors such as diabetes, blood pressure, obesity, age, gender are associated with an increased incidence of cytokine storm and mortality. It seems that in the treatment of COVID-19, in addition to antiviral drugs, we need drugs that regulate the activity of the immune system and counteract the cytokine storm. Perhaps in the future, the drugs used to treat COVID-19 will be Immune system-specific drugs, and the use of antiviral drugs alone will not have much effect on disease control.

Conclusion

It seems that if we want to find a successful treatment for coronavirus, in addition to antiviral drugs, we must use drugs that regulate the immune system. Also, if the immune system in people with coronavirus does not enter the cytokine storm phase, the disease can be better controlled. Not all COVID-19 patients enter the cytokine storm phase, and some underlying factors might increase its occurrence. Therefore, treatments used to control cytokine storms will only be effective for patients who have entered the inflammatory phase, and the use of this treatment in patients who have not entered the inflammatory phase can be very effective in the progression of the disease. Therefore, in addition to the need for appropriate drugs to control the cytokine storm, the correct and timely diagnosis of this storm will effectively reduce mortality.

Footnotes

Acknowledgements

The authors would like to thank all the staff of the Tarbiat modares University of Medical Sciences, Iran.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Hamid Chegni

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