BMB Reports 2022; 55(1): 11-19  https://doi.org/10.5483/BMBRep.2022.55.1.152
Hyper-inflammatory responses in COVID-19 and anti-inflammatory therapeutic approaches
Hojun Choi1 & Eui-Cheol Shin2,3,*
1ILIAS Biologics Inc., Daejeon 34014, 2Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, 3The Center for Epidemic Preparedness, KAIST, Daejeon 34141, Korea
Correspondence to: Tel: +82-42-350-4236; Fax: +82-42-350-4240; E-mail: ecshin@kaist.ac.kr
Received: October 10, 2021; Revised: November 24, 2021; Accepted: December 3, 2021; Published online: January 31, 2022.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
The coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe COVID-19 exhibit hyper-inflammatory responses characterized by excessive activation of myeloid cells, including monocytes, macrophages, and neutrophils, and a plethora of pro-inflammatory cytokines and chemokines. Accumulating evidence also indicates that hyperinflammation is a driving factor for severe progression of the disease, which has prompted the development of anti-inflammatory therapies for the treatment of patients with COVID-19. Corticosteroids, IL-6R inhibitors, and JAK inhibitors have demonstrated promising results in treating patients with severe disease. In addition, diverse forms of exosomes that exert anti-inflammatory functions have been tested experimentally for the treatment of COVID-19. Here, we briefly describe the immunological mechanisms of the hyper-inflammatory responses in patients with severe COVID-19. We also summarize current anti-inflammatory therapies for the treatment of severe COVID-19 and novel exosome-based therapeutics that are in experimental stages.
Keywords: Anti-inflammation, COVID-19, Exosome, Hyper-inflammation, Therapy
INTRODUCTION

The coronavirus disease 2019 (COVID-19) was first found in patients with unidentified pneumonia in Wuhan, China, in December 2019 and rapidly spread worldwide (1). The World Health Organization (WHO) announced the COVID-19 outbreak to be a pandemic on 11 March, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus with high sequence homology to bat coronaviruses (CoVs). Other CoVs have exhibited severe infections in humans. These include SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV, which emerged in 2003 and 2012, respectively (2). SARS-CoV-2 uses its spike protein to bind the angiotensin-converting enzyme 2 (ACE2) receptor expressed on the cell membrane for entry into host cells (3, 4). Although SARS-CoV-2 is not as lethal as MERS-CoV and SARS-CoV-1 (5), its substantial spread has resulted in severe casualties and caused overwhelming pressure for the medical system worldwide.

Nearly 20% of patients with COVID-19 experience severe disease (6, 7). Accumulating evidence suggests that hyper-inflammatory responses of the host to SARS-CoV-2 infection lead to severe forms of COVID-19 (8, 9). Immunopathological features, such as excess infiltration of patients’ lungs by macrophages and neutrophils, as well as increased serum cytokine and chemokine levels, are characteristics of severe COVID-19 (6, 10, 11). Anti-inflammatory therapies, including corticosteroids, are currently considered the standard of care in treating patients with severe COVID-19 (12). The clinical efficacy of other anti-inflammatory therapies is being investigated in various clinical trials.

Here, we review the mechanisms of hyper-inflammatory responses in COVID-19 and describe recent advances in anti-inflammatory therapies for COVID-19. We also highlight the potential roles of exosomes as novel anti-inflammatory therapeutics for the treatment of COVID-19.

THE DYSREGULATED IMMUNE RESPONSE IN PATIENTS WITH COVID-19

Severe COVID-19 pathology results from massive initial viral replication that arises because the SARS-CoV-2 can evade and inhibit the host innate immune recognition system and interferon (IFN) responses (13). Type I IFNs (IFN-αs and IFN-β) and type III IFNs (IFN-λs) are the major first-line defenses against viruses (14), but SARS-CoV-2 has developed various strategies to evade and suppress the production and functions of type I and III IFNs and IFN-stimulated genes (ISGs) (15-17). These mechanisms allow SARS-CoV-2 to replicate robustly, leading to excessive activation of monocytes, macrophages, and neutrophils. Excessively activated myeloid cells then produce excessive pro-inflammatory cytokines and chemokines, resulting in hyper-inflammatory responses (13, 18-20).

Excessive neutrophil activation and infiltration

Patients with severe COVID-19 exhibit increased neutrophil counts with a high neutrophil-to-lymphocyte ratio as an independent risk factor for severity (21-23). A transcriptome analysis of bronchoalveolar lavage fluid (BALF) from patients with COVID-19 showed that SARS-CoV-2 infection induces excessive neutrophil infiltration compared to other forms of pneumonia (24). In addition, patients with severe COVID-19 exhibit increased tissue infiltration of neutrophils in the upper airways of the lungs (25) and the bronchoalveolar space (26, 27). A recent study found that NSP10 of SARS-CoV-2 interacts with the NF-κB repressor NKRF to induce IL-8 production, which augments IL-8-mediated chemotaxis of neutrophils and the over-exuberant host inflammatory responses in COVID-19 (28). Furthermore, increased formation of neutrophil extracellular traps (NETs), which are net-like structures composed of DNA, antimicrobials and oxidant enzymes released by neutrophils, exacerbates lung injury and inflammation in patients with severe COVID-19 (29, 30). These findings imply that the dysregulated activation of neutrophils contributes to hyper-inflammatory responses in severe cases of COVID-19.

Dysregulated activation of macrophages and monocytes

Macrophage activation, especially in the lungs, plays a key role in the progression of dysregulated immune responses in patients with severe COVID-19. Single-cell RNA sequencing (scRNA-seq) analysis of BALF from patients with COVID-19 has shown elevated numbers of pro-inflammatory macrophages in the lungs of such patients (24, 26). The lung macrophages of such patients have shown increased expression of pro-inflammatory cytokine genes, such as IL1B, IL6, and TNF, as well as chemokine genes, such as MCP1/CCL2, MIP1A/CCL3, MIP1B/CCL4, and MCP3/CCL7 (24, 26). Dysregulated activation of monocytes also contributes to severe progression of COVID-19. Elevated numbers of inflammatory monocytes have been identified in the blood of patients with severe COVID-19 (31, 32). A recent large-scale single-cell transcriptome atlas study claimed that monocytes in the peripheral blood are key contributors to the cytokine storm in such patients (32). This is supported by a study showing that inflammatory monocytes in the blood of patients with COVID-19 exhibit elevated gene expression related to classical M1 macrophages (33). Strikingly, scRNA-seq analyses showed that pro-inflammatory cytokines trigger the activation and expansion of circulating monocytes, suggesting positive feedback between the activation of monocytes and production of pro-inflammatory cytokines (33, 34). These observations collectively suggest that SARS-CoV-2 infection triggers dysregulated activation of macrophages and monocytes, resulting in the secretion of a plethora of pro-inflammatory cytokines and chemokines.

Mechanistic model of hyper-inflammation in severe COVID-19

A mechanistic model that explains the contribution of delayed IFN responses to the exacerbated inflammatory response in patients with severe COVID-19 has been proposed (Fig. 1) (13, 20). After SARS-CoV-2 infection of respiratory epithelial cells, the virus efficiently evades host innate immune recognition and IFN responses by blocking the type I and III IFN responses. The viral load rapidly increases, and myeloid cells, such as monocytes and macrophages, are stimulated by viral components via Toll-like receptors (TLRs). Then the monocytes and macrophages produce type I and III IFNs. Positive feedback occurs between the production of IFNs and chemokines and the accumulation and activation of monocytes and macrophages, thus producing large amounts of pro-inflammatory cytokines, such as TNF, IL-6, and IL-1β. This model explains how delayed but exaggerated IFN responses contribute to hyper-inflammation and severe progression of COVID-19.

CURRENT ANTI-INFLAMMATORY THERAPIES FOR COVID-19

Accumulating evidence of hyper-inflammation in patients with severe COVID-19 has provoked the development of anti-inflammatory therapies. Currently, more than 6000 clinical trials testing various therapeutics for treating COVID-19 are registered at clinicaltrials.gov, many of them with anti-inflammatory therapeutics. Various anti-inflammatory agents, such as corticosteroids, IL-6R inhibitors, and JAK inhibitors, have already been shown to be effective in ameliorating hyper-inflammation in COVID-19 (Table 1).

Corticosteroids

Glucocorticoids strongly inhibit the immune system. Glucocorticoids function as glucocorticoid receptor (GR) agonists. Binding of the glucocorticoids to the GR activates the receptor to exert anti-inflammatory effects, such as suppressing the production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, etc.) (35, 36). A controlled, open-label, randomized RECOVERY trial evaluated the efficacy of the glucocorticoid dexametha-sone in hospitalized patients with COVID-19 (12). There were 2104 COVID-19 patients who received 6 mg of dexamethasone once daily for up to 10 days; these patients were compared with 4321 patients who received usual care (12). The trial demonstrated a lower 28-day death rate in the dexamethasone group versus the usual care group (22.9% versus 25.7%; P < 0.001) (12). In particular, the use of dexamethasone significantly lowered the 28-day death rate for those who received either invasive mechanical ventilation or oxygen alone at randomization, but not for those receiving no respiratory support (12), which implies that dexamethasone is effective only in severe patients with ongoing hyper-inflammation. Early meta-analyses also suggested therapeutic use of corticosteroids in severe COVID-19 patients who require respiratory support or mechanical ventilation (37, 38).

IL-6R inhibitors

IL-6 is an important cytokine involved in the hyper-inflammatory response in patients with severe COVID-19, which promp-ted the use of selective IL-6 inhibitors for treatment of these patients. Tocilizumab, a recombinant humanized monoclonal antibody for IL-6 receptor (IL-6R), exerts therapeutic effects by blocking the binding of IL-6 to IL-6R (39). Tocilizumab was previously found be effective against the cytokine release syndrome resulting from chimeric antigen-receptor T-cell therapy (40). Several studies have shown the therapeutic effect of tocilizumab in treating severe COVID-19 by rapidly decreasing inflammatory markers, improving oxygenation, and reducing the death rate in COVID-19 patients who are on mechanical ventilation (41-43). Nevertheless, there is a debate regarding the therapeutic effect of tocilizumab in treating COVID-19. On the one hand, Gupta et al. conducted a multicenter cohort study of 4485 COVID-19 patients with intensive care unit (ICU) admission and reported that the risk of in-hospital death was lower in patients treated with tocilizumab in the first two days of ICU admission (44). On the other hand, Stone et al. did a randomized, double-blind, placebo-controlled trial with 243 COVID-19 patients with hyper-inflammation and concluded that tocilizumab was not effective at preventing intubation or death in moderately ill patients hospitalized with COVID-19 (45). However, Leaf et al. argued that the result was severely underpowered, by pointing out that the percentage of patients with primary outcomes such as intubation or death was 12.5% in the placebo group, which is far lower than the expected 30% (46). They claimed that the percentage of primary outcomes and number of patients enrolled (n = 243) would have made it nearly impossible for the trial to have demonstrated a therapeutic effect (46). Salama et al. also reported that tocili-zumab did not improve survival in a randomized trial of hos-pitalized COVID-19 patients with pneumonia, but treatment reduced the likelihood of progression to mechanical ventilation or death (47). Similarly, in a randomized trial of 452 hospitalized patients with severe COVID-19 accompanied by pneumonia, Rosas et al. reported that the use of tocilizumab did not lead to improved clinical status or lower death rate than did a placebo at 28 days (48). Another monoclonal anti-body for IL-6R, sarilumab, has also had controversial results in COVID-19 patients (49, 50). Thus, the therapeutic efficacy of the IL-6R inhibitor for COVID-19 patients should be carefully examined in further clinical studies.

JAK inhibitors

Inhibitors of the Janus kinases (JAKs) are powerful anti-inflammatory agents that effectively ameliorate various inflammatory diseases, such as rheumatoid arthritis (51). JAK inhibitors suppress the kinase activity of JAKs by competitively binding to the ATP-binding site of JAKs, thereby inhibiting signal transduction of a wide variety of cytokines (51). In a preclinical study, baricitinib, a clinically approved JAK1/JAK2 inhibitor, suppressed the production of pro-inflammatory cytokines and chemokines from lung macrophages and the recruitment of neutrophils in SARS-CoV-2-infected rhesus macaques (52). In addition, a double-blind, randomized, placebo-controlled trial evaluating the effect of baricitinib plus remdesivir in 1033 hospitalized adults with COVID-19 reported that this combination was more effective than remdesivir alone in reducing the recovery time and im-proving clinical status among patients with severe COVID-19 who were receiving high-flow oxygen or non-invasive ventilation (53). In a retrospective, uncontrolled patient cohort with moderate-to-severe COVID-19, treatment with baricitinib plus hydroxychloroquine demonstrated clinical improvement in 11 of 15 patients (54). In July 2021, baricitinib was approved by the US Food and Drug Administration as a single treatment for hospitalized patients with COVID-19.

Another JAK inhibitor, ruxolitinib, demonstrated clinical improvement in 18 critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) (55). In a prospective, multicenter, single-blind, randomized controlled phase II trial involving 43 patients, no significant difference was observed in ruxolitinib-treated patients compared to controls, though ruxolitinib recipients had faster clinical improvement (56).

EXOSOMES AS POTENTIAL THERAPEUTICS IN COVID-19

Characteristics of exosomes

Extracellular vesicles (EVs) are natural nanoparticles secreted by the cell. They are classified into three subgroups: exosomes, microvesicles, and apoptotic bodies, which have different biological properties in their biogenesis, content, and size (exosomes, 30-150 nm; microvesicles, 0.1-1 μm; and apoptotic bodies, 1-5 μm) (57, 58). Exosomes are enclosed by a single lipid bilayer which are generated by inward budding of vesicles into endosomes that mature into multivesicular bodies or by direct budding of lipid vesicles from the plasma membrane (59). Exosomes are known to be secreted by all cell types and are present in various body fluids (60-65). Exosomes participate in intercellular delivery of diverse biological molecules, such as nucleic acids (DNA, RNA), proteins, lipids, and carbohydrates. Many efforts have been made to apply exosomes for various therapeutic application via the engineering of exosomes or exosome-producing cells for incorporating active pharmaceutical ingredients (APIs) into exosomes and inducing targetability to specific cells or organs (66-68).

Exosome-based therapeutics for treating COVID-19

Mesenchymal stem cells (MSCs), which are multipotent adult stem cells, are an easily accessible type of stem cell that are present in various human tissues. Considerable interest in MSCs has been raised for their therapeutic efficacy in tissue repair and in suppressing inflammation. Interestingly, enough research has shown that MSCs exert therapeutic effects by secreting EVs, not by a differentiation mechanism (69, 70). In line with this finding, MSC-derived exosomes have demonstrated regenerative potential, immune-modulatory functions, and anti-inflammatory effects (71).

Recent studies have highlighted the therapeutic potential of MSC-derived exosomes for treating COVID-19. In a prospective, non-randomized, open-label cohort study, the efficacy of exosomes derived from allogenic bone-marrow (BM) MSCs was evaluated in 24 COVID-19 patients with moderate-to-severe ARDS (72). BM MSC-derived exosomes demonstrated a survival rate of 83%, with 17 of 24 (71%) patients recovered showing no adverse effects observed within 72 hours of exosome administration (72). In addition, improved respiratory function (PaO2/FiO2) and reduced neutrophil count and acute phase reactants (i.e., C-reactive protein, ferritin, and D-dimer) were observed (72). However, the clinical outcome of this study must be carefully interpreted because little information was provided about the characteristics, biological properties, or proposed biological or therapeutic actions of the BM-MSC-derived exosomes used in this study (73). Four clinical trials, mostly phase 1 or 2, evaluating the therapeutic effect of MSC-derived exosomes in COVID-19-associated pneumonia are currently in progress (NCT04276987, NCT04798716, NCT04602442, NCT04491240, Table 2).

Engineered exosomes demonstrating potent anti-inflammatory effects have potential to act as effective immunomodulators to ameliorate the excessive inflammation observed in patients with severe COVID-19. Recently, a clinical trial (NCT0474574, Table 2) conducted in Israel completed a phase 1 trial, in which 30 patients with moderate or worse COVID-19 were treated with CD24-expressing exosomes (EXO-CD24). More results are awaited regarding the therapeutic effect of anti-inflammatory exosomes in relieving immunopathogenesis in severe COVID-19.

Therapeutic exosome platform technologies for efficient intracellular cargo delivery

Various exosome engineering platform technologies that can generate exosomes armed with therapeutic cargo have been developed. APIs could be ‘post-incorporated’ into isolated exosomes through exogenous methods, or ‘pre-incorporated’ into exosomes through endogenous methods by modifying the exosome-producing cells (Fig. 2). Exogenous cargo loading methods involves loading APIs into exosomes through methods such as sonication, electroporation, freeze-thaw cycles, and extrusion (Fig. 2B) (74-79). However, a major caveat of these methods is damage to the exosomal membranes during the loading process (80). Endogenous cargo loading uses exosome-producing cells to load APIs into exosomes during natural exosome biogenesis. For example, biological agents can be endogenously incorporated into exosomes by genetically modifying the exosome-producing cells to overexpress the desired proteins or nucleic acids, which are then naturally loaded into exosomes. Macrophage-derived EVs loaded with IL-10 by transfecting the IL10 gene to EV-producing cells exerted therapeutic efficacy in ischemia/reperfusion induced acute kidney injury (AKI) by ameliorating the renal tubular injury and inflammation and driving M2 macrophage polarization via targeted delivery of EVs to macrophages (81). Endogenous cargo loading can be improved by inducing additional modification to the cargo, such as by anchoring the cargo onto the inner/outer membrane of exosomes via conjugation with membrane proteins of exosomes, such as PTGFRN (Fig. 2C) (82). However, the drawback of this approach is that APIs remain attached to the membrane of exosomes after delivery to the target cell, which may dramatically restrict its biological function. Alternatively, a novel technology called EXosomes for Protein Loading via Optically Reversible protein-protein interaction (EXPLOR) has been developed which could load non-anchored free-form proteins into exosomes using light-induced hetero-dimerizing modules, cryptochrome 2 (CRY2), and the N-terminal of CRY-interacting basic-helix-loop-helix 1 (CIBN) isolated from Arabidopsis thaliana (83). CRY2 and CIBN undergo hetero-dimerization in a blue light-specific manner, but reversibly and rapidly dissociate with each other in the absence of blue light (84, 85). By fusing CRY2 with the cargo protein and CIBN with the exosomal membrane protein CD9, cargo proteins can be loaded into exosomes with high yield under blue light via the natural exosome biogenesis pathway (Fig. 2D).

EXPLOR technology has been applied to generate anti-inflammatory exosomes loaded with anti-inflammatory proteins that inhibit the NF-κB signaling pathway. Exosomes loaded with super-repressor IκB (srIκB), a dominant active form of IκBα, generated by EXPLOR technology has demonstrated a promising therapeutic effect in inflammatory diseases, such as sepsis (86-88). SrIκB is a degradation-resistant form of NF-κB-inhibiting protein IκBα, which blocks the nuclear translocation of NF-κB even when pro-inflammatory stimulus is present. Administration of exosomes loaded with srIκB (Exo-srIκB) to septic mouse models ameliorated the death rate and systemic inflammation by reducing the levels of circulating pro-inflammatory cytokines and alleviating acute organ injury (86). Intravital imaging revealed that the administered exosomes are taken up mainly by neutrophils and monocytes, which are attractive target cells for treating hyper-inflammation in COVID-19 (86). Exosomes are cleared by phagocytic cells, such as macrophages and neutrophils, after systemic injection, which makes these cells a primary target for exosomal therapeutics (89, 90). In an AKI model of C57BL/6 mice, Exo-srIκB treatment has demonstrated an anti-inflammatory effect by decreasing gene expression of pro-inflammatory cytokines and adhesion molecules in post-ischemic kidneys (88). In addition, Exo-srIκB administration affects the post-ischemic kidney immune-cell population, reducing the neutrophil, monocyte, and macrophage populations (88). As suppression of the NF-κB pathway has been implied as a potential therapeutic approach for treating patients with severe COVID-19 (91, 92), results demonstrating the therapeutic efficacy of Exo-srIκB in various inflammation-related disorders suggest a possibility of applying Exo-srIκB in the treatment of hyper-inflammation in patients with severe COVID-19.

SUMMARY AND PERSPECTIVE

Excessive activation of myeloid cells, such as monocytes, macrophages, and neutrophils, and exaggerated production of pro-inflammatory cytokines result in hyper-inflammation, leading to severe progression of COVID-19. Anti-inflammatory agents, such as dexamethasone and baricitinib, have shown promising results in ameliorating hyper-inflammation in patients with severe COVID-19, which implies that targeting hyper-inflammation is an appropriate strategy for ameliorating the severity of COVID-19. In addition, exosomes have arisen as a novel therapeutic modality for treating dysregulated inflammatory responses in COVID-19, either as a naïve form or a bioactive cargo delivery vehicle. Promising results of anti-inflammatory exosome therapeutics in ameliorating various inflammatory diseases have indicated the possibility of applying exosomes in the treatment of hyper-inflammation in COVID-19. Recent studies and clinical trials have reported a therapeutic potential of anti-inflammatory exosomes in treating patients with COVID-19. Nonetheless, more research is needed, as well as randomized clinical trials, with enough enrolled patients to verify the efficacy of exosomes in treating patients with severe COVID-19.

CONFLICTS OF INTEREST

H.C. is a minor shareholder of ILIAS Biologics Inc. The authors have no additional financial interests.

FIGURES
Fig. 1. Mechanistic model of hyper-inflammation in COVID-19. After respiratory epithelial cells are infected (A), SARS-CoV-2 proteins block viral-recognition signaling and type I and III interferon (IFN) responses (B). The viral load increases (C) and myeloid cells, such as monocytes and macrophages, are stimulated by viral components via Toll-like receptors, producing type I and III IFNs (D). IFNs further stimulate the production of chemokines and induce the accumulation and activation of monocytes and macrophages, thus producing excessive amounts of pro-inflammatory cytokines (E). This process can be amplified by a positive feedback mechanism.
Fig. 2. Engineering methods for loading therapeutic agents into exosomes. The techniques for loading cargo into exosomes can be divided into four approaches. (A) Using naïve exosomes (e.g., MSC-derived exosomes) requires relatively simple techniques to generate therapeutic exosomes, but the drawback is the difficulty in controlling the bioactive molecules contained in the exosomes. (B) Exogenous cargo loading is based on the use of sonication, repeated freeze/thaw cycles, or electroporation to destabilize the integrity of exosomal membranes and thus allow drugs to be introduced into the exosomes. (C, D) Endogenous cargo loading spontaneously loads molecules of interest by hijacking the natural exosome biogenesis pathway. These techniques are divided into two approaches based on whether the cargo is anchored onto the exosomal membrane (C) or resides as a free form inside the lumen of the exosome (D).
TABLES

Mechanisms of action and therapeutic efficacy of current anti-inflammatory therapeutics for severe COVID-19

Therapeutics Mechanisms of action and therapeutic efficacy
Corticosteroids
  • - Glucocorticoids exert anti-inflammatory effects by binding to glucocorticoid receptor.

  • - Dexamethasone reduced the 28-day death rate in patients with severe COVID-19 (12).

  • - Dexamethasone is recommended for use in severe COVID-19 patients with ongoing hyper-inflammation.

IL-6R inhibitors
  • - IL-6R inhibitors are recombinant humanized antibodies for IL-6R that block the binding of IL-6 to IL-6R.

  • - IL-6R inhibitors have controversial therapeutic efficacy in COVID-19.

JAK inhibitors
  • - JAK inhibitors suppress the kinase activity of JAKs by competitively binding to the ATP-binding site of JAKs.

  • - Baricitinib was approved by the US FDA for the treatment of hospitalized patients with COVID-19.


Ongoing clinical trials evaluating the efficacy of exosome therapeutics in COVID-19

Therapeutic exosomes Delivery method Dosage Phase NCT number
Exosomes overexpressing CD24 Inhalation 1010 particles in 4 ml normal saline 2 NCT04969172
CovenD24 (exosomes overexpressing CD24) Inhalation 109, 1010particles 2 NCT04902183
Ardoxso (MSC-derived exosomes) Intravenous infusion 2 × 109, 4 × 109, 8 × 109 particles 1, 2 NCT04798716
EXO 1, EXO 2 (MSC-derived exosomes) Inhalation 0.5-2 × 1010 particles in 3 ml special solution 2 NCT04602442
EXO-CD24 (exosomes overexpressing CD24) Inhalation 1 × 108-1 × 1010 particles per 2 ml saline 1 NCT04747574
EXO 1, EXO 2 (MSC-derived exosomes) Inhalation 0.5-2 × 1010 particles in 3 ml special solution 1 NCT04491240
CSTC-Exo (COVID-19-specific T cell-derived exosomes) Inhalation 2 × 108 particles in 3 ml 1 NCT04389385
MSC-derived exosomes Inhalation 2 × 108 particles in 3 ml 1 NCT04276987

REFERENCES
  1. Zhu N, Zhang DY, Wang WL et al (2020) A novel Coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382, 727-733
    Pubmed KoreaMed CrossRef
  2. Fung TS and Liu DX (2019) Human Coronavirus: host-pathogen interaction. Annu Rev Microbiol 73, 529-557
    Pubmed CrossRef
  3. Lu RJ, Zhao X, Li J et al (2020) Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395, 565-574
    Pubmed KoreaMed CrossRef
  4. Wan YS, Shang J, Graham R, Baric RS and Li F (2020) Receptor recognition by the novel Coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS Coronavirus. J Virol 94, e00127-20
    Pubmed KoreaMed CrossRef
  5. Fauci AS, Lane HC and Redfield RR (2020) Covid-19-navigating the uncharted. N Engl J Med 382, 1268-1269
    Pubmed KoreaMed CrossRef
  6. Huang C, Wang Y, Li X et al (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497-506
    Pubmed KoreaMed CrossRef
  7. Richardson S, Hirsch JS, Narasimhan M et al (2020) Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 323, 2052-2059
    Pubmed KoreaMed CrossRef
  8. Mehta P, McAuley DF, Brown M et al (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395, 1033-1034
    Pubmed KoreaMed CrossRef
  9. Gustine JN and Jones D (2021) Immunopathology of Hyperinflammation in COVID-19. Am J Pathol 191, 4-17
    Pubmed KoreaMed CrossRef
  10. Zhou F, Yu T, Du R et al (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054-1062
    Pubmed KoreaMed CrossRef
  11. Del Valle DM, Kim-Schulze S, Huang HH et al (2020) An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 26, 1636-1643
    Pubmed KoreaMed CrossRef
  12. Group RC, Horby P, Lim WS et al (2021) Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 384, 693-704
    Pubmed KoreaMed CrossRef
  13. Kim YM and Shin EC (2021) Type I and III interferon responses in SARS-CoV-2 infection. Exp Mol Med 53, 750-760
    Pubmed KoreaMed CrossRef
  14. Mesev EV, LeDesma RA and Ploss A (2019) Decoding type I and III interferon signalling during viral infection. Nat Microbiol 4, 914-924
    Pubmed KoreaMed CrossRef
  15. Park A and Iwasaki A (2020) Type I and type III interferons - induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 27, 870-878
    Pubmed KoreaMed CrossRef
  16. Ribero MS, Jouvenet N, Dreux M and Nisole S (2020) Interplay between SARS-CoV-2 and the type I interferon response. PLoS Pathog 16, e1008737
    Pubmed KoreaMed CrossRef
  17. Choi H and Shin EC (2021) Roles of type I and III interferons in COVID-19. Yonsei Med J 62, 381-390
    Pubmed KoreaMed CrossRef
  18. Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L and Remuzzi G (2021) Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol 17, 46-64
    Pubmed KoreaMed CrossRef
  19. Lee JS, Park S, Jeong HW et al (2020) Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Sci Immunol 5, eabd1554
    Pubmed KoreaMed CrossRef
  20. Galani IE, Rovina N, Lampropoulou V et al (2021) Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison. Nat Immunol 22, 32-40
    Pubmed CrossRef
  21. Wang D, Hu B, Hu C et al (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus-infected pneumonia in Wuhan, China. JAMA 323, 1061-1069
    Pubmed KoreaMed CrossRef
  22. Liu J, Liu Y, Xiang P et al (2020) Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J Transl Med 18, 206
    Pubmed KoreaMed CrossRef
  23. Carissimo G, Xu W, Kwok I et al (2020) Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19. Nat Commun 11, 5243
    Pubmed KoreaMed CrossRef
  24. Zhou Z, Ren L, Zhang L et al (2020) Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe 27, 883-890
    Pubmed KoreaMed CrossRef
  25. Chua RL, Lukassen S, Trump S et al (2020) COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat Biotechnol 38, 970-979
    Pubmed CrossRef
  26. Liao M, Liu Y, Yuan J et al (2020) Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 26, 842-844
    Pubmed CrossRef
  27. Wauters E, Van Mol P, Garg AD et al (2021) Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res 31, 272-290
    Pubmed KoreaMed CrossRef
  28. Li J, Guo M, Tian X et al (2021) Virus-host interactome and proteomic survey reveal potential virulence factors influencing SARS-CoV-2 pathogenesis. Med (N Y) 2, 99-112
    Pubmed KoreaMed CrossRef
  29. Middleton EA, He XY, Denorme F et al (2020) Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 136, 1169-1179
    Pubmed KoreaMed CrossRef
  30. Zuo Y, Yalavarthi S, Shi H et al (2020) Neutrophil extracellular traps in COVID-19. JCI Insight 5, e138999
    CrossRef
  31. Bost P, Giladi A, Liu Y et al (2020) Host-viral infection maps reveal signatures of severe COVID-19 patients. Cell 181, 1475-1488
    Pubmed KoreaMed CrossRef
  32. Ren X, Wen W, Fan X et al (2021) COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell 184, 1895-1913
    Pubmed KoreaMed CrossRef
  33. Wen W, Su W, Tang H et al (2020) Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov 6, 31
    Pubmed KoreaMed CrossRef
  34. Guo C, Li B, Ma H et al (2020) Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm. Nat Commun 11, 3924
    Pubmed KoreaMed CrossRef
  35. Williams DM (2018) Clinical pharmacology of corticosteroids. Respir Care 63, 655-670
    Pubmed CrossRef
  36. Brattsand R and Linden M (1996) Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther 10 Suppl 2, 81-90; discussion 91-82
    Pubmed CrossRef
  37. Pulakurthi YS, Pederson JM, Saravu K et al (2021) Corticosteroid therapy for COVID-19: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 100, e25719
    Pubmed KoreaMed CrossRef
  38. Johns M, George S, Taburyanskaya M and Poon YK (2021) A review of the evidence for corticosteroids in COVID-19. J Pharm Pract, 897190021998502
    Pubmed CrossRef
  39. Sebba A (2008) Tocilizumab: the first interleukin-6-receptor inhibitor. Am J Health Syst Pharm 65, 1413-1418
    Pubmed CrossRef
  40. Le RQ, Li L, Yuan W et al (2018) FDA approval summary: Tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 23, 943-947
    Pubmed KoreaMed CrossRef
  41. Xu X, Han M, Li T et al (2020) Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 117, 10970-10975
    Pubmed KoreaMed CrossRef
  42. Sciascia S, Apra F, Baffa A et al (2020) Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 38, 529-532
    Pubmed
  43. Guaraldi G, Meschiari M, Cozzi-Lepri A et al (2020) Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol 2, e474-e484
    Pubmed KoreaMed CrossRef
  44. Gupta S, Wang W, Hayek SS et al (2021) Association between early treatment with Tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med 181, 41-51
    Pubmed KoreaMed CrossRef
  45. Stone JH, Frigault MJ, Serling-Boyd NJ et al (2020) Efficacy of Tocilizumab in patients hospitalized with Covid-19. N Engl J Med 383, 2333-2344
    Pubmed KoreaMed CrossRef
  46. Leaf DE, Gupta S and Wang W (2021) Tocilizumab in Covid-19. N Engl J Med 384, 86-87
    Pubmed CrossRef
  47. Salama C, Han J, Yau L et al (2021) Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 384, 20-30
    Pubmed KoreaMed CrossRef
  48. Rosas IO, Brau N, Waters M et al (2021) Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med 384, 1503-1516
    Pubmed KoreaMed CrossRef
  49. Della-Torre E, Campochiaro C, Cavalli G et al (2020) Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study. Ann Rheum Dis 79, 1277-1285
    Pubmed KoreaMed CrossRef
  50. Lescure FX, Honda H, Fowler RA et al (2021) Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 9, 522-532
    Pubmed KoreaMed CrossRef
  51. Morinobu A (2020) JAK inhibitors for the treatment of rheumatoid arthritis. Immunol Med 43, 148-155
    Pubmed CrossRef
  52. Hoang TN, Pino M, Boddapati AK et al (2021) Baricitinib treatment resolves lower-airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell 184, 460-475
    Pubmed KoreaMed CrossRef
  53. Kalil AC, Patterson TF, Mehta AK et al (2021) Baricitinib plus Remdesivir for hospitalized adults with Covid-19. N Engl J Med 384, 795-807
    Pubmed KoreaMed CrossRef
  54. Titanji BK, Farley MM, Mehta A et al (2021) Use of Baricitinib in patients with moderate to severe Coronavirus disease 2019. Clin Infect Dis 72, 1247-1250
    Pubmed KoreaMed CrossRef
  55. Capochiani E, Frediani B, Iervasi G et al (2020) Ruxo-litinib rapidly reduces acute respiratory distress syndrome in COVID-19 disease. Analysis of data collection From RESPIRE protocol. Front Med (Lausanne) 7, 466
    Pubmed KoreaMed CrossRef
  56. Cao Y, Wei J, Zou L et al (2020) Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): a multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol 146, 137-146
    Pubmed KoreaMed CrossRef
  57. Raposo G and Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200, 373-383
    Pubmed KoreaMed CrossRef
  58. Thery C, Zitvogel L and Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2, 569-579
    Pubmed CrossRef
  59. Pegtel DM and Gould SJ (2019) Exosomes. Annu Rev Biochem 88, 487-514
    Pubmed CrossRef
  60. Peng H, Ji W, Zhao R et al (2020) Exosome: a significant nano-scale drug delivery carrier. J Mater Chem B 8, 7591-7608
    Pubmed CrossRef
  61. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G and Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17, 879-887
    Pubmed CrossRef
  62. Pisitkun T, Shen RF and Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 101, 13368-13373
    Pubmed KoreaMed CrossRef
  63. Michael A, Bajracharya SD, Yuen PS et al (2010) Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 16, 34-38
    Pubmed KoreaMed CrossRef
  64. Admyre C, Johansson SM, Qazi KR et al (2007) Exosomes with immune modulatory features are present in human breast milk. J Immunol 179, 1969-1978
    Pubmed CrossRef
  65. Vojtech L, Woo S, Hughes S et al (2014) Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic Acids Res 42, 7290-7304
    Pubmed KoreaMed CrossRef
  66. Jafari D, Shajari S, Jafari R et al (2020) Designer exosomes: a new platform for biotechnology therapeutics. BioDrugs 34, 567-586
    Pubmed KoreaMed CrossRef
  67. Zipkin M (2019) Exosome redux. Nat Biotechnol 37, 1395-1400
    Pubmed CrossRef
  68. Kim J, Song Y, Park CH and Choi C (2021) Platform technologies and human cell lines for the production of therapeutic exosomes. Extracell Vesicles Circ Nucl Acids 2, 3-17
    CrossRef
  69. Caplan AI and Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98, 1076-1084
    Pubmed CrossRef
  70. Baek G, Choi H, Kim Y, Lee HC and Choi C (2019) Mesenchymal stem cell-derived extracellular vesicles as therapeutics and as a drug delivery platform. Stem Cells Transl Med 8, 880-886
    Pubmed KoreaMed CrossRef
  71. Suh JH, Joo HS, Hong EB, Lee HJ and Lee JM (2021) Therapeutic application of exosomes in inflammatory diseases. Int J Mol Sci 22, 1144
    Pubmed KoreaMed CrossRef
  72. Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A and Bremer N (2020) Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev 29, 747-754
    Pubmed KoreaMed CrossRef
  73. Lim SK, Giebel B, Weiss DJ, Witwer KW and Rohde E (2020) Re: "Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19" by Sengupta et al. Stem Cells Dev 29, 877-878
    Pubmed KoreaMed CrossRef
  74. Sun D, Zhuang X, Xiang X et al (2010) A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 18, 1606-1614
    Pubmed KoreaMed CrossRef
  75. Kim MS, Haney MJ, Zhao Y et al (2016) Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 12, 655-664
    Pubmed KoreaMed CrossRef
  76. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S and Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341-345
    Pubmed CrossRef
  77. Lamichhane TN, Jeyaram A, Patel DB et al (2016) Oncogene knockdown via active loading of small rnas into extracellular vesicles by sonication. Cell Mol Bioeng 9, 315-324
    Pubmed KoreaMed CrossRef
  78. Hood JL (2016) Post isolation modification of exosomes for nanomedicine applications. Nanomedicine (Lond) 11, 1745-1756
    Pubmed KoreaMed CrossRef
  79. Kamerkar S, LeBleu VS, Sugimoto H et al (2017) Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498-503
    Pubmed KoreaMed CrossRef
  80. Hood JL, Scott MJ and Wickline SA (2014) Maximizing exosome colloidal stability following electroporation. Anal Biochem 448, 41-49
    Pubmed KoreaMed CrossRef
  81. Tang TT, Wang B, Wu M et al (2020) Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI. Sci Adv 6, eaaz0748
    Pubmed KoreaMed CrossRef
  82. Dooley K, McConnell RE, Xu K et al (2021) A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties. Mol Ther 29, 1729-1743
    Pubmed KoreaMed CrossRef
  83. Yim N, Ryu SW, Choi K et al (2016) Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat Commun 7, 12277
    Pubmed KoreaMed CrossRef
  84. Shalitin D, Yang H, Mockler TC et al (2002) Regulation of Arabidopsis cryptochrome 2 by blue-light-dependent phosphorylation. Nature 417, 763-767
    Pubmed CrossRef
  85. Kennedy MJ, Hughes RM, Peteya LA, Schwartz JW, Ehlers MD and Tucker CL (2010) Rapid blue-light-mediated induction of protein interactions in living cells. Nat Methods 7, 973-975
    Pubmed KoreaMed CrossRef
  86. Choi H, Kim Y, Mirzaaghasi A et al (2020) Exosome-based delivery of super-repressor IkappaBalpha relieves sepsis-associated organ damage and mortality. Sci Adv 6, eaaz6980
    Pubmed KoreaMed CrossRef
  87. Sheller-Miller S, Radnaa E, Yoo JK et al (2021) Exosomal delivery of NF-kappaB inhibitor delays LPS-induced preterm birth and modulates fetal immune cell profile in mouse models. Sci Adv 7, eabd3865
    Pubmed CrossRef
  88. Kim S, Lee SA, Yoon H et al (2021) Exosome-based delivery of super-repressor IkappaBalpha ameliorates kidney ischemia-reperfusion injury. Kidney Int 100, 570-584
    Pubmed CrossRef
  89. Choi H, Choi Y, Yim HY, Mirzaaghasi A, Yoo JK and Choi C (2021) Biodistribution of exosomes and engineering strategies for targeted delivery of therapeutic exosomes. Tissue Eng Regen Med 18, 499-511
    Pubmed KoreaMed CrossRef
  90. Imai T, Takahashi Y, Nishikawa M et al (2015) Macro-phage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice. J Extracell Vesicles 4, 26238
    Pubmed KoreaMed CrossRef
  91. Kircheis R, Haasbach E, Lueftenegger D, Heyken WT, Ocker M and Planz O (2020) NF-kappaB pathway as a potential target for treatment of critical stage COVID-19 patients. Front Immunol 11, 598444
    Pubmed KoreaMed CrossRef
  92. Hariharan A, Hakeem AR, Radhakrishnan S, Reddy MS and Rela M (2021) The role and therapeutic potential of nf-kappa-b Pathway in Severe COVID-19 patients. Inflammopharmacology 29, 91-100
    Pubmed KoreaMed CrossRef


This Article

e-submission

Archives