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VIROLOGY

Cytokine storm is the cryptic killer behind coronavirus disease-2019 infections, review of the current evidence to identify therapeutic options

Alrahmany, Diaaa; Ghazi, Islam M.b

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Reviews in Medical Microbiology: January 2021 - Volume 32 - Issue 1 - p 57-65
doi: 10.1097/MRM.0000000000000242
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Abstract

Background

December 2019 in Wuhan seafood market was the salience of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), symbolized by [coronavirus disease 2019 (COVID-19)], the early reported cases of COVID-19 were linked to consumption of seafood and wildlife animal products [1], followed by dreadful occurrence of mass person-to-person spread across the globe which led the WHO to declare COVID-19 as pandemic. COVID-19 is the seventh novel member of the family of coronaviruses that infect humans and the most recent member of the group 2-β with approximately 70% similarity in genetic sequence to SARS-CoV [2], as well as, sharing the same cellular receptor [angiotensin-converting enzyme II (ACE II)] leading to a comparable viral tropism [3]. Fever, malaise, cough, shortness of breath and severe respiratory distress symptoms of COVID-19 may appear in as few as 2 or as long as 14 days after exposure [4,5].

The COVID-19 receptor binding domain conjugate to the alveolar epithelial extracellular domain of ACE II receptors through a transmembrane protease serine 2 [6], the viral trimer spike protein (S protein) binds to ACE II with 20 folds higher affinity when compared with SARS-CoV [7]. ACE II receptors are widely popularized in body tissues, which could explain the multiorgan dysfunction in critically ill patients. The invasion of the alveolar epithelial cells causes downregulation of ACE II receptors and elevated angiotensin II levels, this over-stimulates angiotensin II type 1a receptors in the lungs, leading to increased capillary permeability and pulmonary oedema, which consequently aggravates dry cough, extreme fatigue, lung inflammation, and damage.

Objective

The objective of this article is to review the involvement of inflammatory mediators in cytokine storm syndrome (CSS) and highlight the possibility of targeting the pivotal molecules in the process with therapeutic agents already available (drug repurposing) or provide insights for near future research. All with ultimate objective of minimizing morbidity and mortality with COVID-19 infections.

The cytokine storm syndrome

Coronaviruses trigger an excessive aberrant life-threatening immune response in alveolar epithelial cells manifested as hypercytokinemia ‘CSS’ [8]. CSS is a predictor of severity of illness and COVID-19-related mortality rate in addition to severe infections caused by older members of coronavirus SARS [9] and Middle Eastern Respiratory Syndrome (MERS) [10], as well as H5N1 [11] and H7N9 [12] influenza. The profound lung damage consequent to SARS-related hypercytokinemia is a direct wage of elevated expression of chemokines IL-1, IL-6, IL-8, IL-12, IFN-γ, and monocyte chemoattractant protein-1 (MCP-1) [9], while, in case of MERS-CoV it was related to towering levels of IFN-γ, IL-15, IL-17, and TNF-α [10]. Furthermore, H5N1 and H7N9-related hypercytokinemia is manifested by elevated levels of IFN-γ, IL-6, IL-8, IL-10, IL-18, MCP-1 [11,12], In case of COVID-19, CSS is displayed as lymphopenia (CD4+ and CD8+ T cells), augmentation of cytokines and chemokines levels (IL-6, IL-1β, IL-2, IL-10, and TNF-α), and over-expression of IFNγ [13] (Fig. 1).

Fig. 1
Fig. 1:
Cytokine storm syndrome and potential targets.

For these infections, it has been proposed that downregulating inflammatory immune responses side-by-side with antiviral medication may ameliorate outcomes. Repression of respiratory epithelial cells inflammation and fibrosis mediated by the release of IL-1β and IL-6 subsequent to the attachment of COVID-19 to the epithelial cells Toll-like receptors (TLRs) using immunosuppressant is a suggested strategy [14]. Hypercytokinemia is significantly reported in critically ill COVID-19 patients [15], as well as elevated levels of IL-6, C-reactive protein, and ferritin in nonsurvivor patients [16].

The uncontrolled cytokines-derived migration of T cells and macrophages to infection site and overstimulation of these cells to secrete more cytokines is the proposed pathway of CSS, that may cause significant damage to end organs. For instance, in the lungs, CSS will cause accumulation of fluids and macrophages. The failure of downregulating this pathway will eventually lead airways block, resulting in death. Both proinflammatory cytokines-TNF-α, IL-1, and IL-6 and anti-inflammatory cytokines are elevated in the serum of patients experiencing a CSS. Existence of cytokine storm reflects on clinical manifestations like high-grade fever and confusion, and laboratory markers like hyperferritinemia, lymphopenia, prolonged prothrombin time, elevated lactate dehydrogenase, elevated IL-6, elevated C-reactive protein, and elevated soluble CD25. Early curbing of the cytokine storm induced by COVID-19 using anticytokine drugs targeting specially IL-1, IL-6, and IL-18 will predispose to better clinical outcomes.

Potential therapies

Cytokine/Chemokine clearance

Artificial-liver-blood-purification (ALBP) and The Molecular Adsorbents Recirculating System [17] approaches using plasma exchange, plasma absorption, and plasma filtration [18] were used in the remediation of confirmed CSS in critically ill patients infected by H7N9 influenza [19]. These techniques depend on replacing the toxic-molecule-burdened plasma with albumin-enriched fresh high plasma, to clear toxins and excess cytokines, repeated settings will dilute the tissue-accumulated cytokines and other inflammatory mediators. Limited use of these techniques is due to the requirements of massive stock of frozen plasma, modern technology, and plasma filtration membranes. The process needs a plasma exchange rate of 1 l/h for 6–8 h to give a good washout effect, which will be elusive in harsh conditions related to the pandemic. ALBP system using with COVID-19 critically ill patients in Hospital of Zhejiang University-China rapidly remove inflammatory mediators (endotoxin, TNF-α, and IL-6) and attenuates the CSS [20], ALBP showed noteworthy reduced levels of basic fibroblast growth factor, granulocyte-colony-stimulating factor, IFN-γ, IL-1 receptor antagonist, IL-12, IL-17A, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-9, TNF-α, and vascular endothelial growth factor [19]. This technique demonstrated more efficient cytokines-clearance outcomes when compared with continuous veno-venous hemofiltration module [18] and offers a possibility of last resort to critically ill patients.

Cytokine-targeted therapy

IL-1 blockade

IL-1α or IL-1β are the initiating cytokines of the inflammation process, they unchain a cascade of inflammatory mediators, chemokines and other cytokines. When COVID-19 binds to TLRs, the formation of pro-IL-1 and synthesis of IL-1 is activated [13] leading to elevated levels of IL-1 in patients developed SARS-CoV and COVID-19 in the early course of infection as reported in the literature [9,21].

Anakinra is a recombinant, nonglycosylated human IL-1 receptor antagonist (IL-1Ra) used to treat rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease, with acceptable safety profile and variable dosage forms, it competes with IL-1β for the receptor binding site [22]. A multicentre study conducted in 91 centres from 11 countries in Europe and North America in 2016 found that using anakinra was associated with significant improvement in survival of patients with sepsis and macrophage activation syndrome [23]. Furthermore; many studies reported lower fatigue symptoms mediated by hypercytokinemia in primary Sjogren's syndrome patients treated with anakinra [24]. Eloseily et al.[25] observed improved survival rates across patients having systematic juvenile idiopathic arthritis-related CSS. Based on aforementioned studies, the Italian government has approved an ongoing randomized multicentred trial aiming to measure the proportion of COVID-19 patients not requiring invasive mechanical ventilation or extracorporeal membrane oxygenation using anakinra 400 mg/day in four divided doses [26].

Rilonacept is dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the IL-1 receptor component (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) linked to the fragment-crystallizable portion of human IgG1 that binds and neutralizes IL-1β [27]. It is used in the treatment of cryopyrin-associated periodic syndromes (CAPS) [28], familial cold auto-inflammatory syndrome (FCAS) and Muckle–Wells Syndrome (MWS), in adults and children greater than 12 years old. All these are considered as hereditary autoinflammatory disorders characterized by genetically dysregulation of the innate immune system driven by excessive release of (IL-1β) [29] Rilonacept produced rapid and profound improvements in resolution of the signs and symptoms in patients of CAPS [30].

Canakinumab, a monoclonal anti-IL-1β antibody indicated for a wide range of inflammatory disorders including the treatment of CAPS, it was associated with a rapid remission of symptoms in most patients [31–33]. Based on in-vitro studies, inflammation caused by coronavirus may be inhibited by anti-IL-1 agents [34,35], further clinical studies are needed to correlate the promising outcomes of rilonacept and canakinumab in halting CSS in CAPS, FCAS, and MWS to that caused by COVID-19.

IL-6 blockade

IL-6 is another major proinflammatory cytokine with pleotropic effects on the immune system, released in response to cellular stress conditions like injury, malignancy, and viral infections, it stimulates the acute phase responses, haematopoiesis, and immune reactions. Reinforcement of T-helper and natural killer (NK) cells production and maturation of B lymphocytes by IL-6 is embroiled in process of fibrosis through stimulation of fibroblasts production and the release of procollagen and fibronectin [36,37]. The SARS-CoV associated lung epithelial cells damage was a consequence of exaggerated IL-6 release rather than the genuine effect of the viral infection [38]. COVID-19 increased expression of IL-6 in serum is correlated to the severity of the sepsis and patient's prognosis [13,39], rendering therapeutic agents targeting IL-6 an appealing option for the treatment of CSS relevant to COVID-19 [40] (Table 1).

Table 1 - Potential immunological treatments for cytokine storm syndrome.
Drug Trade name Mechanism of action Indication References
Anakinra Kineret Recombinant, nonglycosylated human IL-1 receptor antagonist Rheumatoid arthritis neonatal-onset multisystem inflammatory disease [22,24,25]
Rilonacept Arcalyst Dimeric fusion protein that neutralizes IL-1β Treatment of CAPS Familial cold auto-inflammatory syndrome Muckle–Wells syndrome [27,29,30]
Canakinumab Ilaris Monoclonal anti-IL-1β antibody Treatment of CAPS [31–35]
Tocilizumab Actemra mAb that inhibits IL-6 Treatment of rheumatoid arthritis [40–42]
Siltuximab Sylvant Human–mouse chimeric IgG1-kappa mAb against human IL-6 Idiopathic multicentric Castleman disease [43]
Mycophenolate mofetil CellCept T and B lymphocytes proliferation inhibitor Prevent transplanted organ rejection autoimmune disorders [44–50]
Tacrolimus Prograf T and B lymphocytes suppressant Prevent transplanted organ rejection severe atopic dermatitis [51–55]
Chloroquine phosphate Aralen Antimalarial activity anti-inflammatory effect Antimalarial anti-inflammatory antiviral [56,58–74]
Hydroxychloroquine Plaquinil Antimalarial activity anti-inflammatory effect (DMARD) used in the treatment of acute and chronic rheumatoid arthritis, and systemic lupus erythematosus [75–77]
Etanercept golimumab adalimumab Enbrel simponi humira TNF-α antagonists Rheumatoid arthritis arthrosclerosis skin conditions inflammatory bowel diseases ankylosing spondylitis viral pneumonitis [84–91]
Epstein–Barr virus protein BZLF1 Myxoma virus protein T7 IFNγ inhibitors Viral component [95,96]
Emapalumab Gamifant mAb IFNγ inhibitors Treatment of hemophagocytic lympho-histiocytosis [97–99]
IL-37 and IL-38 Intrinsic biological anti-inflammatory cytokines [13,100–103]
CAPS, cryopyrin-associated periodic syndromes; DMARD, disease-modifying antirheumatic drug.

Tocilizumab is a mAb that inhibits IL-6 used for treatment of RA, it is approved in the United States for severe life-threatening CSS caused by chimeric antigen receptor T-cell immunotherapy, a multicentre, randomized controlled trial of tocilizumab, has been approved in patients with COVID-19 pneumonia and elevated IL-6 in China and Italy, showing preliminary promising outcomes. Reducing severity of illness; prompt fever normalization, improved oxygenation and absorption of lung lesion on computed tomography scans [40,41]. Although promising outcomes are observed with tocilizumab, further large-scale investigation is needed to estimate its effect of restoration of T cells count in such patients [42].

Siltuximab is human-mouse chimeric IgG1-kappa mAb against human IL-6 used for idiopathic multicentric Castleman disease (iMCD), successfully improving clinical, laboratory, and radiologic parameters of iMCD patients [43]. Up to the time of writing this article, no studies investigating the use siltuximab to treat COVID-19 associated CSS were found. However, it is considered a potential target for further research.

Immunosuppressants

Mycophenolate mofetil is a prodrug of mycophenolic acid (MPA), it inhibits T and B lymphocytes proliferation through suppression of inosine monophosphate dehydrogenase leading to suppressed immune response [44]. The molecule is clinically used in combination with other immunosuppressants to prevent transplanted organ rejection and autoimmune disorders [45]. In-vitro studies have demonstrated the inhibitory effect of MPA on the stimulated IL-6 expression of renal tubular epithelial cells [46]. Furthermore, mycophenolate in combination with IFN-β showed strong in-vitro inhibition against MERS-Cov, with an IC50 of 2.87 μmol/l [47]. Studies have demonstrated that mycophenolate in vitro is able to inhibit MERS-CoV papain-like proteases [48,49]. The beneficial effect of this finding was corroborated later by the survival of Saudi patients treated with mycophenolate mofetil during the MERS-CoV outbreak in 2014 [50]. Introducing mycophenolate mofetil in clinical trials for treatment of COVID-19 could prove to be of value in light of the previous experience with MERS-CoV.

Tacrolimus is a macrolide T and B lymphocytes suppressant, it reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating the FKBP12–FK506 complex, which inhibits calcineurin involved in the production of IL-2 which in turn inhibits T-lymphocyte signal transduction and IL-2 transcription [51]. Clinically, it is used to prevent transplanted organ rejection, additionally used topically in the treatment of severe atopic dermatitis, and the skin vitiligo [52]. In-vitro studies showed that tacrolimus markedly inhibited the growth of human coronavirus [53], which in concert with a case reports of a survived patient using tacrolimus with MERS-CoV infection concomitant to renal transplantation [54,55]. Currently, a clinical trial on the effect of tacrolimus and sirolimus in hindering the CSS caused by COVID-19 is ongoing on.

Chloroquine phosphate is 4-aminoquinoline with antimalarial activity [56], it was shown to demoralize the parasitic enzyme heme-polymerase that converts the toxic heme into nontoxic hemozoin, thereby resulting in the accumulation of toxic heme within the parasite [57]. The anti-inflammatory effect of chloroquine was extensively studied in animal models as well as in humans [58–60]. It is found that chloroquine is able to ravel tumour necrosis factor and high mobility group box 1, a late mediator of lethal endotoxemia. Chloroquine reduces TNF-α mRNA levels by an alkalinization of endo-lysosomes which also inhibits TNF-α gene expression and extend to inhibit IL-1β and IL-6b release [61]. In addition, interference of chloroquine with sialic acid biosynthesis accounts for failure of viral glycosylation of ACE2 receptors leading to hindered viral entry to epithelial cells [62]. Chloroquine proved antiviral activity against rabies virus [63], hepatitis A virus [64], hepatitis B virus [65], hepatitis C virus [66], influenza A and B viruses [67,68], and Ebola virus [69], and the recent COVID-19 outbreak uncovered the role that chloroquine may play in counteracting the related CSS. Reduced onset of symptoms, sepsis exacerbations and accelerated viral clearance were linked to chloroquine use leading to emergent recommendation for the prevention and treatment of COVID-19 [70–72]. As suggested by experts consensus, the appropriate dose and duration of chloroquine in COVID-19 treatment is much higher than regular dose [73], which necessitates definitive toxicological and therapeutic monitoring studies [74].

Hydroxychloroquine is an aminoquinoline-like chloroquine, with similar pharmacokinetics to that of chloroquine but better safety profile as high doses for extended periods were well tolerated. It is a disease-modifying antirheumatic drug used in the treatment of acute and chronic RA, and systemic lupus erythematosus [75]. This drug regulates the immune response through the same mechanism of action described above for chloroquine. In-vitro testing of antiviral activity and dose optimization of hydroxychloroquine, revealed higher potency as compared with chloroquine, to inhibit COVID-19 [76]. Another French nonrandomized open-label trial in COVID-19 patients receiving a combination of hydroxychloroquine and azithromycin showed decreased viral load and carriage duration, with concerns about small number of patients included (n = 36) [77]. In absence of targeted antiviral treatment chloroquine and hydroxychloroquine are cost-effective promising treatment option of COVID-19, both needs longer term clinical and toxicological studies to assess outcomes and safety profile.

Anti-TNF-α antibodies

TNF-α is a pivotal proinflammatory cytokine secreted predominantly from activated alveolar macrophages or dendritic cells at early phases of immune responses to tissue injury or infection [78]. The activated TNF-α binds to receptors (TNFR1 and TNFR2) with variable affinities, initializing complex cascades of interactions controlling proinflammatory cytokines, prostaglandins and platelet activating factor [79]. TNF-α is correlated to inflammatory manifestations related to RA, arthrosclerosis, skin conditions, inflammatory bowel diseases, ankylosing spondylitis (AS) and viral pneumonitis in SARS-CoV, H5N1 and COVID-19 [13,80–82], TNF-α antagonists are suggested to combat CSS-related to COVID-19, as promising results (reduced inflammatory cells recruitment, reduced cytokines release, and reduced severity of illness) were demonstrated by using TNF-α antagonists for treatment of respiratory syncytial virus or influenza virus in animal models [83].

Anti-TNF-α biological molecules; etanercept [84], golimumab [85], adalimumab [86] are recombinant human soluble fusion protein of TNFR2 coupled to the fragment-crystallizable portion of IgG, achieving significant favourable clinical outcomes in RA patients. Infliximab is a monoclonal chimeric human-mouse anti-TNF-α antibody with effective and well tolerated outcomes in halting RA-related exaggerated immune response [87]. Intravenous injection of certolizumab (a PEGylated TNFα mAb) yielded effective, well tolerated, and extended action in management of inflammatory manifestations in RA [88]. The above agents are Food and Drug Administration approved for the treatment of a variety of autoimmune diseases; severe Crohn's disease, RA, ulcerative colitis, psoriatic arthritis, AS, juvenile idiopathic arthritis, and chronic plaque psoriasis.

Anti-TNFα antibodies are hypothesized to arrest COVID-19 propagation and through inhibition of TNF-α and downregulation of ACE2 expression. Although some studies reported no superiority of anti-TNFα in acute respiratory infections in animals due to impaired delivery to respiratory system tissues [89], earlier promising results in SARS-CoV suggested anti-TNFα antibodies to be included in trials for the treatment of COVID-19 infections [90,91].

IFNγ antibodies

IFNγ is mainly produced by NK cells and macrophages, its levels were found to be 500–2000-fold higher than normal at the early phases of SARS-CoV-2 infection, and returned to normal within a month of viral clearance, it appears to be responsible for the induction of apoptosis, stimulation of macrophages, chemokine production [92,93]. An experimental trial in animal models suggested that the antihistaminic drugs like pyrilamine, diphenhydramine, and thioperamide can suppress IFNγ production in activated splenocytes [94], which is a good opportunity for clinical trials of the anti IFNγ effect of already recognized safe drugs in supressing CSS in human. Furthermore, some viruses found to secrete IFN-receptor-like decoy factors or antagonizing protein that are able to form complexes with IFNγ receptors, reducing receptor expression or promote receptor degradation, like been found with Epstein Barr virus protein BZLF1 [95] and Myxoma virus protein T7 [96]. These biological molecules could be potential targets for further in-vitro studies.

Emapalumab is a mAb that deactivates IFNγ through competition at the binding site in the cell surface proteins, it is used for treatment of hemophagocytic lymphohistiocytosis (HLH) [97], especially relapsed and progressive cases [98]. Subsidence of inflammatory manifestations, normalized ferritin levels, corrected neutrophil and platelet counts, electrolyte rebalance, and restoration of end organ functions were noticed within hours to few days of using emapalumab in HLH [99], as such the molecule could be a candidate for clinical trials to mitigate COVID-19-related CSS.

Intrinsic biological anti-inflammatory cytokines

IL-37 and IL-38 the cytokines family members produced by B cells and macrophages showed a suppressor effect towards IL-1β and other proinflammatory IL-family members, revealing an opportunity for a therapeutic target for CSS [13]. IL-37 achieves its immunosuppressant effect through different mechanisms, acting on mTOR and increasing the adenosine monophosphate kinase that inhibits class II histocompatibility complex molecules and inflammation cascade by suppressing MyD88 and subsequently IL-1β, IL-6, TNF [100]. As for IL-38, it inhibits the production of T-cell cytokines IL-1β, IL-8, IL-17, and IL-22. IL-38 involved in inflammation and immune responses [101]. Mutual use of IL-37 with mesenchymal stem cells transplanted in mice displayed reduced expression of proinflammatory cytokines, T cells production, improved survival and reduced signs of systemic lupus erythematosus [102]. As for IL-38, there is a growing trend to investigate its use in suppressing the inflammatory response in dermatitis, asthma, autoimmune diseases and cancer [103]. The two anti-inflammatory cytokines portray beneficial role in supressing inflammation and should be included in research pipelines as there is currently no approval for their use (or analogues) in the clinic.

The discussion above was presented to provide some insights to clinicians and research in this critical situation, with time constraints at present, to incorporates therapeutics in controlled clinical trials to combat the COVID-19 pandemic and ameliorate patient outcomes.

Acknowledgements

There was no funding received to conduct this study.

Conflicts of interest

All authors declare no conflict of interest.

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Keywords:

coronavirus; coronavirus disease 2019; cytokine storm; hypercytokinemia

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