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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 5  |  Page : 41-48

Cytokine storm in COVID-19 and the treatment simulacrum


Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

Date of Submission13-Jun-2020
Date of Acceptance15-Jul-2020
Date of Web Publication13-Aug-2020

Correspondence Address:
Dr. Seyed Mohammad Reza Hashemian
Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_128_20

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  Abstract 


Following the outbreak of the severe acute respiratory syndrome-coronavirus (SARS-CoV-2) in December 2019 at Wuhan, China, it spread through the world rapidly, and this disease was declared as a pandemic by the World Health Organization on March 11, 2020. A high mortality rate has been detected due to this respiratory involvement; this novel virus like the previous ones, SARS-CoV-1, from this family, can lead to lethal pneumonia, acute lung injury, and eventually acute respiratory distress syndrome (ARDS), which was reported in 20% of patients. Surprisingly, this ARDS can have a mortality rate of 40%–50%. As it is known that infection can manifest in a wide variety of symptoms, from a mild respiratory disease to life-threatening ARDS, multiorgan dysfunction, shock, and death, the exact mechanism of this ARDS in COVID-19 pneumonia is not known completely. There are ongoing studies, but the term “cytokine storm” can be a possible clue of the transformation of a mild disease to a lethal one, and also an explanation of this rapid and deadly inflammatory response which take a place in the lungs. Our goal in this review is to express a better definition of molecular and cellular pathways of cytokine storms and also discuss some recent trials of the effect of different classes of drugs on this immunologic and inflammatory pathway of CoV infection. In this study, we have addressed evidences for more efficient immunomodulatory drugs for this vivid storm.

Keywords: Cytokine, COVID-19, SARS-CoV-2


How to cite this article:
Karimi A, Hashemian SM. Cytokine storm in COVID-19 and the treatment simulacrum. Biomed Biotechnol Res J 2020;4, Suppl S1:41-8

How to cite this URL:
Karimi A, Hashemian SM. Cytokine storm in COVID-19 and the treatment simulacrum. Biomed Biotechnol Res J [serial online] 2020 [cited 2022 Jan 25];4, Suppl S1:41-8. Available from: https://www.bmbtrj.org/text.asp?2020/4/5/41/292078




  Cytokine Storm Top


Nowadays, the term “cytokine storm” is prevalent in the explanation of the pathologic pathway of COVID-19 mortality. Despite its expanded use and several ongoing studies and efforts, its exact mechanism is unknown. The first and foremost thing that comes to our mind is the concept of outburst of the immunologic responses and releases of pro-inflammatory cytokines. Our knowledge of the exact factor which starts this vicious cycle is limited, and there is not much understanding about this molecular pathway which leads to this excessive destruction of tissues. The interaction between these cytokines and their effects on each other, will make this even more complicated; this lack of knowledge can make it harder for us to manage and prevent this lethal storm.[1]

There are several families of cytokines which participate in the cytokine storm such as:

  • Interferons (IFNs) which have a major part in initiating the immune system response, which are classified in three groups of types I, II, and III based on their receptor[2],[3]
  • Interleukins (ILs) which are a diverse family of immune system regulators that function primarily in immune cell differentiation and activation[4]
  • Chemokines which constitute the largest family with 44 members and the number is increasing[5]
  • Colony-stimulating factors (CSFs) such as granulocyte macrophage CSF (GM-CSF), macrophage CSF (M-CSF), and granulocyte colony-stimulating factor (G-CSF), which stimulate hematopoietic progenitor cell proliferation and differentiation[6]
  • Tumor necrosis factor (TNF), which is of the highest significance and has an important role in cytokine storm. It is known as a central cytokine in acute viral infections. This component detects increased number of inflammatory factors in autoimmune diseases, which explains why anti-TNF agents are shown to be useful in treating patients with inflammatory bowel disease, psoriasis, and rheumatoid arthritis.[7],[8],[9]


Cytokines are responsible for a proper immunologic response which is crucial for limiting the infection and they are also necessary for our body's defense system. However, the balance between inflammatory cytokines and anti-inflammatory agents is the key which determines whether or not this regulation is appropriate. On the other hand, excess of inflammatory agents can lead to diffuse tissue injuries in different parts of the body, thereby leading to a cytokine storm.

The concept of “cytokine storm” was first used in 1993 in graft-versus-host diseases.[10] Following this, it became more prevalent in articles which describe infectious disease pathologic events such as Cytomegalovirus,[10] Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis,[11] Group A Streptococcus,[12] influenza virus,[13] variola virus,[14] and severe acute respiratory syndrome-coronavirus (SARS-CoV).[15] As soon as when the term “cytokine storm” was used in the explanation of avian influenza in 2005, the concept of cytokine storm gained widespread popularity, which led to an increasing number of articles published on infectious and noninfectious diseases with wider usage of the term “cytokine storm.”.[16] In 2003, again, this concept has gained attention due to its relation with SARS and its high mortality rate and end-organ damages.[17]

When a localized destruction occurs in a body, it causes inflammation and if cytokine storm happens, it starts first localized to the primarily injured tissue, as it is well known that blood flow through the injured site increases and it can carry the pro-inflammatory and inflammatory agents through the body and spread it all over the body.[18],[19]

This syndrome can be manifested clinically with cytopenias (lymphopenia, thrombocytopenia), coagulation disorders (decreased platelets and fibrinogen, also elevated D-dimer), hepatitis (increased aspartate transaminase, alanine aminotransaminase, and lactate dehydrogenase), macrophage, and hepatocyte activation (elevated ferritin level).[19],[20],[21]

The syndrome can injure different tissues and organs and with multiorgan failure, it exacerbates the primary disorder, for example, acute lung injury (ALI). ALI refers to the damage caused by an infection within the lung tissue or other tissues due to the cytokine storm which can be from the alveolar space or systemic circulation.[22] In the mechanism of cellular events of this injury, the destructive inflammatory response occurs in mononuclear cells and neutrophils in the acute phase followed by fibrosis and proliferation in the chronic phase.[23] This local infection and inflammation of lung can spread to systemic circulation and lead to sepsis.

As mentioned above, infection is the common cause of ALI, or more severe acute respiratory distress syndrome (ARDS), influenza, and SARS coronavirus (SARS-CoV)-virus are a well-known pathogen for this event. COVID-19 is a potential cause of ALI and subsequent ARDS.

IL-1 is the most frequent cytokine which is found in the bronchoalveolar lavage fluid of an injured lung.[24] Several studies conducted on the duration of the systemic inflammatory responses have demonstrated that TNF, IL-1B, and the chemotactic cytokines IL-8 and Monocyte Chemoattractant Protein-1(MCP-1) appeared in the acute phase, IL-6 will be more dominant in the chronic phase.[25] Hence, IL-6 is considered a good marker for demonstrating the intensity of inflammatory response.[26]

Can the COVID-19 infection be related to cytokine storm?

The term “cytokine storm” has previously been used to explain the pathologic events in SARS-CoV-1, which is of the same viral family.[15] In order to prove this theory, plasma cytokine levels had been evaluated in patients with COVID-19 infection, wherein IL-6 and pro-inflammatory mediators have been elevated in this group of patients, but when compared to patients with typical ARDS (due to other reasons), these mediators were found to be lower,[27],[28],[29],[30] i.e., they were detected to be 10–200 folds greater in typical ARDS. This finding can be seen confounding with the theory of cytokine storm, but further studies in larger populations are required in order to discover the relation of COVID-19, ARDS, and dysregulated cytokine pathways.[24],[31]

  • In another study of COVID-19 patients, Huang et al. found that IL-2, IL-7, IL-10, G-CSF, interferon-inducible protein 10 (IP-10), MCP-1, macrophage inflammatory protein 1 alpha (MIP-1a), and TNF-α levels correlated with the disease severity, and higher levels of cytokines were found in patients admitted to the intensive care unit (ICU).[32] Also, another study at Diao et al. confirmed the correlation between elevated TNF-α, IL-6, and IL-10 levels and the severity of the disease[33]
  • A retrospective study from Wuhan, China, on 150 confirmed cases of COVID-19 infection showed that the median ferritin level in nonsurvivors of this infection was 1297.6 ng/ml and was detected to be 6114.0 ng/ml in survivors. IL-6 (P < 0.0001) is a predictor of fatality and severe disease; these findings can make the theory of secondary hyper-inflammation due to viral infection more relevant[34]
  • In a published study in JAMA,[35] the disease course of 138 patients was well studied. It was revealed that as the disease progressed and the patients' situation deteriorated, the number of neutrophil counts, D-dimer level, blood urea nitrogen, and creatinine increased and the lymphocyte count decreased, which, in turn, describe that a probable cytokine storm can be the reason of elevated neutrophils which can also lead to activation of coagulation cascades, hypoxia, shock, and acute kidney injury; these findings correlate with the pattern of death of our patients[36]
  • Another clue which can confirm this theory is the similarity of COVID-19 ARDS cytokine profile to sHLH, named “secondary hemophagocytic lymphohistiocytosis,” which is a hyper-inflammatory syndrome. It is defined by cytokine release syndrome, cytopenia, and multiorgan failure,[37] which are mostly triggered by viral infections. These conditions triggered by viral infections, with an elevated cytokine level, can lead to multiorgan failure.[32] Comparatively, sHLH is also known as a spectrum of cytokine storm because they both share the same pathobiological and clinical profile
  • In histopathological studies of lung tissue of COVID-19 patients, alveolar edema, proteinaceous exudate, and patchy inflammatory cellular infiltration had been detected,[38],[39] which can confirm the theory of cytokine storm. Moreover, the subsequent pulmonary inflammation due to this aggressive host immune response[40] cytokine storm is more prevalent when sudden death appears in patients with mild symptoms and even in patients who are recovered considerably[41],[42]
  • In a study of SARS-CoV-infected old nonhuman primates, the death was more relevant to the increased cytokine levels rather than the viral load[43]
  • CoV infects monocytes, macrophages, and dendritic cells. Once these cells are involved, they are activated and start to release inflammatory cytokines and IL-6. IL-6 has a pro-inflammatory effect, a prominent signaling effect, and cis signaling and trans signaling effects, each of which can lead to different pathways[44],[45]
  • This cytokine storm is not only limited to the lungs but also it will damage different body tissues during the infection, for example in kidneys, it can cause renal insufficiency; in peripheral vessels with vasculitis, it can lead to “CoV toes;” and with the involvement of central nervous system, it can cause headache and loss of smelling sensation.[46]


Treatments

We have explained some theories and findings about dysregulation and uncontrolled cytokine activation in COVID-19 infection, which had been mostly happened after the primary viremic phase. With the acceptance of the cytokine storm theory, it is rationale to evaluate immunomodulatory therapies in addition to antiviral therapy and supportive care.

Although the high mortality of this pandemic with no specific treatment led to the search of treatment modalities which can be wisely related to the virus, still there is a lack of evidence. Trials on each drug group should be done, and selecting the group of patients who will benefit more from this drugs and the right timing for applying these drugs can impact on the whole management.

Our main emphasis in this article is on the immunomodulatory drugs from different families and their impact on the cytokines [Figure 1].[47],[48]
Figure 1: Cytokines can be affected by the immune system and various drugs during COVID-19 infection

Click here to view


Immunomodulators

Interleukin-6 pathway inhibitors

In normal circumstances, the level of IL-6 is very low, but right after an injury or infection, it will be rapidly synthesized and enhance the body's immune responses and strengthens the body, but exaggerated release of IL-6 can lead to cytokine storm.[49]

IL-6 is an important element of cytokine storm as it initiates the signaling which can lead to dysregulation of cytokines. Initial studies in China have shown that the severity of the disease will correlate with the level of this IL, so humanized monoclonal antibody against IL-6 receptors such as tocilizumab, sarilumab, and siltuximab are probably be effective based on the biological pathways.

Tocilizumab is an US FDA-approved drug for the treatment of cytokine storm. In a retrospective study in China on 21 patients in the ICU, administration of tocilizumab showed to improve the clinical signs and symptoms, however this drug is not mentioned in the guidelines of China for cytokine storm. However, this drug is indicated to be part of China's guideline “Diagnosis and Treatment Plan of Novel CoV Pneumonia (Seventh trial edition)”.[18],[50] for patients infected with COVID-19 with extensive bilateral lung lesions and detected with high IL-6 levels.

In another study, reduction of oxygen requirement was detected in the 1st day of tocilizumab administration in approximately 75% of patients. In addition, the body temperature of severely ill patients after the administration of this drug dropped to normal within 24 h, respiratory function and oxygenation improved in 75% of patients, the number of lymphocytes increased in 52%, an abnormally elevated C-reactive protein returned to normal in 80% of patients, and computed tomography (CT) lesions decreased in 90% of the patients.[18],[51],[52],[53]

In a retrospective, observational, cohort study conducted in Italy on 1351 COVID-19 patients,[54] a nonrandom group of patients received tocilizumab in addition to a standard care (supplemental oxygen therapy, hydroxychloroquine, azithromycin, antiretrovirals, and low-molecular-weight heparin). The study had some limitations and the study population intended to be treated with additional tocilizumab was not randomly chosen. However, overall, it has been detected that tocilizumab can decrease the need of invasive ventilation and mortality.[54]

Nevertheless, we must consider that tocilizumab with weakening of the immune system can cause opportunistic infections.[55],[56] In a cohort study, approximately one-third of the patients were diagnosed with positive candida culture on respiratory cultures and some herpes simplex activation had been reported.[55],[56],[57]

Interleukin-1 receptor antagonist

Anakinra is a recombinant human Il-1 receptor antagonist; this drug has shown improvement in sepsis patients without any significant adverse effect. As it is known that IL-1B has a crucial role in the dysregulation of cytokines and high levels of cytokines are detected in patients with COVID-19 infection, in theory, it seems to be effective, but there is a long way to confirm this hypothesis.[58]

Janus kinase inhibitors

These drugs inhibit Janus kinase (JAK) enzyme, which can impede JAK_STAT signaling pathways, which will probably block the entry of the virus into the pneumocystis.[59]

Baricitinib is one such drug which is currently used for treating Rheumatoid arthritis (RA), and it has also been detected to have some antiviral effects and reduces endocytosis.[59]

In a study by the Cantini et al.[60] Baricitinib respiratory function and CRP levels significantly improved after 2 weeks when compared to the control group, But with all these more studies are required to evaluate the effect of this drug on COVID-19.[59]

Anti-tumor necrosis factor-α agents

TNF-alpha is a signaling protein which has a prominent signaling effect in inflammatory and cytokine regulation pathways; this agent has been proven to increase survival in sepsis patients.[61],[62],[63] Large amounts of these elements have been identified in COVID patients; only limited trials on adalimumab are available till date and a lot more need to be done.[64]

Interferons

IFNs are a class of proteins that are produced in response to stimuli; they have an antiviral effect and in addition to this, they contribute in the regulation of immune system response to an infection.[65],[66],[67] These antiviral effects include inhibition of viral replication, protein synthesis, and maturation and release of the virus from the host cell.[52],[57] There are three main classes: types I (alpha and beta), II (gamma), and III (lambda).[68]

Previous studies have shown that some CoVs are susceptible to IFN-β-1ain vitro and also in vivo.

In a study, the effect of IFN-β-1a administration in COVID-19 patients was evaluated. In that prospective study, the combination of hydroxychloroquine, lopinavir/ritonavir, and IFN-β-1a on twenty patients showed a noticeable response, which was confirmed by lung computed tomography and chest X-ray, with no adverse effects and mortality detected.[69]

IFN-gamma activates epithelial cells, enhances antiviral effects, and reduces pro-inflammatory activity of IFN-alpha and beta, and decreases the migration of neutrophils to the injured tissue.[70],[71] Taken together, IFN-gamma can be an ideal treatment, but other drug combinations in the regimen at the time of administration has a prominent role. It has been shown that the early administration can improve the clinical state and decrease viral load but without decreasing the mortality rate;[72],[73],[74] in delayed administration, It will not have a better effect than a placebo.[74]

In a study of MERS-CoV patients, administration of remdesivir with IFN-beta showed better antiviral therapy,[75] so combination of remdesivir and IFN-beta would be a good treatment suggestion in COVID-19 patients.[67],[76],[77],[78] Administration of recombinant IFNs in the treatment of SARS-CoV-2, SARS-CoV, and MERS-CoV can be beneficial, due to the prevention of protein synthesis and elimination of virus replication.[74],[79],[80] Overall, IFN-beta has shown more subsequential benefits compared to others.[81]

Corticosteroids

Corticosteroids with anti-inflammatory effects have been used in the management of SARS and MERS. During the SARS epidemic in 2003, administration of corticosteroids showed early improvement such as reducing fever, decreasing lung infiltration, and improving oxygen levels.[42],[82],[83],[84]

They are useful in sepsis-associated ARDS, however in SARS and MERS, they did not improve mortality and also caused prolonged clearance of virus.[47]

On the other hand, the theory of cytokine storm and uncontrolled immunological responses must be the possible reason of this administration, but the adverse effects of this drugs, such as increasing secondary infections, increasing viral load, prolonged clearance of virus, and probably exacerbation of the disease, should be taken into account, which make a huge conflict about the efficacy of this drug in the management of CoV infections.[85],[86],[87]

In a study of Iranian protocol by Jamaati et al.,[88] steroid therapy with high-dose dexamethasone, in the form of Amp dexamethasone 20 mg/day intravenous (IV) for 5 days followed by Amp dexamethasone 10 mg/day IV for 5 days, was applied to all patients independent of their disease severity; This protocol showed positive results based on existing studies.[88],[89]

Another interesting finding is that the time of administration of dexamethasone showed a huge difference. The effect of dexamethasone on patients who had symptoms for more than 7 days appears to be more beneficial, when compared to those had symptoms for less than 7 days. The possible reason could be the importance of immune response in the early stages of infection, which can decrease the viral load, but in later stages, the imbalance between inflammatory and anti-inflammatory responses is the leading problem, which can make corticosteroids a good choice for management at this time.[90] It has also been shown that dexamethasone will improve 28-day mortality in patients who receive invasive mechanical ventilation but not among patients with no respiratory support.[91] It is obvious that patient selection, timing of administration of the drug, and the dosage of glucocorticoids play an important role.[82],[92]

Cyclosporine

Cyclosporine has immunomodulatory effects. It prevents “nuclear factor-activated T-cell” (NF-AT) activation and eventually prevents T cell proliferation. Cyclosporine a dual role in treating T cell-associated autoimmune syndromes and also in preventing organ rejection after transplant, rheumatoid arthritis, systemic lupus erythematosus, and interstitial lung diseases.[93],[94]

It is fascinating that SARS-CoV induces the expression of IL-2 through the activation of NF-AT,[95],[96] which makes cyclosporine a relevant drug for the treatment and prevention of cytokine storm in COVID.

From another perspective, it can prevent lung cell injury through mitochondrial pathway, which is a potential pathway for cell injuries. Cyclosporine can inhibit the mitochondrial permeability transition pore.[93] Another hypothesis is that it can reduced replication of virus.[96],[97]

In another study of cyclosporine administration[98] on patients with allograft renal transplantation, who must receive life long immunosuppressants failure of which could make them susceptible to infections such as COVID-19, it was shown that conversion of low dosage of corticosteroids to a calcineurin inhibitor such as cyclosporine in these patients will improve the clinical profile and faster discharge.

We need more data in order to address the effect of cyclosporine in the management of COVID-19 patients; for this purpose, we have a trial code, IRCT20150107020592N22, which can be reached online.

α-1 adrenergic receptor antagonists

Another possible way to control dysregulated cytokines is with inhibition of adrenergic receptors because it has been detected that cytokine storms are accompanied with a surge in catecholamines.[99]

Catecholamines with exacerbation of inflammatory responses and increasing IL-6 production can be a factor in deteriorating patient statement.[99] Previous retrospective studies have shown that patients with a history of pneumonia, ARDS, or α1-AR antagonists (during the year before hospitalization) are less likely to require mechanical ventilation and are less likely to die.[100],[101]

Colchicine

Colchicine is an immunomodulatory drug used in the treatment of gout, familial Mediterranean fever, and Behcet disease; it has the ability to reduce the production of IL-1[102] and can make this drug a candidate for treating CoV infection. A multicentric trial (colcorona (colchicine COVID)) is evaluating the effect of this drug, which is not reported yet (ClinicalTrials.gov Identifier: NCT04322682).[68],[102]

Blood purification treatments

In blood purification treatments, the pro-inflammatory and inflammatory agents can be removed from blood and the plasma can be exchanged. This prevents a cytokine storm with elimination of the agents from the circulatory system, but more and more trials are needed to prove this finding.[103] In addition, in a case report, continuous renal replacement therapy was applied,[104] which showed promising results.


  Conclusion Top


The new CoV infection can manifest with a wide spectrum from mild or even severe life-threatening lung disease and ARDS. Due to the considerable mortality rate of this new pandemic, there is an urge to evaluate the different mechanisms of injury and death pattern and possible treatments. In this review, we focused on the relation between COVID-19 infection and cytokine storm and possible treatments such as antivirals and immunomodulatory treatments and newer treatments. Uncontrolled cytokines in this infection make the usage of immunosuppressive drugs more important and make the combination of antiviral and anti-immune drugs to be a good choice for treatment; We discuss and evaluate the various mechanisms available for possible options.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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