Mediators of Inflammation

Mediators of Inflammation / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 8198963 | https://doi.org/10.1155/2020/8198963

Mujahed I. Mustafa, Abdelrahman H. Abdelmoneim, Eiman M. Mahmoud, Abdelrafie M. Makhawi, "Cytokine Storm in COVID-19 Patients, Its Impact on Organs and Potential Treatment by QTY Code-Designed Detergent-Free Chemokine Receptors", Mediators of Inflammation, vol. 2020, Article ID 8198963, 7 pages, 2020. https://doi.org/10.1155/2020/8198963

Cytokine Storm in COVID-19 Patients, Its Impact on Organs and Potential Treatment by QTY Code-Designed Detergent-Free Chemokine Receptors

Academic Editor: Mirella Giovarelli
Received06 May 2020
Accepted09 Sep 2020
Published23 Sep 2020

Abstract

The novel coronavirus is not only causing respiratory problems, but it may also damage the heart, kidneys, liver, and other organs; in Wuhan, 14 to 30% of COVID-19 patients have lost their kidney function and now require either dialysis or kidney transplants. The novel coronavirus gains entry into humans by targeting the ACE2 receptor that found on lung cells, which destroy human lungs through cytokine storms, and this leads to hyperinflammation, forcing the immune cells to destroy healthy cells. This is why some COVID-19 patients need intensive care. The inflammatory chemicals released during COVID-19 infection cause the liver to produce proteins that defend the body from infections. However, these proteins can cause blood clotting, which can clog blood vessels in the heart and other organs; as a result, the organs are deprived of oxygen and nutrients which could ultimately lead to multiorgan failure and consequent progression to acute lung injury, acute respiratory distress syndrome, and often death. However, there are novel protein modification tools called the QTY code, which are similar in their structure to antibodies, which could provide a solution to excess cytokines. These synthetic proteins can be injected into the body to bind the excess cytokines created by the cytokine storm; this will eventually remove the excessive cytokines and inhibit the severe symptoms caused by the COVID-19 infection. In this review, we will focus on cytokine storm in COVID-19 patients, their impact on the body organs, and the potential treatment by QTY code-designed detergent-free chemokine receptors.

1. Introduction

In the seafood market in Wuhan, China, a novel virus has emerged in December 2019, which was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is still a debate about the source of this virus; nevertheless, bats are the most likely source since it is a well-known natural reservoir of a diversity of corona viruses [14]. The initial name of the disease was 2019-nCoV acute respiratory disease, then later, the World Health Organization (WHO) officially named the disease as coronavirus disease 2019 (COVID-19). After the local spread throughout China, the disease spread rapidly across the globe. Hence, on 30 January 2020, WHO officially declared that the COVID-19 has become a pandemic and it is to be considered as public health emergency of international concern [5, 6].

The approximate mean incubation period of SARS-CoV-2 is 5.1 days [7]. Interestingly, not all COVID-19 patients develop the same symptoms, but the immunological determinants of a poor prognosis are unknown. More than 50% of patients with SARS-CoV-2 showed no signs of fever before administrated a prober healthcare [8]. Strikingly, COVID-19 can be transmitted by asymptomatic patients, who show no inflammatory, respiratory or other organs symptoms and who also have normal chest computed tomography (CT) [9, 10] which hinder the effort to prevent the spread of COVID-19. The situation is further complicated by the observation that SARS-CoV-2 can be transmitted through the aerosols, and it can remain infectious up to 7 days on the surfaces [11]. Despite the fact that the fever and respiratory symptoms are the most common type of presentations, yet a recent report from Shandong, China, disclosed that a subset of patients did not suffer from these kind of symptoms, but rather had predominately neurologic symptoms [1214]; more young people infected with COVID-19 are dying of strokes in their 30s–40s, while the average age of people who have strokes is usually 74. Moreover, they did not show signs of severe infections or in some cases no sign at all. SARS-CoV-2 causes large vessel occlusions (LVOs) in some of COVID-19 patients; this can ultimately lead to death [15, 16]. How exactly the virus causes blood clots is still unclear. Some researchers believe it could be because of cytokine storm while others believe that SARS-CoV-2 disrupts the function of angiotensin converting enzyme 2 (ACE2) which causes imbalance in the renin-angiotensin-aldosterone system [17]. Interestingly, and although there are many vaccine candidates under study [1824], no effective treatment or vaccine has been developed so far [2527].

Lu et al. provide direct evidence that the SARS-CoV-2 has recently developed mutations capable of significantly altering its pathogenicity. However, novel coronavirus still gains entry into humans by targeting ACE2 receptor that is found on lung cells, which destroy human lungs through cytokine storms, and this leads to hyperinflammation, forcing the immune cells to destroy healthy cells, which could be the reason behind COVID-19 patients’ frequent intensive care admission [28]. This review deals with cytokine storm in COVID-19 patients, their impact on the organs, and the potential treatment by QTY code-designed detergent-free chemokine receptors.

2. Cytokine Storm and Multiorgan Failure

Cytokine storm is considered to be one of the major causes of multiple-organ failure in COVID-19 infections. Excessive infiltration of the inflammatory cells like monocyte and neutrophil into lung tissue will lead to lung injury. Another source of damage to the lung is through cytokine-induced apoptosis of lung epithelial cells.

IFN-αβ and IFN-γ induce inflammatory cell infiltration through two major mechanisms involving Fas–Fas ligand (FasL) or TRAIL–death receptor 5 (DR5) and cause the apoptosis of airway and alveolar epithelial cells. This will lead to alveolar edema and hypoxia and hence cause acute respiratory distress syndrome (ARDS) [29]. In cytokine storm, the following cytokine levels are elevated IL-1b, IL-2, IL-7, IL-8, IL-9, IL-10, IL-17, G-CSF, GMCSF, IFNg, TNFa, IP10, MCP1, MIP1A, and MIP1B [30, 31], which are associated with the increased severity of the disease [32], along with the development of ARDS and cardiac injury in patients with underling heart problems [33].

2.1. Cardiac Damage

Patients with underling cardiovascular condition are vulnerable to cardiac injury and irregular heart rhythm, even more, some patients who have no recorded history of heart disease still develop cardiac injury when became infected with SARS-CoV-2 due to the damage by the induced cytokines [34]. Cytokines are also implicated in developing myocarditis and pericarditis in COVID-19 patients, which is probably why treatment with cytokine inhibitor (like IL-6-targeting therapies) in these patients has shown promising results [35, 36].

In a retrospective cohort study was done by Zhou et al. in Wuhan, China, involving 191 COVID-19 patients. Increased high-sensitivity cardiac troponin I during hospital admission was noticed in more than half of those who died [37]. Furthermore, it was found that d-dimer rise above 1 μg/mL is associated with fatal outcome. Systemic proinflammatory cytokine responses are thought to be mediators of atherosclerosis leading to plaque rupture through local inflammation, induction of procoagulant factors, and haemodynamic changes, which eventually lead to ischaemia and thrombosis. In addition, the ACE2 receptor for SARS-CoV-2, which is expressed on myocytes and vascular endothelial cells, could be playing a role in myocardial injury [3840].

2.2. Acute Respiratory Distress Syndrome (ARDS)

Pneumonia associated with COVID-19 could be complicated by acute respiratory disease syndrome which is confirmed by the appearance of bilateral glass appearance on the computer tomography [41].

The pathophysiology of COVID-19-associated ARDS has a similarity to that of severe community-acquired pneumonia induced by other viruses [42]. Activation of coagulation pathways in cytokine storm syndrome will lead to progressive lung injury. Furthermore, thrombin plays a vital role in promoting clot formation and preventing bleeding, but another significant role is the augmentation of inflammation via proteinase-activated receptors (PARs), particularly PAR-1, which is why PAR-1 antagonists is a promising mode of treatment in alleviating the lung damage associated with cytokine storm. Thrombin generation is regulated by many factors, such as antithrombin III, tissue factor pathway inhibitor, and the protein C system, which all became impaired during inflammation leading to the formation of microthrombosis and acute lung injury [43, 44].

2.3. Renal

The incidence of acute kidney injury in COVID-19 patients was estimated to be up to 5%. It is more common in the intensive care setting and could be considered as a poor prognostic factor for survival [45].

The inflammatory response associated with cytokine storm will lead to hypoperfusion injury to the renal tubules coupled with increased vascular permeability and cardiomyopathy, which may lead to developing cardio renal syndrome type 1, a condition characterized by pleural effusions, edema, intravascular fluid depletion, and hypotension [46]. In addition, direct cytopathic damage caused by SARS-CoV-2 is thought to be one of the underlying mechanisms of renal damage associated with COVID-19 [47, 48].

2.4. Liver

It was thought that COVID-19 causes direct liver injury through viral hepatitis, which is accompanied by the rise in bilirubin and aminotransferase levels in COVID-19 patients [49, 50], yet studies suggested that clinical liver injury is uncommon on the course of the disease. So it is possible that elevated liver enzymes may not be from the liver alone, and confounding factors like myositis could be the cause behind this rise [51].

2.5. Central Nervous System

In a retrospective, observational case series, involving 214 patients with COVID-19, neurological manifestations like headache, ataxia, and seizure were noticed in 36.4% of them. These manifestations were more common in patients with severe forms of the disease. These symptoms could be due to ACE receptor involvement, in addition to the elevated proinflammatory cytokines in serum associated with cytokine storm, which may lead to neurological symptoms due to skeletal muscle damage [52, 53].

3. Immune Dysfunction

Peripheral CD4 and CD8 T cells showed hyperactivation in severe COVID-19 patients. This high concentration of proinflammatory CD4 T cells and cytotoxic granule CD8 T cells is suggestive of antiviral immune responses and overactivation of T cells [54]. Furthermore, numerous studies have described lymphopenia as a common feature of COVID-19 [34, 55]. All these dynamic factors may account for the severity and mortality associated sometimes with the disease.

4. The QTY-Modified Protein Concept

Zhang et al. designed a novel protein called QTY code, through which hydrophobic amino acids leucine (L), isoleucine (I), valine (V), and phenylalanine (F) are replaced by glutamine (Q), threonine (T), and tyrosine (Y). “The QTY code is based on the fact that the electron density map of hydrophobic L is similar to that of hydrophilic N and Q; the electron density maps of hydrophobic I and V are similar to that of hydrophilic T; and the electron density map of hydrophobic F is similar to that of the hydrophilic Y” [56]. QTY variant receptors have almost the same physiological characteristics to those of innate receptors without the existence of hydrophobic sides [57]. Currently, there are 20 Fc-fusion proteins in demand [58], although there have been reported several dissolvable proteins in the innate form [58, 59].

Levin et al. bioengineered the QTY variants to considerably increase the half-life of the designed protein in human plasma. It can also enhance the welfare of the fused proteins as a result of decreased immunogenicity [60].

Zhang et al. “described the application of the QTY code on six variants of cytokine receptors, including interleukin receptors IL4αR and IL10αR, chemokine receptors CCR9 and CXCR2, as well as interferon receptors IFNγR1 and IFNλR1” (Figure 1). The QTY receptors may be engineered to facilitate to cure autoimmune diseases, infectious diseases, and cancers. The QTY receptors are engineered simply to make easy to redesigned and used widely [56].

5. Treatment of Cytokine Storm by QTY Code-Designed Detergent-Free Chemokine Receptors

Cytokine storm is the leading side effect of cellular immunotherapy, which is potentially a life-threatening event. It can also be triggered by viral infections such as COVID-19 infections. COVID-19 triggers cytokine storm in many stages of its pathological course that causes lung fibrosis, acute respiratory distress syndrome, and eventually leads to multiorgan failure [34, 54, 61]. That is why to alleviate the symptoms and treat the disease, it is vital to remove excessive cytokines efficiently and rapidly [33].

At early stages of COVID-19 pandemic, Hao et al. tested their Fc-fusion water-soluble receptors to see if it has any influence to COVID-19; they found that it inhibits the excessive cytokines released during CAR-T treatment, therefore reducing organ damage and toxicity. Cytokine receptor–Fc-fusion proteins serve as an antibody-like decoy to dampen the excessive cytokine levels associated with cytokine storm in COVID-19 infection [57].

6. Alternative Treatment Approaches with Cytokine Storm

6.1. Stem Cell Therapy

In addition to self-renewal and differentiation, mesenchymal stem cells (MSCs) have anti-inflammatory and immune regulatory roles, as it can inhibit the secretion of proinflammatory cytokines, such as IL-1, TNF-α, IL-6, IL-12, and IFN-γ, and hence suppressing the activation of cytokine storms [62, 63]. Furthermore, MSC can secrete IL-10, keratinocyte, hepatocyte, and vascular endothelial growth factors, which collectively will help in resisting the formation of fibrosis and in the repairing of damaged lung tissues [64]. MSC seems to be an effective strategy for the treatment cytokine storm.

6.2. The Artificial Liver Technology

Another interesting treatment modality is the blood purification treatments such as plasma exchange and filtration that are currently used in some hospitals, which can reduce inflammation, through the removal of inflammatory elements and thus preventing the formation of cytokine storm in COVID-19 patients [65, 66].

6.3. Chloroquine

Chloroquine is thought to suppress the cytokine storm in COVID-19 patients through inhibiting the production of inflammatory mediators like TNF and IL-6. Building on the early positive reports, chloroquine phosphate has been used successfully in the treatment of adult COVID-19 patients in China with varied success rate [67]. The recommended dose in one of the associated clinical trials was as follows: “If the weight is more than 50 kg, 500 mg each time, 2 times a day, 7 days as a treatment course; If the weight is less than 50 kg, 500 mg each time on the first and second days, twice a day, 500 mg each time on the third to seventh days, once a day” [67].

6.4. IFN-λ

IFN-λ mainly acts on epithelial cells and diminishes the mononuclear macrophage-mediated proinflammatory activity of IFN-αβ [68]. Furthermore, IFN-λ inhibits the recruitment of the early inflammatory cells (neutrophil) to the inflammation sites [69]. It is known that SARS-CoV-2 primarily infects alveolar epithelial cells (AEC), and that IFN-λ can trigger the antiviral genes in these cells, thus improving the antiviral effects against the virus. Although interferons can reduce the viral load and improves the symptoms of patients [7072], still, it fails to reduce mortality rates [72].

7. Advantages and Limitations of Cytokine Storm Inhibition by QTY Code-Designed Detergent-Free Chemokine Receptors

The main advantage of QTY receptors is to serve as an antibody-like structure to decrease the excessive cytokine levels related with cytokine storm syndrome in COVID-19 infection.

Levin et al. bioengineered the QTY variants to considerably increase the half-life of the designed protein in human plasma. It can also enhance the welfare of the fused proteins as a result of decreased immunogenicity [60].

Another advantage is that the Fc region can be engineered and used widely. QTY receptors, particularly CCR9 and CXCR2, are distinctive due to it provides a novel relatively simple stage for additional design of QTY receptors for therapeutic purposes [57].

The main limitation of QTY code-designed detergent-free chemokine receptors is that it had been tested only in mice, while the human clinical trials had just been recently started in April 2020 [57].

8. Conclusion

Cytokine storm is the leading side effect during cellular immunotherapy which is a potentially life-threatening occurrence. It can also be triggered by viral infections such as COVID-19 infections. Importantly, COVID-19 has many consequences induced by the cytokine storm in many stages of its pathological course which include lung fibrosis, acute respiratory distress syndrome, and multiorgan failure leading eventually to the death of the patient. To alleviate the symptoms, it is vital to inhibit cytokine storm efficiently and rapidly. The QTY-modified proteins could provide a solution to these excess cytokines. These synthetic proteins can be injected into the body to bind the excessive cytokines generated by the cytokine storm; this will eventually remove them from the circulation and probably inhibit the severe complications caused by the COVID-19 infection.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

All authors contributed to collecting of data, writing, editing, and revising of the manuscript. All authors read and approved the final manuscript.

References

  1. T. Hampton, “Bats may be SARS reservoir,” Jama, vol. 294, no. 18, 2005. View at: Publisher Site | Google Scholar
  2. A. Banerjee, K. Kulcsar, V. Misra, M. Frieman, and K. Mossman, “Bats and coronaviruses,” Viruses, vol. 11, no. 1, 2019. View at: Publisher Site | Google Scholar
  3. W. Li, Z. Shi, M. Yu et al., “Bats are natural reservoirs of SARS-like coronaviruses,” Science, vol. 310, no. 5748, pp. 676–679, 2005. View at: Publisher Site | Google Scholar
  4. Q. Ye, B. Wang, J. Mao et al., “Epidemiological analysis of COVID-19 and practical experience from China,” Journal of Medical Virology, vol. 92, no. 7, pp. 755–769, 2020. View at: Publisher Site | Google Scholar
  5. R. Lu, X. Zhao, J. Li et al., “Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding,” Lancet, vol. 395, no. 10224, pp. 565–574, 2020. View at: Publisher Site | Google Scholar
  6. S. A. Meo, T. Al-Khlaiwi, A. M. Usmani, A. S. Meo, D. C. Klonoff, and T. D. Hoang, “Biological and Epidemiological Trends in the Prevalence and Mortality Due to Outbreaks of Novel Coronavirus COVID-19,” Journal of King Saud University-Science, vol. 32, no. 4, pp. 2495–2499, 2020. View at: Publisher Site | Google Scholar
  7. S. A. Lauer, K. H. Grantz, Q. Bi et al., “The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application,” Annals of internal medicine, vol. 172, no. 9, pp. 577–582, 2020. View at: Publisher Site | Google Scholar
  8. W.-j. Guan, Z.-y. Ni, Y. Hu et al., “Clinical characteristics of coronavirus disease 2019 in China,” New England Journal of Medicine, vol. 382, no. 18, pp. 1708–1720, 2020. View at: Publisher Site | Google Scholar
  9. Y. Bai, L. Yao, T. Wei et al., “Presumed Asymptomatic Carrier Transmission of COVID-19,” Jama, vol. 323, no. 14, pp. 1406-1407, 2020. View at: Publisher Site | Google Scholar
  10. Z. Hu, C. Song, C. Xu et al., “Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China,” Science China Life Sciences, vol. 63, no. 5, pp. 706–711, 2020. View at: Publisher Site | Google Scholar
  11. N. van Doremalen, T. Bushmaker, D. H. Morris et al., “Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1,” The New England Journal of Medicine, vol. 382, no. 16, pp. 1564–1567, 2020. View at: Publisher Site | Google Scholar
  12. J. Sellner, P. Taba, S. Ozturk, and R. Helbok, “The need for neurologists in the care of COVID-19 patients,” European Journal of Neurology, vol. 27, no. 9, 2020. View at: Publisher Site | Google Scholar
  13. K. Roe, “Explanation for COVID-19 infection neurological damage and reactivations,” Transboundary and Emerging Diseases, vol. 67, no. 4, pp. 1414-1415, 2020. View at: Publisher Site | Google Scholar
  14. H. S. Markus and M. Brainin, “COVID-19 and stroke—A global World Stroke Organization perspective,” International journal of stroke, vol. 15, no. 4, pp. 361–364, 2020. View at: Publisher Site | Google Scholar
  15. T. J. Oxley, J. Mocco, S. Majidi et al., “Large-vessel stroke as a presenting feature of Covid-19 in the young,” New England Journal of Medicine, vol. 382, no. 20, 2020. View at: Publisher Site | Google Scholar
  16. R. M. Dafer, N. D. Osteraas, and J. Biller, “Acute stroke care in the coronavirus disease 2019 pandemic,” Journal of Stroke and Cerebrovascular Diseases, vol. 29, no. 7, article 104881, 2020. View at: Publisher Site | Google Scholar
  17. C. A. Romero, M. Orias, and M. R. Weir, “Novel RAAS agonists and antagonists: clinical applications and controversies,” Nature Reviews Endocrinology, vol. 11, no. 4, pp. 242–252, 2015. View at: Publisher Site | Google Scholar
  18. M. I. Abdelmageed, A. H. Abdelmoneim, M. I. Mustafa et al., “Design of multi epitope-based peptide vaccine against E protein of human 2019-nCoV: an immunoinformatics approach,” 2020, bioRxiv 2020.02.04.934232. View at: Publisher Site | Google Scholar
  19. M. Enayatkhani, M. Hasaniazad, S. Faezi et al., “Reverse vaccinology approach to design a novel multi-epitope vaccine candidate against COVID-19: an in silico study,” Journal of Biomolecular Structure and Dynamics, pp. 1–16, 2020. View at: Publisher Site | Google Scholar
  20. M. Bhattacharya, A. R. Sharma, P. Patra et al., “Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): immunoinformatics approach,” Journal of medical virology, vol. 92, no. 6, pp. 618–631, 2020. View at: Publisher Site | Google Scholar
  21. V. Baruah and S. Bose, “Immunoinformatics-aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019-nCoV,” Journal of medical virology, vol. 92, no. 5, pp. 495–500, 2020. View at: Publisher Site | Google Scholar
  22. E. Prompetchara, C. Ketloy, and T. Palaga, “Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic,” Asian Pacific Journal ofAllergy and Immunology, vol. 38, no. 1, pp. 1–9, 2020. View at: Publisher Site | Google Scholar
  23. B. Shanmugaraj, K. Siriwattananon, K. Wangkanont, and W. Phoolcharoen, “Perspectives on monoclonal antibody therapy as potential therapeutic intervention for coronavirus disease-19 (COVID-19),” Asian Pacific Journal ofAllergy and Immunology, vol. 38, no. 1, pp. 10–18, 2020. View at: Publisher Site | Google Scholar
  24. R. Zhang, X. Wang, L. Ni et al., “COVID-19: melatonin as a potential adjuvant treatment,” Life Sciences, vol. 250, article 117583, 2020. View at: Publisher Site | Google Scholar
  25. B. Cao, Y. Wang, D. Wen et al., “A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19,” New England Journal of Medicine, vol. 382, no. 19, pp. 1787–1799, 2020. View at: Publisher Site | Google Scholar
  26. M. Hoffmann, H. Kleine-Weber, S. Schroeder et al., “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor,” Cell, vol. 181, no. 2, pp. 271–280.e8, 2020. View at: Publisher Site | Google Scholar
  27. Z. Wang and X. Xu, “scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells,” Cells, vol. 9, no. 4, 2020. View at: Publisher Site | Google Scholar
  28. H. Yao, X. Lu, Q. Chen et al., Patient-Derived Mutations Impact Pathogenicity of SARS-CoV-2, MedRxiv, 2020. View at: Publisher Site
  29. Q. Ye, B. Wang, and J. Mao, “The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19,” Journal of infection, vol. 80, no. 6, pp. 607–613, 2020. View at: Publisher Site | Google Scholar
  30. D. Wu and X. O. Yang, “TH17 responses in cytokine storm of COVID-19: an emerging target of JAK2 inhibitor Fedratinib,” Journal of Microbiology, Immunology and Infection, vol. 53, no. 3, pp. 368–370, 2020. View at: Publisher Site | Google Scholar
  31. Y. Zhang, L. Yu, L. Tang et al., “A promising anti-cytokine-storm targeted therapy for COVID-19: the artificial-liver blood-purification system,” Engineering (Beijing), 2020. View at: Publisher Site | Google Scholar
  32. M. Zhao, “Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies,” International journal of antimicrobial agents, vol. 55, no. 6, article 105982, 2020. View at: Publisher Site | Google Scholar
  33. V. Q. Chau, E. Oliveros, K. Mahmood et al., “The imperfect cytokine Storm,” JACC Case Reports, vol. 2, no. 9, pp. 1315–1320, 2020. View at: Publisher Site | Google Scholar
  34. C. Huang, Y. Wang, X. Li et al., “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China,” The lancet, vol. 395, no. 10223, pp. 497–506, 2020. View at: Publisher Site | Google Scholar
  35. P. A. Ascierto, B. Fox, W. Urba et al., “Insights from immuno-oncology: the Society for Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19,” Journal for ImmunoTherapy of Cancer, vol. 8, no. 1, article e000878, 2020. View at: Publisher Site | Google Scholar
  36. J. M. Michot, L. Albiges, N. Chaput et al., “Tocilizumab, an anti-IL-6 receptor antibody, to treat Covid-19-related respiratory failure: a case report,” Annals of Oncology, vol. 31, no. 7, pp. 961–964, 2020. View at: Publisher Site | Google Scholar
  37. F. Zhou, T. Yu, R. Du et al., “Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study,” Lancet, vol. 395, no. 10229, pp. 1054–1062, 2020. View at: Publisher Site | Google Scholar
  38. L. Smeeth, S. L. Thomas, A. J. Hall, R. Hubbard, P. Farrington, and P. Vallance, “Risk of myocardial infarction and stroke after acute infection or vaccination,” New England Journal of Medicine, vol. 351, no. 25, pp. 2611–2618, 2004. View at: Publisher Site | Google Scholar
  39. P. E. Gallagher, C. M. Ferrario, and E. A. Tallant, “Regulation of ACE2 in cardiac myocytes and fibroblasts,” American Journal of Physiology-Heart and Circulatory Physiology, vol. 295, no. 6, pp. H2373–H2379, 2008. View at: Publisher Site | Google Scholar
  40. E. Mendoza-Torres, A. Oyarzún, D. Mondaca-Ruff et al., “ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension,” Therapeutic Advances in Cardiovascular Disease, vol. 9, no. 4, pp. 217–237, 2015. View at: Publisher Site | Google Scholar
  41. L. Gattinoni, D. Chiumello, and S. Rossi, “COVID-19 pneumonia: ARDS or not?” Critical Care, vol. 24, no. 1, 2020. View at: Publisher Site | Google Scholar
  42. L. A. Perrone, J. K. Plowden, A. Garcia-Sastre, J. M. Katz, and T. M. Tumpey, “H5N1 and 1918 pandemic influenza virus infection results in early and excessive infiltration of macrophages and neutrophils in the lungs of mice,” PLoS Pathogenes, vol. 4, no. 8, article e1000115, 2008. View at: Publisher Site | Google Scholar
  43. R. J. Jose, A. E. Williams, and R. C. Chambers, “Proteinase-activated receptors in fibroproliferative lung disease,” Thorax, vol. 69, no. 2, pp. 190–192, 2014. View at: Publisher Site | Google Scholar
  44. R. J. Jose and A. Manuel, “COVID-19 cytokine storm: the interplay between inflammation and coagulation,” The Lancet Respiratory Medicine, vol. 8, no. 6, pp. e46–e47, 2020. View at: Publisher Site | Google Scholar
  45. Y. Cheng, R. Luo, K. Wang et al., “Kidney disease is associated with in-hospital death of patients with COVID-19,” Kidney International, vol. 97, no. 5, pp. 829–838, 2020. View at: Publisher Site | Google Scholar
  46. C. Ronco and T. Reis, “Kidney involvement in COVID-19 and rationale for extracorporeal therapies,” Nature Reviews Nephrology, vol. 16, no. 6, pp. 308–310, 2020. View at: Publisher Site | Google Scholar
  47. R. Durvasula, T. Wellington, E. McNamara, and S. Watnick, “COVID-19 and kidney failure in the acute care setting: our experience from Seattle,” American Journal of Kidney Diseases, vol. 76, no. 1, pp. 4–6, 2020. View at: Publisher Site | Google Scholar
  48. G. Pei, Z. Zhang, J. Peng et al., “Renal involvement and early prognosis in patients with COVID-19 pneumonia,” Journal of the American Society of Nephrology, vol. 31, no. 6, pp. 1157–1165, 2020. View at: Publisher Site | Google Scholar
  49. G. Ianiro, B. H. Mullish, C. R. Kelly et al., “Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel,” The Lancet Gastroenterology & Hepatology, vol. 5, no. 5, pp. 430–432, 2020. View at: Publisher Site | Google Scholar
  50. D. Raoult, A. Zumla, F. Locatelli, G. Ippolito, and G. Kroemer, “Coronavirus infections: epidemiological, clinical and immunological features and hypotheses,” Cell Stress, vol. 4, no. 4, pp. 66–75, 2020. View at: Publisher Site | Google Scholar
  51. M. N. Bangash, J. Patel, and D. Parekh, “COVID-19 and the liver: little cause for concern,” The Lancet. Gastroenterology & Hepatology, vol. 5, no. 6, pp. 529-530, 2020. View at: Publisher Site | Google Scholar
  52. L. Mao, H. Jin, M. Wang et al., “Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China,” JAMA neurology, vol. 77, no. 6, pp. 683–690, 2020. View at: Publisher Site | Google Scholar
  53. C. Cabello-Verrugio, M. G. Morales, J. C. Rivera, D. Cabrera, and F. Simon, “Renin-angiotensin system: an old player with novel functions in skeletal muscle,” Medicinal research reviews, vol. 35, no. 3, pp. 437–463, 2015. View at: Publisher Site | Google Scholar
  54. Z. Xu, L. Shi, Y. Wang et al., “Pathological findings of COVID-19 associated with acute respiratory distress syndrome,” The Lancet respiratory medicine, vol. 8, no. 4, pp. 420–422, 2020. View at: Publisher Site | Google Scholar
  55. N. Zhu, D. Zhang, W. Wang et al., “A novel coronavirus from patients with pneumonia in China, 2019,” The New England Journal of Medicine, vol. 382, no. 8, pp. 727–733, 2020. View at: Publisher Site | Google Scholar
  56. S. Zhang, F. Tao, R. Qing et al., “QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities,” Proceedings of the National Academy of Sciences, vol. 115, no. 37, pp. E8652–E8659, 2018. View at: Publisher Site | Google Scholar
  57. S. Hao, D. Jin, S. Zhang, and R. Qing, “QTY code-designed water-soluble Fc-fusion cytokine receptors bind to their respective ligands,” QRB Discovery, vol. 1, pp. 1–18, 2020. View at: Publisher Site | Google Scholar
  58. D. Czajkowsky, J. Hu, Z. Shao, and R. Pleass, “Fc-fusion proteins: new developments and future perspectives,” EMBO molecular medicine, vol. 4, no. 10, pp. 1015–1028, 2012. View at: Publisher Site | Google Scholar
  59. D. Mekhaiel, D. Czajkowsky, J. Andersen et al., “Polymeric human Fc-fusion proteins with modified effector functions,” Scientific reports, vol. 1, no. 1, 2011. View at: Publisher Site | Google Scholar
  60. D. Levin, B. Golding, S. E. Strome, and Z. E. Sauna, “Fc fusion as a platform technology: potential for modulating immunogenicity,” Trends in biotechnology, vol. 33, no. 1, pp. 27–34, 2015. View at: Publisher Site | Google Scholar
  61. L. A. Henderson, S. W. Canna, G. S. Schulert et al., “On the Alert for Cytokine Storm: Immunopathology in COVID-19,” Arthritis & Rheumatology, vol. 72, no. 7, pp. 1059–1063, 2020. View at: Publisher Site | Google Scholar
  62. A. Uccelli and N. K. de Rosbo, “The immunomodulatory function of mesenchymal stem cells: mode of action and pathways,” Annals of the New York Academy of Sciences, vol. 1351, no. 1, pp. 114–126, 2015. View at: Publisher Site | Google Scholar
  63. T. Ben-Mordechai, D. Palevski, Y. Glucksam-Galnoy, I. Elron-Gross, R. Margalit, and J. Leor, “Targeting macrophage subsets for infarct repair,” Journal of cardiovascular pharmacology and therapeutics, vol. 20, no. 1, pp. 36–51, 2014. View at: Publisher Site | Google Scholar
  64. J. Lee, X. Fang, A. Krasnodembskaya, J. Howard, and M. Matthay, “Concise review: mesenchymal stem cells for acute lung injury: role of paracrine soluble factors,” Stem cells, vol. 29, no. 6, pp. 913–919, 2011. View at: Publisher Site | Google Scholar
  65. H. Cai, Y. Shen, Q. Ni, and Y. Chen, “Management of corona virus disease-19 (COVID-19): the Zhejiang experience,” Journal of Zhejiang University (medical science), vol. 49, no. 2, pp. 147–157, 2020. View at: Publisher Site | Google Scholar
  66. S. Zuccari, E. Damiani, R. Domizi et al., “Changes in cytokines, haemodynamics and microcirculation in patients with sepsis/septic shock undergoing continuous renal replacement therapy and blood purification with CytoSorb,” Blood Purification, vol. 49, no. 1-2, pp. 107–113, 2020. View at: Publisher Site | Google Scholar
  67. J. Gao, Z. Tian, and X. Yang, “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies,” Bioscience trends, vol. 14, no. 1, pp. 72-73, 2020. View at: Publisher Site | Google Scholar
  68. S. Davidson, T. McCabe, S. Crotta et al., “IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment,” EMBO molecular medicine, vol. 8, no. 9, pp. 1099–1112, 2016. View at: Publisher Site | Google Scholar
  69. K. Blazek, H. Eames, M. Weiss et al., “IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1β production,” The Journal of experimental medicine, vol. 212, no. 6, pp. 845–853, 2015. View at: Publisher Site | Google Scholar
  70. Y. M. Arabi, S. Shalhoub, Y. Mandourah et al., “Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study,” Clinical Infectious Diseases, vol. 70, no. 9, pp. 1837–1844, 2020. View at: Publisher Site | Google Scholar
  71. A. Omrani, M. Saad, K. Baig et al., “Ribavirin and interferon alfa-2a for severe middle east respiratory syndrome coronavirus infection: a retrospective cohort study,” The Lancet Infectious Diseases, vol. 14, no. 11, pp. 1090–1095, 2014. View at: Publisher Site | Google Scholar
  72. A. Zumla, J. Chan, E. Azhar, D. Hui, and K.-Y. Yuen, “Coronaviruses - drug discovery and therapeutic options,” Nature reviews Drug discovery, vol. 15, no. 5, pp. 327–347, 2016. View at: Publisher Site | Google Scholar

Copyright © 2020 Mujahed I. Mustafa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views37130
Downloads1706
Citations

Related articles

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.