Secondary Logo

Journal Logo


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

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



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.


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:
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.


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.


There was no funding received to conduct this study.

Conflicts of interest

All authors declare no conflict of interest.


1. Ji W, Wang W, Zhao X, Zai J, Li X. Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol 2020; 92:433–440.
2. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020; 63:457–460.
3. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020; 367:1444–1448.
4. Cheng VCC, Wong SC, To KKW, Ho PL, Yuen KY. Preparedness and proactive infection control measures against the emerging Wuhan coronavirus pneumonia in China. J Hosp Infect 2020; 104:254–255.
5. Hui DS, E IA, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health – the latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis 2020; 91:264–266.
6. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436:112–116.
7. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020; 94:e00127–e00120.
8. Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am 2012; 59:329–344.
9. Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004; 136:95–103.
10. Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 2018; 104:8–13.
11. de Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med 2006; 12:1203–1207.
12. Guo J, Huang F, Liu J, Chen Y, Wang W, Cao B, et al. The serum profile of hypercytokinemia factors identified in H7N9-infected patients can predict fatal outcomes. Sci Rep 2015; 5:10942.
13. Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 2020; 34: DOI: 10.23812/conti-e.
14. Yang X, Yu Y, Xu J, Shu H, Xia JA, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine 2020; 8:475–481.
15. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395:497–506.
16. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020; 46:846–848.
17. Paules CI, Marston HD, Fauci AS. Coronavirus infections—more than just the common cold. JAMA 2020; 323:707–708.
18. Hughes RD. Review of methods to remove protein-bound substances in liver failure. Int J Artif Organs 2002; 25:911–917.
19. Liu X, Zhang Y, Xu X, Du W, Su K, Zhu C, et al. Evaluation of plasma exchange and continuous veno-venous hemofiltration for the treatment of severe avian influenza A (H7N9): a cohort study. Ther Apher Dial 2015; 19:178–184.
20. Xu K, Cai H, Shen Y, Ni Q, Chen Y, Hu S, et al. Management of corona virus disease-19 (COVID-19): the Zhejiang experience. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020; 49:
21. Chen L, Liu HG, Liu W, Liu J, Liu K, Shang J, et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43:203–208.
22. Cvetkovic RS, Keating G. Anakinra. BioDrugs 2002; 16:303–311. discussion 313–304.
23. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med 2016; 44:275–281.
24. Norheim KB, Harboe E, Goransson LG, Omdal R. Interleukin-1 inhibition and fatigue in primary Sjogren's syndrome – a double blind, randomised clinical trial. PLoS One 2012; 7:e30123.
25. Eloseily EM, Weiser P, Crayne CB, Haines H, Mannion ML, Stoll ML, et al. Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2020; 72:326–334.
26. A phase 2/3, randomized, open-label, parallel group, 3-arm, multicentre study investigating the efficacy and safety of intravenous administrations of emapalumab, an antiinterferon gamma (anti-IFNg) monoclonal antibody, and anakinra, an interleukin-1 (IL-1) receptor antagonist, versus standard of care, in reducing hyper-inflammation and respiratory distress in patients with SARS-CoV-2 infection.
27. Kapur S, Bonk ME. Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin-associated periodic syndromes. P T 2009; 34:138–141.
28. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009; 360:2416–2425.
29. Hull KM, Shoham N, Chae JJ, Aksentijevich I, Kastner DL. The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol 2003; 15:61–69.
30. Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 2008; 58:2443–2452.
31. Walsh GM. Canakinumab for the treatment of cryopyrin-associated periodic syndromes. Drugs Today (Barc) 2009; 45:731–735.
32. Church LD, McDermott MF. Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther 2009; 11:81–89.
33. Savic S, McDermott MF. Inflammation: canakinumab for the cryopyrin-associated periodic syndromes. Nat Rev Rheumatol 2009; 5:529–530.
34. Tseng CT, Perrone LA, Zhu H, Makino S, Peters CJ. Severe acute respiratory syndrome and the innate immune responses: modulation of effector cell function without productive infection. J Immunol 2005; 174:7977–7985.
35. Sheng WH, Chiang BL, Chang SC, Ho HN, Wang JT, Chen YC, et al. Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome. J Formos Med Assoc 2005; 104:715–723.
36. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6:a016295.
37. Choy E, Rose-John S. Interleukin-6 as a multifunctional regulator: inflammation, immune response, and fibrosis. J Scleroderma Relat Disord 2017; 2: (2_Suppl): S1–S5.
38. Wang W, Ye L, Ye L, Li B, Gao B, Zeng Y, et al. Up-regulation of IL-6 and TNF-alpha induced by SARS-coronavirus spike protein in murine macrophages via NF-kappaB pathway. Virus Res 2007; 128:1–8.
39. Lu H. Drug treatment options for the new coronavirus (2019-nCoV). BioSci Trends 2020; 14:69–71.
40. Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents 2020; 55:105954.
41. Harrison C. Coronavirus puts drug repurposing on the fast track. Nat Biotechnol 2020; 38:379–381.
42. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). medRxiv 2020; 11:827.
43. Min GJ, Jeon YW, Park SS, et al. The clinical, laboratory, and radiologic improvement due to siltuximab treatment in idiopathic multicentric Castleman's disease [published online ahead of print, 2020 Feb 24]. Korean J Intern Med 2020; 10.3904/kjim.2019.330. doi:10.3904/kjim.2019.330.
44. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005; 14: (Suppl 1): s2–s8.
45. Allison AC, Eugui EM. Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 2005; 80: (2 Suppl): S181–S190.
46. Baer PC, Wegner B, Geiger H. Effects of mycophenolic acid on IL-6 expression of human renal proximal and distal tubular cells in vitro. Nephrol Dial Transplant 2004; 19:47–52.
47. Hart BJ, Dyall J, Postnikova E, Zhou H, Kindrachuk J, Johnson RF, et al. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014; 95 (Pt 3):571–577.
48. Lin MH, Moses DC, Hsieh CH, Cheng SC, Chen YH, Sun CY, et al. Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes. Antiviral Res 2018; 150:155–163.
49. Cheng K-W, Cheng S-C, Chen W-Y, Lin M-H, Chuang S-J, Cheng IH, et al. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res 2015; 115:9–16.
50. Al Ghamdi M, Alghamdi KM, Ghandoora Y, Alzahrani A, Salah F, Alsulami A, et al. Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. BMC Infect Dis 2016; 16:174.
51. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit 1995; 17:584–591.
52. Malecic N, Young H. Tacrolimus for the management of psoriasis: clinical utility and place in therapy. Psoriasis (Auckl) 2016; 6:153–163.
53. Carbajo-Lozoya J, Ma-Lauer Y, Malesevic M, Theuerkorn M, Kahlert V, Prell E, et al. Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by nonimmunosuppressive cyclosporine A-derivatives including Alisporivir. Virus Res 2014; 184:44–53.
54. AlGhamdi M, Mushtaq F, Awn N, Shalhoub S. MERS CoV infection in two renal transplant recipients: case report. Am J Transplant 2015; 15:1101–1104.
55. Carbajo-Lozoya J, Müller MA, Kallies S, Thiel V, Drosten C, von Brunn A. Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506. Virus Res 2012; 165:112–117.
56. Olatunde IA. The present status of chloroquine in the drug treatment of malaria. Afr J Med Sci 1972; 3:77–91.
57. National Center for Biotechnology Information. PubChem Database. Chloroquine, CID=2719, [Accessed 4 April 2020]
58. Yang M, Cao L, Xie M, Yu Y, Kang R, Yang L, et al. Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis. Biochem Pharmacol 2013; 86:410–418.
59. Oh S, Shin JH, Jang EJ, Won HY, Kim HK, Jeong MG, et al. Anti-inflammatory activity of chloroquine and amodiaquine through p21-mediated suppression of T cell proliferation and Th1 cell differentiation. Biochem Biophys Res Commun 2016; 474:345–350.
60. Al-Bari A. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015; 70:1608–1621.
61. Weber SM, Levitz SM. Chloroquine antagonizes the proinflammatory cytokine response to opportunistic fungi by alkalizing the fungal phagolysosome. J Infect Dis 2001; 183:935–942.
62. Olofsson S, Kumlin U, Dimock K, Arnberg N. Avian influenza and sialic acid receptors: more than meets the eye? Lancet Infect Dis 2005; 5:184–188.
63. Tsiang H, Superti F. Ammonium chloride and chloroquine inhibit rabies virus infection in neuroblastoma cells. Arch Virol 1984; 81:377–382.
64. Bishop NE. Examination of potential inhibitors of hepatitis A virus uncoating. Intervirology 1998; 41:261–271.
65. Kouroumalis EA, Koskinas J. Treatment of chronic active hepatitis B (CAH B) with chloroquine: a preliminary report. Ann Acad Med Singapore 1986; 15:149–152.
66. Mizui T, Yamashina S, Tanida I, Takei Y, Ueno T, Sakamoto N, et al. Inhibition of hepatitis C virus replication by chloroquine targeting virus-associated autophagy. J Gastroenterol 2010; 45:195–203.
67. Ooi EE, Chew JSW, Loh JP, Chua RCS. In vitro inhibition of human influenza A virus replication by chloroquine. Virol J 2006; 3:39.
68. Shibata M, Aoki H, Tsurumi T, Sugiura Y, Nishiyama Y, Suzuki S, et al. Mechanism of uncoating of influenza B virus in MDCK cells: action of chloroquine. J Gen Virol 1983; 64:1149–1156.
69. Dowall SD, Bosworth A, Watson R, Bewley K, Taylor I, Rayner E, et al. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model. J Gen Virol 2015; 96:3484–3492.
70. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020; 55:105932.
71. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; 14:72–73.
72. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care 2020; 57:279–283.
73. Multicenter Collaboration Group of Department of Science; Technology of Guangdong Provience; Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020; 43:E019.
74. Duan YJ, Liu Q, Zhao SQ, Huang F, Ren L, Liu L, et al. Trial of chloroquines in the treatment of COVID-19 and its research progress in forensic toxicology. Fa Yi Xue Za Zhi 2020; 36:157–163.
75. Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993; 23: (2 Suppl 1): 82–91.
76. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [published online ahead of print, 2020 Mar 9]. Clin Infect Dis 2020; ciaa237doi:10.1093/cid/ciaa237.
77. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial. Int J Antimicrob Agents 2020; 105949[Epub ahead of print].
78. Wang A, Creasey A, Ladner M, Lin L, Strickler J, Van Arsdell J, et al. Molecular cloning of the complementary DNA for human tumor necrosis factor. XXX 1985; 228:149–154.
79. Clark IA. How TNF was recognized as a key mechanism of disease. Cytokine Growth Factor Rev 2007; 18:335–343.
80. Parameswaran N, Patial S. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 2010; 20:87–103.
81. Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003; 361:1773–1778.
82. Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 2002; 360:1831–1837.
83. Hussell T, Pennycook A, Openshaw PJ. Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur J Immunol 2001; 31:2566–2573.
84. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340:253–259.
85. Zhou H, Jang H, Fleischmann RM, Bouman-Thio E, Xu Z, Marini JC, et al. Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007; 47:383–396.
86. den Broeder AA, Joosten LA, Saxne T, Heinegard D, Fenner H, Miltenburg AM, et al. Long term antitumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation. Ann Rheum Dis 2002; 61:311–318.
87. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of antitumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41:1552–1563.
88. Choy EH, Hazleman B, Smith M, Moss K, Lisi L, Scott DG, et al. Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology (Oxford) 2002; 41:1133–1137.
89. Atanasova K, Van Gucht S, Van Reeth K. Anti-TNF-α therapy does not ameliorate disease in a model of acute virus-endotoxin mediated respiratory disease in pigs. Vet Immunol Immunopathol 2010; 137:12–19.
90. Mahase E. Covid-19: what treatments are being investigated? BMJ 2020; 368:m1252.
91. Tobinick E. TNF-α inhibition for potential therapeutic modulation of SARS coronavirus infection. Curr Med Res Opin 2004; 20:39–40.
92. de Min C, Buatois V, Chatel L, Cons L, De Benedetti F, Kosco-Vilbois M, et al. Interferon gamma (IFNg) drives disease in the TLR9-mediated cytokine storm syndrome in mice. Pediatr Rheumatol Online J 2015; 13: (Suppl 1): O63–O63.
93. Huang K-J, Su I-J, Theron M, Wu Y-C, Lai S-K, Liu C-C, et al. An interferon-γ-related cytokine storm in SARS patients. J Med Virol 2005; 75:185–194.
94. Kamei M, Otani Y, Hayashi H, Nakamura T, Yanai K, Furuta K, et al. Suppression of IFN-gamma production in murine splenocytes by histamine receptor antagonists. Int J Mol Sci 2018; 19:4083.
95. Morrison TE, Mauser A, Wong A, Ting JP, Kenney SC. Inhibition of IFN-gamma signaling by an Epstein-Barr virus immediate-early protein. Immunity 2001; 15:787–799.
96. Upton C, Mossman K, McFadden G. Encoding of a homolog of the IFN-gamma receptor by myxoma virus. Science 1992; 258:1369–1372.
97. Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol 2013; 162:376–382.
98. Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood 2019; 134:1783–1786.
99. Lounder DT, Bin Q, de Min C, Jordan MB. Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections. Blood Adv 2019; 3:47–50.
100. Cavalli G, Dinarello CA. Suppression of inflammation and acquired immunity by IL-37. Immunol Rev 2018; 281:179–190.
101. Garraud T, Harel M, Boutet MA, Le Goff B, Blanchard F. The enigmatic role of IL-38 in inflammatory diseases. Cytokine Growth Factor Rev 2018; 39:26–35.
102. Xu J, Chen J, Li W, Lian W, Huang J, Lai B, et al. Additive therapeutic effects of mesenchymal stem cells and IL-37 for systemic lupus erythematosus. J Am Soc Nephrol 2020; 31:54–65.
103. Lauritano D, Ronconi G, Caraffa A, Enrica Gallenga C, Kritas SK, Di Emidio P, et al. New aspect of allergic contact dermatitis, an inflammatory skin disorder mediated by mast cells: can IL-38 help? Med Hypotheses 2020; 139:109687.

coronavirus; coronavirus disease 2019; cytokine storm; hypercytokinemia

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.