key: cord-0897342-de3cyn2u
authors: Sunkara, Haripriya; Masudur Rahman Dewan, Syed
title: Coronavirus disease-2019: A review on the disease exacerbation via cytokine storm and concurrent management
date: 2021-08-06
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2021.108049
sha: 31b903f94e6870d6fe1a4df01b925e94f7e10509
doc_id: 897342
cord_uid: de3cyn2u

Setting up treatment strategies is the highest concern today to reduce the fatality of COVID-19. Due to a very new kind of virus attack, no specific treatment has been discovered to date. The most crucial way to dominate the disease severity is now the repurposing of drugs. In this review, we focused on the current treatment approaches targeting the crucial causative factors for the disease burden through cytokine storm or cytokine release syndrome. Several vaccines have been developed and have been applied already for prevention purposes, and several are on the way to be developed, although the effects and side effects are under observation. Presently, regulation of the immune response through intervention treatment methods has been adjusted on the basis of the COVID-19 severity stage and generally includes vaccines, immunotherapies including convalescent plasma and immunoglobulin treatment, monoclonal antibodies, cytokine therapy, complement inhibition, regenerative medicine, and repurposed anti-inflammatory and immune-regulatory drugs. Combination therapy is not acceptable in all respects because there is no concrete evidence in clinical trials or in vivo data. Target-specific drug therapies, such as inhibition of cytokine-producing signaling pathways, could be an excellent solution and thus reduce the severity of inflammation and disease severity. Therefore, gathering information about the mechanism of disease progression, possible goals, and drug efficacy of immune-based approaches to combat COVID-19 in the context of orderly review analysis is consequential.

In late December 2019, the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) outbreak initially started in the Hubei province of Wuhan, China [1] . It created great havoc in March 2020, and therefore, the World Health Organization (WHO) declared that, following [3] .

Coronavirus belongs to the order Nidovirales and subfamily Coronavirinae. Coronavirinae is further categorized into alpha, beta, gamma, and delta Coronavirus based on serology where SARS-CoV-2 belongs to the beta coronavirus group [4, 5] . Coronaviruses are zoonotic. Based on past evidence and available literature, it has been hypothesized that coronaviruses are transmitted to humans because of eating bats, and they abruptly spread within humans through respiratory droplets and secretions where the virus remains viable for at least 3 hours and also through direct contact [6] . Asymptomatic carriers can also transmit viruses depending on factors, including viral load in their upper respiratory tract. Its incubation period ranges from 1 to 14 days, then symptoms appear [4, 7] . SARS-CoV-2 is associated with high rates of mortality and fatality. It causes fatality in infected individuals by causing respiratory failure, complicated by shock or multiorgan failure.

Coronavirus-induced respiratory complications are mostly attributed to its unique host cell entry mechanisms and pathogenesis associated with flush of cytokine release into the body, leading to cytokine storm [8] .

In this review, we explored the detailed mechanism of viral cell entry and particularly cytokine storm intending to focus on the importance of repurposing drugs that target viral cell entry mechanisms and drugs that inhibit signaling pathways responsible for the release of cytokines as well as drugs that block potent cytokines involved in cytokine storm with a brief view on clinical trials undergoing on the same.

The actual history of the human coronavirus began around 1960, when two unusual types of viruses, B814 and 229E, were discovered by Tyrrell and Bynoe, Hamre and Procknow respectively at different time frames in samples obtained from the respiratory tracts of people with colds. Later, Tyrrell, along with a group of virologists, identified that these were similar to those of the bronchitis virus of chickens, mouse hepatitis virus, and gastroenteritis virus of swine, and named this new group of viruses as the Corona virus (corona denoting the crown-like appearance of the surface projections) and later this group of viruses was officially accepted as a new genus of viruses [9] . These coronaviruses cause a wide range of diseases in both animals and humans. Several and viral load of this variant is higher than the existing variants [11] .

SARS-CoV-2 is an enveloped spherical virus. Its envelope is formed by the interaction of three glycoproteins-Envelope (E) protein, Membrane (M) protein, and Spike protein (SP) [12] . The SP is club-shaped and protrudes out of the viral envelope, giving it a crown-like appearance under an electron microscope. SP carries the main antigenic epitopes recognized by antibodies and is responsible for host infection and membrane fusion [13] . The internal core of the virus contains a positive-sense single-stranded RNA (+ssRNA) [4] .

The virus enters the cell by using SP. It uses angiotensin-converting enzyme 2 (ACE-2) receptors on the surface of targeted cell membranes as cellular receptors enter the cells and then the life cycle of the virus begins [14] . Zhao et al. reported that SP contains two subunits, S1 and S2. S1 contains a receptor-binding domain (RBD), which is responsible for initial contact of the virus with the host cell's surface, and S2 for membrane fusion and intracellular trafficking inside the host cell [15] . The SP will be in metastable prefusion conformation initially. When the S1 subunit of SP fuses with the host cell receptor, it undergoes hinge-like confirmation and enters the host cell [16] . 6 Although, the principal receptor and cofactor for SARS-CoV-2 cellular entrance have been identified as ACE-2 and transmembrane serine protease 2 (TMPRSS2 [17, 18] , recent evidence suggests that basigin (CD147) functions as a receptor and furin functions as a cofactor in SARS-CoV-2 pathogenicity [19, 20] . In addition, the VEGF-A receptor neuropilin 1 (NRP1) has also been shown to be the host factor receptor for furin-cleaving SARS-CoV-2 spike peptides recently [21, 22] . Infectivity and entrance are reduced when NRP1 is blocked, and NRP1 reliance is lost when the furin location is changed. In a hamster pathogenesis disease model, deletion of the furin peptide in spike causes decreased replication in Calu3, increased replication and better fitness in Vero E6, and mitigated illness [21, 22] . Viral entry occurs by two mechanisms-the non-endosomal pathway and receptor-mediated endocytosis [23] . In the non-endosomal pathway (Fig. 1A) , SP of virus interacts polarly with ACE-2 unlocking receptor-binding domain (RBD) of S1, which is essential for the fusion of the virus to the host cell membrane. After fusing the virus releases its genome into the target host cell [24, 25] .

In receptor-mediated endocytosis (Fig. 1B) , the interaction of SP with ACE-2 leads to the formation of virus -ACE-2 endosome and endocytosis of virus along with ACE-2 occur, when H+ influx occurs in the endosome, then host cell proteases mainly Cysteine protease cathepsin of lysosomes (Cathepsin L) gets activate and, cleaves SP and facilitates viral fusion into host cell leading to +ssRNA release [25, 26] .

Along with viral SP, ACE-2 of the host should also undergo cleavage in order to bind with SP.

Many studies reported that the internalization of ACE-2 into the host cell gives positive feedback to a host cellular protease called disintegrin and metallopeptidase domain (ADAM17). TMPRSS2 along with ADAM17 cleaves ACE-2 enzyme ectodomain into the extracellular space thus further 7 facilitating viral entry into the host cell [23] . Following their entry, the viral genome translates into two polyproteins (pp) 1a and ab that further undergo proteolysis by the main protease Mpro and Papain-like protease PLpro to yield 16 nonstructural proteins (16 NSPs) [27] . These elements constitute the RNA replicate-transcriptase protein complex and control viral +ssRNA replication and transcription. Out of 16 NSPs, NSP-12 acts as RNA-dependent-RNA polymerase (RdRp) [28] through which +ssRNA replicates and translates into structural and nonstructural proteins.

Subsequently, these protein elements, RNA genome, and nucleocapsids assemble in the host cytoplasm and thereby mature viral particles released from the host cell via its internal membrane through exocytosis [5] .

Milanetti et al., by their research, explained that SARS-CoV-2 has dual entry points i.e., along with ACE-2 receptor, S protein also uses Sialic acid as an entry point [29] . As very less literature is published till now on viral utilization of Sialic acid as an entry point, advanced research is being suggested in this aspect. 

Cytokines are the protein molecules released by lymphocytes, leukocytes, dendritic cells, T-helper cells (Th) cells, endothelium, epithelium, and leukocytes, play important roles in the inflammatory cascades (Table 1) . Prolonged and major fatality in COVID-19 has been manifested due to cytokine storm [30, 31] , which can be described as the release of several pro-inflammatory cytokines from hyperactive/dysregulated host immune system at levels that are injurious to host cells [32] . Cytokine storm can be broadly defined by three criteria-increased levels of circulating cytokines, acute systemic inflammatory symptoms, and cytokine-driven organ dysfunction [33] .

Cytokines that worsen inflammation are called pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IL-17, IFN-α, INF-β, IFN-γ), and those which serve to reduce inflammation and promotes healing are called anti-inflammatory cytokines (IL-12, IL-10) [34] . Under normal conditions, cytokines are essential to fight against infection, but in the case of a cytokine storm, excessive release of cytokines and chemokines causes infiltration of immune cells and thereby aggravation of inflammation leading to multi-organ complications [35] .

As per the literature, plasma levels of COVID-19 patients showed elevated levels of proinflammatory interleukins particularly IL-1, IL-2, IL-4, IL-6, IL-7, IL-13, IL-17, colonystimulating factors (G-CSF, M-CSF, GM-CSF), Interferon γ inducible protein 10 (IP-10), interferons (IFN-γ, IFN-α), chemokines (CCL2, CCL3, CCl5), tumor necrosis factor (TNF-α), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) [36] [37] [38] .

Drugs targeting the cytokines may play a potential therapeutic role in the treatment of cytokine storm and complications that may be upregulated due to COVID-19. [34, [38] [39] [40] [41] [42] [43] [44] . cytokines [45] . Hyperactivation of these signaling pathways is responsible for cytokine storm in

Along with the pro-inflammatory cytokines released by innate immunity, Antigen-presenting cells

cytotoxic cells. These APCs and Th cells also produce cytokines contributing to cytokine storm [46, 47] .

As inflammation and cytokine storm are the major contributors to COVID-19 pathophysiology and post-COVID complications, in our review we focused on signaling pathways responsible for cytokine storm. As hyper-responsiveness of these pathways is responsible for inducing cytokine storm, drug therapies targeting these pathways along with antiviral agents may play a key role in the therapy of COVID-19.

p38 MAPK is an intracellular signaling molecule involved in pro-inflammatory cytokine production. This pathway activates when growth factor receptors (GFR) or Angiotensin-II receptors (AngIIR), activate the Grb2-SOS complex which interacts and activates membranebound Ras molecule [46] . The activated Ras molecule stimulates Raf (MAPKKK), which then activates MEK1/2 (MAPKK). MEK1/2 thereby activates ERK1/2 (MAPK) which finally activates terminal molecules responsible for the initiation of transcription of cytokines and other inflammatory mediators [47] (Fig. 2 ). AngII along with vasoconstriction is also responsible for pro-inflammatory cytokine production through activation of p38 MAPK. AngII is converted to Ang 1-7, in the presence of ACE-2. This Ang 1-7 binds to Mas receptors, which inhibits p38 MAPK and thereby inhibits cytokine release from AngII [48] . In the case of COVID-19, because of downregulation of ACE-2 receptors, production of Ang 1-7 decreases, and thereby activation of p38 MAPK occurs by upregulated levels of AngII and thereby increased levels of proinflammatory mediators. Apart from AngII, and growth factors some upstream PRRs and the inflammatory cytokines such as IL-1β, and TNF-α, also stimulates phosphorylation of p38 MAPK leading to activation of transcriptional factors which further mediates inflammatory responses [42] . ORF7a, and N proteins of SARS-CoV-2) [49] . Many factors such as cytokines, viral RNA, and other particles stimulate IKK which thereby leads to degradation of IκB by the proteasome and induces the NF-κB transcriptional pathway [49] . NF-κB, after activation, translocates into the nucleus and induces transcription of pro-inflammatory cytokines, chemokines, adhesion molecules, and co-stimulatory molecules that activates innate and adaptive immunity [35, 50] .

Several cell types have been reported to be affected/activated by the SARS-CoV-2 such as the epithelium of the respiratory tract, endothelium linings, macrophages, mast cells, peripheral mononuclear cells such as monocytes, dendritic cells, and T-cells [20, 51, 52] . The NF-κB signaling has been identified as the major pathway for the pro-inflammatory cytokine/chemokine response caused by SARS-CoV-2 infection in several recent studies [20, 51, 52] . In human bronchial epithelial cells, SARS-CoV-2 spike protein subunit 1 (S1) was found to cause significant levels of NF-κB activation, production of pro-inflammatory cytokines/chemokines such as IL-1, TNF-α, IL-6, and CCL2/MCP-1, and moderate epithelial damage. S1 interaction with the human ACE-2 receptor was needed for NF-κB activation. S1 had greater activity in NF-κB activation than SARS-CoV-S1, which is likely due to the increased binding affinity of S1 to the ACE-2 receptor [53] . In the COVID-19 patients, cytokines/chemokines such as IL-1β, CCL2/MCP-1, CCL3, cells leading to activation of downstream NF-κB, and/or MAPK pathway and thereby release of pro-inflammatory cytokines and reactive oxygen species, which is responsible for host cell damage [57, 58] . Drugs targeting this pathway may inhibit the activation of NF-κB signaling pathways, which is well-recognized as the major transcriptional factor to produce pro-inflammatory cytokines/chemokines (Fig. 3) . 

As the complement system acts as the interplay between innate immunity and adaptive immunity, it also activates several immune cells and pro-inflammatory cytokines. The anaphylatoxins, C3a

and C5a act by binding to C3aR, and C5aR respectively, and activates neutrophils, macrophages, mast cells, Lymphocytes, and basophils; thereby leading to the release of pro-inflammatory cytokines/chemokines [70] . C3a and C5a are formed by cleaving C3 and C5 by convertases or serine proteases. They seem to be responsible for COVID-19 related lung injury and blood levels of patients with ARDS are detected with C3a and C5a [71] .

Currently, COVID-19 therapy mostly relied on Food and Drug Administration (FDA) approved drugs. Repurposing of drugs that inhibit cytokine signaling pathways and viral entry increases therapeutic options for COVID-19.

To date, naturally available products Nobiletin, Curcumin, Resveratrol, are found to inhibit the NF-κB pathway [72] [73] [74] [75] , and clinical trials are ongoing, although the role of these drugs at molecular levels of the NF-κB pathway is still unknown [76] [77] [78] [79] [80] . The previous report indicates that emetine, fluorosalan, sunitinib, bithionol, tribromsalan, and lestaurtinib inhibit IκBα phosphorylation either reversibly or irreversibly and prevent activation of the NF-κB pathway [81] .

However, concrete studies with double-blind clinical trials are suggested to be carried out before administration to the COVID-19 patients. Although many clinical trials are undergoing on the role of NF-κB inhibitors and IKK inhibitors in cancer therapy, very few studies are conducting on the potential role of these drugs in COVID-19 [82] .

MAPK inhibitors-Losmapimod, Pamapimod, and Semapimod blocks p38 MAPK and downregulates ACE-2 inhibitors thereby decrease the release of pro-inflammatory cytokines, platelet aggregation, and vasodilation [83] . Other drugs that inhibit the MAPK pathway are MEK inhibitors, and they include, Refametinib, Selumetinib, and Trametinib, which can act as potential therapeutic add-ons for treating COVID-19 [64] . Many clinical trials are undergoing on these drugs for the treatment of cancer and other inflammatory drugs, which can be repurposed on COVID-19 (Table 2) . with COVID-19.

Natural surfactant proteins present in the lungs act as innate immunity and removes viruses from the lungs. Literature is saying that lack of surfactants may be one of the responsible factors for viral infection and using these surfactants as therapy may help in removing the virus from bronchi and in inhibiting TLR-4 from activation by viral particles [85, 86] . Therefore, investigating the use 33 of pulmonary surfactants in the therapy of COVID-19 is highly warranted, and therapeutic developments based on this concept may develop drugs against TLR-4 receptors (Table 3) . 

JAK/STAT inhibitors may be administered in treating cytokine storm that may make the disease condition less severe. They may act as a potential therapeutic agent for COVID-19 treatment.

Many clinical trials are currently undergoing on Roxolitinib for its utilization in COVID-19

therapy [89] . Besides, there are some other drugs currently are in the trial as JAK/STAT inhibitors (Table 4 ). 

Drugs that inhibit Wnt/β-catenin pathway are under investigation to treat cancers and other autoimmune diseases as it plays a vital role in immune cell infiltration and regulates the expression of a number of genes essential for immune cell proliferation and differentiation [97, 98] . It is essential to Investigate drugs that may inhibit this pathway in the view of COVID-19. Porcupine-O-Acetyl transferase (PORCN) inhibitors, Secreted Frizzled related proteins (SFRP), FZD antagonist or monoclonal antibodies, β-catenin transcriptional activity inhibitors are under investigation for their role in cancer [99] . Conducting trials on these drugs is essential to develop potential therapeutic targets for COVID-19.

TGF/Smad signaling blockade is finding its significance in lung fibrosis and heart diseases. AS Activation of TGF is the main factor responsible for ARDS, drugs blocking this pathway such as 39 Fresolimumab, Galunisertib [100] , may occupy their role in preventing and treating COVID-19

induced pulmonary ARDS and fibrosis as well as cardiac complications.

Drugs inhibiting the complement system have their scope in treating several immune-related disorders such as Rheumatoid Arthritis, Inflammatory bowel disease, and asthma [101] . Anti-C5monoclonal antibodies such as Eculizumab, C5a receptor blocker Avacopan [102, 103] , and drugs that target C3a and C3a receptors should be widely investigated in terms of COVID-19. Currently,

Eculizumab is under trial to sees its effect in the treatment of COVID-19 patients in the US and France (Table 5 ). posted. [104] the virus with supportive medical care.

During SARS-CoV-2 induced cytokine storm, specific cytokines are being observed in patient blood samples. So, therapeutically it is beneficial to target those specific cytokines in treating and preventing cytokine storm-induced complications, thus several drugs are now in the clinical trials (Table 6 ). patients.

No results posted [106] To study the efficacy and tolerability of [111] 44 duration of viral shedding.

As TMPRSS2 protease plays a pivotal role in the novel coronavirus cell entry by lysing SP and ACE-2 along with ADAM 17. Drugs that inhibit TMPRSS2 can act as a potential treatment in COVID-19 therapy. TMPRSS2 inhibitors can partially block SARS-CoV-2-SP driven cell entry (Fig. 1A) . Nafamostat is already an established drug in treating COVID-19 unrelated conditions such as chronic pancreatitis, and prostate cancer, in many parts of the world [112] . Hoffmann M et al. is the first to provide evidence from their study that blocking of TMPRSS2 by Camostat significantly reduced SARS-CoV-2 infection into lungs [17] . Later Yamamoto M et al., by their quantitative fusion assay reported that Nafamostat is more potentially blocking viral entry when compared to Camostat [113] . Many clinical trials are currently ongoing, to evaluate the more suitability of these agents in treating COVID-19 (Table 7) . posted. [114] To assess the impact of Camostat in COVID-19 disease.

Active, not

Recruiting.

Denmark,

No results posted. [115] Camostat [118] 6. analyzed and proved that Aprotinin significantly inhibits viral entry in culture cells, thus providing evidence that they may play an important role in COVID-19 therapy [72] . Currently, Teicoplanin is under clinical trial to assess its effect against COVID-19 (Table 8) . posted. [122] 

Cytokine storm is a hazardous systemic inflammatory syndrome that involves overexpression of circulating cytokines resulting in immune cell activation, adhesion and transmigration that sets off by monogenic abnormalities, certain drug therapies, pathogen invasion, cancers, and autoimmune states. COVID-19 infection triggers an inflammatory response that includes the release of a huge number of pro-inflammatory cytokines. A number of research examining cytokine profiles from COVID-19 patients found that the cytokine storm was linked to lung damage, multi-organ failure, and a hostile prognosis in serious COVID-19 patients [38, 123, 124] .

Among the proinflammatory mediators IL-1, IL-6, TNFα, and CCL2/MCP-1 are considered as the important cytokines of the innate immune feedback [30, 125] . Principal sources of these cytokines are the macrophages, mast cells, neutrophils, endothelial cells, and epithelial cells [30, 125, 126] .

Overexpression of the complement protein C5a also has been found crucial in the ARDS development in COVID-19 patients [125] . Upregulation of these mediators in the body causes cellular recruitment of the leukocytes especially neutrophils, monocytes/macrophages, and T cells to the site of infection/injury, and consequently damage the vascular endothelium, alveolar cell linings, multiple organs, and finally take towards death. Lung abnormality, especially ARDS is one of the severe health conditions found in the COVID-19 patients [125] . Certain mechanism of development of ARDS in the COVID-19 patients is still under investigation, even then cytokine storm is considered as the principal factors in this disease severity. To use drugs to reduce the disease severity, several approaches should be considered.

Primarily, it was reported that children specially under teenage or teenagers are less affected by the SARS-CoV-2, whereas a recent study on children with inflammatory syndrome with COVID-19, showed elevated levels of expression of IL-1β, IL-6, IL-8, IL-17, and IFN-γ on myeloid cells [127] . In case of management of the inflammatory syndrome in children, resisting the cytokines by administrating anti-inflammatory cytokines (such as IL-37 and IL-38) have been suggested, rather than using other anti-viral drugs as a crucial treatment aspect [128] .

Various immunoregulatory management strategies have been taken in action to resist cytokines mostly found in the COVID-19 patients are IL-6- [113] [114] [115] or IL-1 -receptor antagonists [129] .

Since, several other cytokines have been found prominent in the COVID-19 patients, treatment targeting only a single pro-inflammatory factor has arisen question on the management strategy of the uncontrollable cytokine storm.

In a recent report, crosstalk between IL-6, with the STAT and NF-κB has been manifested in the COVID-19 disease burden [130] . Several recent literatures revealed that the cytokines involved in the COVID-19 mostly are IL-6, IL-18, IFN-γ, IL-15, TNF-α, IL-1α, IL-1β, and IL-2, where none of them singly high concentration gradient to exert the pro-inflammatory effects as well as cellular death. At the same time, when TNF-α along with IFN-γ was administered, that suggested synergistic effects between several other cytokines on the targeted cell levels [131] .

Although, several signaling pathways can be involved in the production of inflammatory cytokines, i.e. JAK/STAT, p38 MAPK, along with other MAPKs [132] , NF-κB signaling pathway has been reported as the central player to produce most of the pro-inflammatory cytokines associated with SARS-CoV-2 infection. Particularly, inflammatory mediators such as IL-1, IL-6, TNFα, CCL2/MCP-1, CCL3/MIP-1α, and -1β/CCL4 are expressed through this pathway during acute stage of COVID-19 patients [54] .

However, JAK signaling pathway inhibition has been considered as an important treatment strategy against cytokine storm in COVID-19 patients [133] , whereas NF-κB signaling inhibition has been found inhibiting dominant inflammatory cytokines/chemokines such as IL-1, IL-6, CCL2/MCP-1, and TNF-α, which are mainly related with the disease exacerbation at cellular level [134] associated with the SARS-CoV-2 infection, rather than cytokines which responds initially to the antiviral treatments e.g., IFN-γ [52, 135, 136] which is primarily JAK/STAT signaling pathway dependent.

Despite the fact that the cytokine storm is not the primary focus of any of the medications commonly used to treat COVID-19, there is increasing evidence that it may have a substantial impact on the disease progression especially in patients with severe condition [137, 138] . In the treatment of COVID-19 patients, several approaches are being followed now a day. The treatment options include anti-viral, anti-inflammatory, anti-cytokine, antibiotic/anti-parasitic, and ACE inhibitors/angiotensin receptor blockers. Most medicines recommended for the treatment of COVID-19 have an anti-inflammatory profile, and the bulk of them would reduce the levels of IL-6 and TNF-α, cytokines that are important targets for COVID-19 drugs [138] . Favipiravir acts to reduce the level of TNF-α [139] ; immunomodulatory antiviral drug IFN-α2b inhibits the replication of SARS-CoV, and increase the level of IL-10 [140] , and reduce the level of TNF-α [141] , Remdesivir lowers the levels of IL-1β, IL-6, and TNF-α [138, 142, 143] ; antineoplastic drug Ruxolitinib reduces the IL-6 and TNF-α level by inhibiting the JAK signaling pathway [89, 144] .

In addition, Azithromycine, Ivermectin, Corticosteroids, Hydroxychloroquines are being used broadly in different countries, based on the previously discovered basic mechanism of action as immunosuppressor or anti-inflammatory effects, and act on reducing levels of IL-1β, IL-6, and TNF-α [138] , concrete data on the effects against the COVID-19 such as multiple in vivo data or clinical trial data have not been revealed to date may be due to lack of time or medical facilities. [145, 146] .

Taken together, in this article we tried to shed a light on the recent management strategies of COVID-19 in the context of cytokine storm induced disease burden. Although, it is considered that vaccines are the best way to prevent the pandemic situation, due to insufficient production and distribution facilities compared with the world demand, prevention are not being gained successfully within a short. At the same time, several reports claiming the side effects about the vaccines in various countries, although concrete proof has not been found, people became confused to take the vaccine for their protection against COVID-19. Therefore, repurposing of drugs has become the major concern to lessen disease severity and mortality, although during convalescent plasma treatment, there was evidence of negative viral loading, proper source/donor is difficult sometimes when needed. Similarly, selecting treatment strategies based on concrete research is recommended. In fine, when treating the SARS-CoV-2 infected patients, proper knowledge on the drug safety and use, drug-drug interaction, side effects, and patient tolerance must be considered as the priority to reduce the post-treatment drug-caused health hazard. 

None declared.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

HS and SMRD collected data, and wrote the manuscript. HS prepared the figures and tables.

SMRD conceptualized and supervised the project. Both the authors approved the manuscript submission.

The authors would like to pay tribute to all front-liners who are devoted and involved in the treatment of COVID-19 patients. They would also like to thank fellow researchers working to combat the current pandemic situation for humankind. 

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IRCT | Effect of curcumin-piperine supplementation on disease duration, severity and clinical signs, and inflammatory factors in patients with coronavirus (COVID-19): A randomized, double-blind, placebo-controlled clinical trial study

The clinical effect of Nano micelles containing curcumin as a therapeutic supplement in patients with COVID-19 and the immune responses balance changes following treatment: A structured summary of a study protocol for a randomised controlled trial

Oral nano-curcumin formulation efficacy in management of mild to moderate hospitalized CORONAVIRUS DISEASE -19 patients: An open label nonrandomized clinical trial

IRCT | Evaluation of the effect of Resveratrol on the effectiveness of antiviral drug regimen in patients with COVID-19

Randomized Double-Blind Placebo-Controlled Proof-of-Concept Trial of a Plant Polyphenol for the Outpatient Treatment of Mild Coronavirus Disease (COVID-19), clinicaltrials.gov

Identification of known drugs that act as inhibitors of NF-κB signaling and their mechanism of action

Nobiletin Inhibits IL-1β-Induced Inflammation in Chondrocytes via Suppression of NF-κB Signaling and Attenuates Osteoarthritis in Mice

p38 MAPK inhibition: A promising therapeutic approach for COVID-19

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Losmapimod in Adult Subjects With COVID-19 (LOSVID STUDY), clinicaltrials.gov

Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties

Phosphatidylglycerol and surfactant: A potential treatment for COVID-19?

A Clinical Trial of Nebulized Surfactant for the Treatment of Moderate to Severe COVID-19, clinicaltrials.gov

Open-label Trial to Assess the Efficacy and Safety of Inhalation Use of the Approved Drug Surfactant-BL (Biosurf LLC, Russia) as a Part of Complex Therapy of Acute Respiratory Distress Syndrome (ARDS) in Patients With

Coronavirus Infection (COVID-19), clinicaltrials.gov

Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial

A Study of Baricitinib (LY3009104) in Participants With COVID-19 -Tabular View -ClinicalTrials.gov

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19

Randomized, Double-blind, Placebocontrolled, Parallel-design Trial of Tofacitinib in Hospitalized Participants With COVID-19 Pneumonia, clinicaltrials.gov

Efficacy and Safety of Tofacitinib in Patients With COVID-19 Pneumonia, clinicaltrials.gov

Investigation of Tofacitinib to Mitigate the Impact of COVID-19 (I-TOMIC) in Moderate SARS-CoV-2 (MODERATE I-TOMIC), clinicaltrials.gov

Ruxolitinib for Treatment of Covid-19

Induced Lung Injury ARDS A Single-arm, Open-label, Proof of Concept Study, clinicaltrials.gov

A Phase-II Clinical Trial for First Line Treatment of Stage II/III Covid-19 Patients to Treat Hyperinflammation, clinicaltrials.gov

Therapeutic potential of targeting the Wnt/β-catenin signaling pathway in colorectal cancer

Wnt/beta-Catenin Signaling and Small Molecule Inhibitors

Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex

Targeting TGF-β Signaling for Therapeutic Gain

Complement-targeted therapy: development of C5-and C5a-targeted inhibition

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

The Complement C3a and C3a Receptor Pathway in Kidney Diseases

SOLIRIS® (Eculizumab) for the Treatment of Participants With Coronavirus Disease 2019 (COVID 19) -An Expanded Access Program for Hospitalbased Emergency Treatment, clinicaltrials.gov

Trial Evaluating Efficacy Of Anakinra In Patients With Covid-19 Infection, Nested In The CORIMUNO-19, clinicaltrials.gov, 2021

Efficacy of Anakinra in the Management of Patients With COVID-19 Infection in Qatar: A Randomized Clinical Trial, clinicaltrials.gov

Multicenter Study on the Efficacy and Tolerability of Tocilizumab in the Treatment of Patients With COVID-19 Pneumonia, clinicaltrials.gov

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

A Phase 2 Randomized, Single-Blind Study of a Single Dose of Peginterferon Lambda-1a (Lambda) Compared With Placebo in Outpatients With Mild COVID-19, clinicaltrials.gov

Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial

The Anticoagulant Nafamostat Potently Inhibits SARS-CoV-2 S Protein-Mediated Fusion in a Cell Fusion Assay System and Viral Infection In Vitro in a Cell-Type-Dependent Manner

CAMOVID : Evaluation of Efficacy and Safety of Camostat Mesylate for the Treatment of SARS-CoV-2 Infection -COVID-19 in Ambulatory Adult Patients -Tabular View -ClinicalTrials.gov

The Impact of Camostat Mesilate on COVID-19 Infection: An Investigator-initiated Randomized, Placebo-controlled, Phase IIa Trial, clinicaltrials.gov

The Potential of Oral Camostat in Early COVID-19 Disease in an Ambulatory Setting to Reduce Viral Load and Disease Burden -Tabular View -ClinicalTrials.gov

A Trial Looking at the Use of Camostat to Reduce Progression of Symptoms of Coronavirus (COVID-19) in People Who Have Tested Positive But Are Able to Stay at Home -Tabular View -ClinicalTrials

Reconvalescent Plasma / Camostat Mesylate Early in Sars-CoV-2 Q-PCR (COVID-19) Positive High-risk Individuals, clinicaltrials.gov, 2021

Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells

Recent Advances in ADAM17 Research: A Promising Target for Cancer and Inflammation

Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients

IRCT | Study of the Efficacy of Teicoplanin on mortality rate of patients with COVID-19 Infection: A randomized clinical trial

Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study

Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19

Clinical Features of Cytokine Storm Syndrome

Complement C5a-triggered differentiated HL-60 stimulates migration of THP-1 monocytic leukocytes via secretion of CCL2

Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection

SARS-CoV-2, which induces COVID-19, causes Kawasaki-like disease in children: role of pro-inflammatory and anti-inflammatory cytokines

How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1

How COVID-19 induces cytokine storm with high mortality

Synergism of TNF-α and IFN-γ triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes

Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19

HiJAKing SARS-CoV-2? The potential role of JAK inhibitors in the management of COVID-19

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis

Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?

Quintans-Júnior, Drug repurposing and cytokine management in response to COVID-19: A review

T-705 (Favipiravir) suppresses tumor necrosis factor α production in response to influenza virus infection: A beneficial feature of T-705 as an anti-influenza drug

An experimental trial of recombinant human interferon alpha nasal drops to prevent COVID-19 in medical staff in an epidemic area, Infectious Diseases (except HIV/AIDS)

IFN-α 2b Increases Interleukin-10

Expression in Primary Activated Human CD8 + T Cells

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

First Case of 2019 Novel Coronavirus in the United States

Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice

Selective JAKinibs: Prospects in Inflammatory and Autoimmune Diseases

A Review on Current Repurposing Drugs for the Treatment of COVID-19: Reality and Challenges, SN Compr