|
1
|
Mink S, Drexel H, Leiherer A, Frick M, Reimann P, Saely CH, Fraunberger P. Interplay of inflammatory markers and anti-SARS-CoV-2 antibodies in COVID-19 mortality: A prospective cohort study. Int J Infect Dis 2024; 143:107016. [PMID: 38521446 DOI: 10.1016/j.ijid.2024.107016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024] Open
Abstract
OBJECTIVES Despite high global vaccination coverage, it remains unclear how vaccination and anti-SARS-CoV-2 antibodies affect immune responses and inflammation levels in patients with COVID-19. It is further unclear whether the inflammatory response differs depending on antibody levels and whether the combination of antibody and inflammation levels in COVID-19 patients affects mortality rates. METHODS We conducted a prospective multicenter cohort study that included 1031 hospitalized COVID-19 patients from five hospitals. Anti-SARS-CoV-2-spike antibodies, interleukin-6 (IL6), and CRP were measured on hospital admission. The prespecified endpoint was all-cause in-hospital mortality. RESULTS We observed significantly lower levels of CRP (P<0.001) and IL6 (P<0.001) in patients with antibody levels above 1200 BAU/ml. After adjusting for potential confounders, patients with high levels of inflammatory markers (CRP>6 mg/dl or IL6>100 pg/ml) combined with low levels of anti-SARS-CoV-2-spike antibodies (<1200 BAU/ml) were approximately 8 times more likely to die than patients with low inflammatory responses and high antibody levels (CRP: aHR 7.973, 95% CI 2.744-23.169, P<0.001; IL6: aHR 8.973, 95% CI 3.549-22.688, P<0.001). CONCLUSION Hospitalized COVID-19 patients presenting with high inflammatory markers and low antibody levels exhibited the highest mortality risks. Higher antibody levels are associated with lower levels of inflammation in hospitalized COVID-19 patients.
Collapse
Affiliation(s)
- Sylvia Mink
- Central Medical Laboratories, Feldkirch, Austria; Private University in the Principality of Liechtenstein, Triesen, Principality of Liechtenstein.
| | - Heinz Drexel
- Private University in the Principality of Liechtenstein, Triesen, Principality of Liechtenstein; VIVIT Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; Drexel University College of Medicine, Philadelphia, PA, USA
| | - Andreas Leiherer
- Central Medical Laboratories, Feldkirch, Austria; VIVIT Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Matthias Frick
- Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Patrick Reimann
- Private University in the Principality of Liechtenstein, Triesen, Principality of Liechtenstein; Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Christoph H Saely
- Private University in the Principality of Liechtenstein, Triesen, Principality of Liechtenstein; VIVIT Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Peter Fraunberger
- Central Medical Laboratories, Feldkirch, Austria; Private University in the Principality of Liechtenstein, Triesen, Principality of Liechtenstein
| |
Collapse
|
|
2
|
Ivashkin VT, Maslennikov RV, Vasilieva EV, Chipurik ML, Semikova PA, Semenets VV, Russkova TA. Sarilumab is not Inferior to Tocilizumab in the Treatment of Cytokine Release Syndrome in COVID-19. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2023; 33:54-64. [DOI: 10.22416/1382-4376-2023-33-5-54-64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Objective. Cytokine release syndrome (CRS) is a dangerous complication of the new coronavirus infection (COVID-19). The study aimed to compare sarilumab (SAR group) with tocilizumab (TOC group) and patients without anticytokine treatment (CON group) in treatment of CRS in COVID-19.Methods. The retrospective real life study included COVID-19 patients with C-reactive protein(CRP) level >60 mg/l.Results. We enrolled 24 patients in SAR group, 27 patients in TOC group and 47 patients in CON group. Mortality was lower in SAR and TOC groups than in CON group (12.5% and 14.8% vs. 31.9%; p=0.021 and p=0.031) with no difference between SAR and TOC groups (p=0.389). SAR patients unlike TOC patients required intensive care unit admission less frequently then CON patients (16.7% and 25.9% vs. 46.3%; p=0.013 and p=0.077). An increase in oxygen saturation was observed in SAR and TOC groups (p=0.001 and p=0.004; greater in SAR group [p=0.022]), but not in CON group (p=0.764) in 7-10 days after administration of these drugs. The decrease in CRP level was greater in SAR and TOC groups than in CON group (p=0.016 and p<0.011), with no difference between SAR and TOC groups (p=0.236).Conclusion. Sarilumab is not inferior to tocilizumab in COVID-19
Collapse
Affiliation(s)
- V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - R. V. Maslennikov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - E. V. Vasilieva
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - M. L. Chipurik
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - P. A. Semikova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. V. Semenets
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - T. A. Russkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| |
Collapse
|
|
3
|
Kumar S, Basu M, Ghosh P, Pal U, Ghosh MK. COVID-19 therapeutics: Clinical application of repurposed drugs and futuristic strategies for target-based drug discovery. Genes Dis 2023; 10:1402-1428. [PMID: 37334160 PMCID: PMC10079314 DOI: 10.1016/j.gendis.2022.12.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/07/2022] [Accepted: 12/16/2022] [Indexed: 06/17/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.
Collapse
Affiliation(s)
- Sunny Kumar
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, Dakshin Barasat, West Bengal 743372, India
| | - Pratyasha Ghosh
- Department of Economics, Bethune College, University of Calcutta, Kolkata 700006, India
| | - Uttam Pal
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K. Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| |
Collapse
|
|
4
|
Granata V, Fusco R, Villanacci A, Grassi F, Grassi R, Di Stefano F, Petrone A, Fusco N, Ianniello S. Qualitative and semi-quantitative ultrasound assessment in delta and Omicron Covid-19 patients: data from high volume reference center. Infect Agent Cancer 2023; 18:34. [PMID: 37245026 DOI: 10.1186/s13027-023-00515-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023] Open
Abstract
OBJECTIVE to evaluate the efficacy of US, both qualitatively and semi-quantitatively, in the selection of treatment for the Covid-19 patient, using patient triage as the gold standard. METHODS Patients admitted to the Covid-19 clinic to be treated with monoclonal antibodies (mAb) or retroviral treatment and undergoing lung ultrasound (US) were selected from the radiological data set between December 2021 and May 2022 according to the following inclusion criteria: patients with proven Omicron variant and Delta Covid-19 infection; patients with known Covid-19 vaccination with at least two doses. Lung US (LUS) was performed by experienced radiologists. The presence, location, and distribution of abnormalities, such as B-lines, thickening or ruptures of the pleural line, consolidations, and air bronchograms, were evaluated. The anomalous findings in each scan were classified according to the LUS scoring system. Nonparametric statistical tests were performed. RESULTS The LUS score median value in the patients with Omicron variant was 1.5 (1-20) while the LUS score median value in the patients with Delta variant was 7 (3-24). A difference statistically significant was observed for LUS score values among the patients with Delta variant between the two US examinations (p value = 0.045 at Kruskal Wallis test). There was a difference in median LUS score values between hospitalized and non-hospitalized patients for both the Omicron and Delta groups (p value = 0.02 on the Kruskal Wallis test). For Delta patients groups the sensitivity, specificity, positive and negative predictive values, considering a value of 14 for LUS score for the hospitalization, were of 85.29%, 44.44%, 85.29% and 76.74% respectively. CONCLUSIONS LUS is an interesting diagnostic tool in the context of Covid-19, it could allow to identify the typical pattern of diffuse interstitial pulmonary syndrome and could guide the correct management of patients.
Collapse
Affiliation(s)
- Vincenza Granata
- Division of Radiology, "Istituto Nazionale Tumori IRCCS Fondazione Pascale - IRCCS di Napoli", 80131, Naples, Italy
| | | | - Alberta Villanacci
- Department of Radiology and Diagnostic Imaging, National Institute for Infectious Diseases IRCCS Lazzaro Spallanzani, 00149, Rome, Italy
| | - Francesca Grassi
- Division of Radiology, "Università degli Studi della Campania Luigi Vanvitelli", Naples, Italy
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Via della Signora 2, 20122, Milan, Italy
| | - Roberta Grassi
- Division of Radiology, "Università degli Studi della Campania Luigi Vanvitelli", Naples, Italy
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Via della Signora 2, 20122, Milan, Italy
| | - Federica Di Stefano
- Department of Radiology and Diagnostic Imaging, National Institute for Infectious Diseases IRCCS Lazzaro Spallanzani, 00149, Rome, Italy
| | - Ada Petrone
- Department of Radiology and Diagnostic Imaging, National Institute for Infectious Diseases IRCCS Lazzaro Spallanzani, 00149, Rome, Italy
| | - Nicoletta Fusco
- Department of Radiology and Diagnostic Imaging, National Institute for Infectious Diseases IRCCS Lazzaro Spallanzani, 00149, Rome, Italy
| | - Stefania Ianniello
- Department of Radiology and Diagnostic Imaging, National Institute for Infectious Diseases IRCCS Lazzaro Spallanzani, 00149, Rome, Italy
| |
Collapse
|
|
5
|
Mohammed MA. Fighting cytokine storm and immunomodulatory deficiency: By using natural products therapy up to now. Front Pharmacol 2023; 14:1111329. [PMID: 37124230 PMCID: PMC10134036 DOI: 10.3389/fphar.2023.1111329] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 03/14/2023] [Indexed: 05/02/2023] Open
Abstract
A novel coronavirus strain (COVID-19) caused severe illness and mortality worldwide from 31 December 2019 to 21 March 2023. As of this writing, 761,071,826 million cases have been diagnosed worldwide, with 6,879,677 million deaths accorded by WHO organization and has spread to 228 countries. The number of deaths is closely connected to the growth of innate immune cells in the lungs, mainly macrophages, which generate inflammatory cytokines (especially IL-6 and IL-1β) that induce "cytokine storm syndrome" (CSS), multi-organ failure, and death. We focus on promising natural products and their biologically active chemical constituents as potential phytopharmaceuticals that target virus-induced pro-inflammatory cytokines. Successful therapy for this condition is currently rare, and the introduction of an effective vaccine might take months. Blocking viral entrance and replication and regulating humoral and cellular immunity in the uninfected population are the most often employed treatment approaches for viral infections. Unfortunately, no presently FDA-approved medicine can prevent or reduce SARS-CoV-2 access and reproduction. Until now, the most important element in disease severity has been the host's immune response activation or suppression. Several medicines have been adapted for COVID-19 patients, including arbidol, favipiravir, ribavirin, lopinavir, ritonavir, hydroxychloroquine, chloroquine, dexamethasone, and anti-inflammatory pharmaceutical drugs, such as tocilizumab, glucocorticoids, anakinra (IL-1β cytokine inhibition), and siltuximab (IL-6 cytokine inhibition). However, these synthetic medications and therapies have several side effects, including heart failure, permanent retinal damage in the case of hydroxyl-chloroquine, and liver destruction in the case of remdesivir. This review summarizes four strategies for fighting cytokine storms and immunomodulatory deficiency induced by COVID-19 using natural product therapy as a potential therapeutic measure to control cytokine storms.
Collapse
Affiliation(s)
- Mona A. Mohammed
- Medicinal and Aromatic Plants Research Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Giza, Egypt
| |
Collapse
|
|
6
|
Pisareva E, Badiou S, Mihalovičová L, Mirandola A, Pastor B, Kudriavtsev A, Berger M, Roubille C, Fesler P, Klouche K, Cristol J, Thierry AR. Persistence of neutrophil extracellular traps and anticardiolipin auto-antibodies in post-acute phase COVID-19 patients. J Med Virol 2023; 95:e28209. [PMID: 36226380 PMCID: PMC9874393 DOI: 10.1002/jmv.28209] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/06/2022] [Accepted: 10/03/2022] [Indexed: 01/27/2023]
Abstract
In the early phase of the pandemic, we were among the first to postulate that neutrophil extracellular traps (NETs) play a key role in COVID-19 pathogenesis. This exploratory prospective study based on 279 individuals showed that plasma levels of neutrophil elastase, myeloperoxidase and circulating DNA of nuclear and mitochondrial origins in nonsevere (NS), severe (S) and postacute phase (PAP) COVID-19 patients were statistically different as compared to the levels in healthy individuals, and revealed the high diagnostic power of these NETs markers in respect to the disease severity. The diagnostic power of NE, MPO, and cir-nDNA as determined by the Area Under Receiver Operating Curves (AUROC) was 0.95, 097, and 0.64; 0.99, 1.0, and 0.82; and 0.94, 1.0, and 0.93, in NS, S, and PAP patient subgroups, respectively. In addition, a significant fraction of NS, S as well as of PAP patients exhibited aCL IgM/IgG and anti-B2GP IgM/IgG positivity. We first demonstrate persistence of these NETs markers in PAP patients and consequently of sustained innate immune response imbalance, and a prolonged low-level pro-thrombotic potential activity highlighting the need to monitor these markers in all COVID-19 PAP individuals, to investigate postacute COVID-19 pathogenesis following intensive care, and to better identify which medical resources will ensure complete patient recovery.
Collapse
Affiliation(s)
- Ekaterina Pisareva
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut Régional du Cancer de MontpellierUniversité de MontpellierMontpellierFrance
| | - Stephanie Badiou
- Department of Biochemistry and Hormonology, INSERM, CNRS, University Hospital Center of MontpellierUniversity of Montpellier, PhyMedExpMontpellierFrance
| | - Lucia Mihalovičová
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut Régional du Cancer de MontpellierUniversité de MontpellierMontpellierFrance
- Faculty of Medicine, Institute of Molecular BiomedicineComenius UniversityBratislavaSlovakia
| | - Alexia Mirandola
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut Régional du Cancer de MontpellierUniversité de MontpellierMontpellierFrance
| | - Brice Pastor
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut Régional du Cancer de MontpellierUniversité de MontpellierMontpellierFrance
| | - Andrei Kudriavtsev
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut Régional du Cancer de MontpellierUniversité de MontpellierMontpellierFrance
| | - Marie Berger
- Department of Internal Medicine, INSERM U1046, CNRS, Montpellier University Hospital, Montpellier, PhyMedExpUniversity of MontpellierMontpellierFrance
| | - Camille Roubille
- Department of Internal Medicine, INSERM U1046, CNRS, Montpellier University Hospital, Montpellier, PhyMedExpUniversity of MontpellierMontpellierFrance
| | - Pierre Fesler
- Department of Internal Medicine, INSERM U1046, CNRS, Montpellier University Hospital, Montpellier, PhyMedExpUniversity of MontpellierMontpellierFrance
| | - Kada Klouche
- Intensive Care Medicine Department, INSERM, CNRS, Lapeyronie HospitalUniversity Hospital of Montpellier, France, and PhyMedExp, University of MontpellierMontpellierFrance
| | - Jean‐Paul Cristol
- Department of Biochemistry and Hormonology, INSERM, CNRS, University Hospital Center of MontpellierUniversity of Montpellier, PhyMedExpMontpellierFrance
| | - Alain R. Thierry
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Institut Régional du Cancer de MontpellierUniversité de MontpellierMontpellierFrance
- Montpellier Cancer Institute (ICM)MontpellierFrance
| |
Collapse
|
|
7
|
Shalaby H, Abd ElMaksoud S, Ezzelregal H, ElDine Salem D. Assessment of interleukin-6 role in detecting coronavirus disease 2019 severity, mortality, and its control: A cohort study. EGYPTIAN JOURNAL OF CHEST DISEASES AND TUBERCULOSIS 2023. [DOI: 10.4103/ecdt.ecdt_75_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023] Open
|
|
8
|
Association of complement pathways with COVID-19 severity and outcomes. Microbes Infect 2022; 25:105081. [PMID: 36494054 PMCID: PMC9726657 DOI: 10.1016/j.micinf.2022.105081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 11/16/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Complement activation has been implicated in COVID-19 pathogenesis. This study aimed to assess the levels of complement activation products and full-length proteins in hospitalized patients with COVID-19 and evaluated if complement pathway markers are associated with outcomes. METHODS Longitudinal measurements of complement biomarkers from 89 hospitalized adult patients, grouped by baseline disease severity, enrolled in an adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial and treated with intravenous sarilumab (200 mg or 400 mg) or placebo (NCT04315298) were performed. These measurements were then correlated with clinical and laboratory parameters. RESULTS All complement pathways were activated in hospitalized patients with COVID-19. Alternative pathway activation was predominant earlier in the disease course. Complement biomarkers correlated with multiple variables of multi-organ dysfunction and inflammatory injury. High plasma sC5b-9, C3a, factor Bb levels, and low mannan-binding lectin levels were associated with increased mortality. Sarilumab treatment showed a modest inhibitory effect on complement activation. Moreover, sera from patients spontaneously deposited C5b-9 complex on the endothelial surface ex vivo, suggesting a microvascular thrombotic potential. CONCLUSION These results advance our understanding of COVID-19 disease pathophysiology and demonstrate the importance of specific complement pathway components as prognostic biomarkers in COVID-19.
Collapse
|
|
9
|
Zebardast A, Latifi T, Shabani M, Hasanzadeh A, Danesh M, Babazadeh S, Sadeghi F. Thrombotic storm in coronavirus disease 2019: from underlying mechanisms to its management. J Med Microbiol 2022; 71. [PMID: 36346830 DOI: 10.1099/jmm.0.001591] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Introduction. Coronavirus disease 2019 (COVID-19) identified in December 2019 in Wuhan, China, is associated with high mortality rates worldwide.Hypothesis/Gap Statement. Thrombotic problems, such as coagulopathy, are common in COVID-19 patients. Despite anticoagulation, thrombosis is more common in patients in the intensive care unit and patients with more severe disease. Although the exact mechanisms of coagulopathy in COVID-19 patients are still unclear, studies showed that overactivation of the renin-angiotensin system (RAS), cytokine storm, endothelial damage, formation of neutrophil extracellular traps (NETs), and also extracellular vesicles (EVs) in response to COVID-19 induced inflammation can lead to systemic coagulation and thrombosis.Aim. The management of COVID-19 patients requires the use of basic and readily available laboratory markers, both on admission and during hospitalization. Because it is critical to understand the pathophysiology of COVID-19 induced coagulopathy and treatment strategies, in this review we attempt to explain the underlying mechanism of COVID-19 coagulopathy, its diagnosis, and the associated successful treatment strategies.Conclusion. The exact mechanisms behind COVID-19-related coagulopathy are still unclear, but several studies revealed some mechanisms. More research is needed to determine the best anticoagulant regimen and to study other therapeutic options.
Collapse
Affiliation(s)
- Arghavan Zebardast
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Tayebeh Latifi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Shabani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hasanzadeh
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Golestan, Iran
| | - Manizheh Danesh
- Assistant Professor, Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sara Babazadeh
- Department of Pathology, Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Farzin Sadeghi
- Cellular & Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| |
Collapse
|
|
10
|
Ascierto PA, Agarwala SS, Blank C, Caracò C, Carvajal RD, Ernstoff MS, Ferrone S, Fox BA, Gajewski TF, Garbe C, Grob JJ, Hamid O, Krogsgaard M, Lo RS, Lund AW, Madonna G, Michielin O, Neyns B, Osman I, Peters S, Poulikakos PI, Quezada SA, Reinfeld B, Zitvogel L, Puzanov I, Thurin M. Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 2nd - 4th, 2021, Italy). J Transl Med 2022; 20:391. [PMID: 36058945 PMCID: PMC9440864 DOI: 10.1186/s12967-022-03592-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/15/2022] [Indexed: 01/18/2023] Open
Abstract
Advances in immune checkpoint and combination therapy have led to improvement in overall survival for patients with advanced melanoma. Improved understanding of the tumor, tumor microenvironment and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. Combination modalities with other immunotherapy agents, chemotherapy, radiotherapy, electrochemotherapy are also being explored to overcome resistance and to potentiate the immune response. In addition, novel approaches such as adoptive cell therapy, oncogenic viruses, vaccines and different strategies of drug administration including sequential, or combination treatment are being tested. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic theràapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers, but they have yet to be fully characterized and implemented clinically. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. Overall, the future research efforts in melanoma therapeutics and translational research should focus on several aspects including: (a) developing robust biomarkers to predict efficacy of therapeutic modalities to guide clinical decision-making and optimize treatment regimens, (b) identifying mechanisms of therapeutic resistance to immune checkpoint inhibitors that are potentially actionable, (c) identifying biomarkers to predict therapy-induced adverse events, and (d) studying mechanism of actions of therapeutic agents and developing algorithms to optimize combination treatments. During the Melanoma Bridge meeting (December 2nd-4th, 2021, Naples, Italy) discussions focused on the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine as well as the impact of COVID-19 pandemic on management of melanoma patients.
Collapse
Affiliation(s)
- Paolo A Ascierto
- Department of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumor IRCCS "Fondazione G. Pascale", Naples, Italy.
| | - Sanjiv S Agarwala
- Hematology & Oncology, Temple University and Cancer Expert Now, Bethlehem, PA, USA
| | | | - Corrado Caracò
- Division of Surgery of Melanoma and Skin Cancer, Istituto Nazionale Tumori "Fondazione Pascale" IRCCS, Naples, Italy
| | - Richard D Carvajal
- Division of Hematology and Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Marc S Ernstoff
- Developmental Therapeutics Program, Division of Cancer Therapy & Diagnosis, NCI, Bethesda, NIHMD, USA
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Bernard A Fox
- Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Cancer Institute, Portland, OR, USA
| | - Thomas F Gajewski
- Department of Pathology and Department of Medicine (Section of Hematology/Oncology), University of Chicago, Chicago, IL, USA
| | - Claus Garbe
- Center for Dermato-Oncology, University-Department of Dermatology, Tuebingen, Germany
| | - Jean-Jacques Grob
- Dermatology Department, Hopital de La Timone, Aix-Marseille, Marseille, France
| | - Omid Hamid
- Medical Oncology, The Angeles Clinic and Research Institute, a Cedar-Sinai Affiliate, Los Angeles, CA, USA
| | - Michelle Krogsgaard
- New York Grossman School of Medicine, New York University Langone, New York, NY, USA
| | - Roger S Lo
- Jonsson Comprehensive Cancer Center David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Amanda W Lund
- Ronald O. Perelman Department of Dermatology, Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
| | - Gabriele Madonna
- Department of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Olivier Michielin
- Precision Oncology Center and Melanoma Clinic, Oncology Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Bart Neyns
- Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Iman Osman
- New York University Langone Medical Center, New York, NY, USA
| | - Solange Peters
- UNIL, Medical Oncology Department European Thoracic Oncology Platform (ETOP), Specialized Thoracic Tumor Consultation, Oncology Department UNIL CHUV Thoracic Tumor Center, Lausanne University ESMO President, Scientific Coordinator, Lausanne, Switzerland
| | - Poulikos I Poulikakos
- Department of Oncological Sciences, Department of Dermatology Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, USA
| | - Sergio A Quezada
- Cancer Immunology Unit, Research Department of Hematology, University College London Cancer Institute, London, UK
| | - Bradley Reinfeld
- Department of Medicine, Department of Medicine, Division of Hematology/Oncology Vanderbilt University Medical Center (VUMC), Graduate Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA
| | - Laurence Zitvogel
- Tumour Immunology and Immunotherapy of Cancer, European Academy of Tumor Immunology, Gustave Roussy, University Paris Saclay, INSERM, Villejuif Grand-Paris, France
| | - Igor Puzanov
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Magdalena Thurin
- Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, Rockville, NIHMD, USA
| |
Collapse
|
|
11
|
Jiang Y, Zhao T, Zhou X, Xiang Y, Gutierrez‐Castrellon P, Ma X. Inflammatory pathways in COVID-19: Mechanism and therapeutic interventions. MedComm (Beijing) 2022; 3:e154. [PMID: 35923762 PMCID: PMC9340488 DOI: 10.1002/mco2.154] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing an inflammatory cytokine storm in severe cases. Cytokine storm leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is an important cause of COVID-19 progression and even death. Among them, activation of inflammatory pathways is a major factor in generating cytokine storms and causing dysregulated immune responses, which is closely related to the severity of viral infection. Therefore, elucidation of the inflammatory signaling pathway of SARS-CoV-2 is important in providing otential therapeutic targets and treatment strategies against COVID-19. Here, we discuss the major inflammatory pathways in the pathogenesis of COVID-19, including induction, function, and downstream signaling, as well as existing and potential interventions targeting these cytokines or related signaling pathways. We believe that a comprehensive understanding of the regulatory pathways of COVID-19 immune dysregulation and inflammation will help develop better clinical therapy strategies to effectively control inflammatory diseases, such as COVID-19.
Collapse
Affiliation(s)
- Yujie Jiang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Tingmei Zhao
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Xueyan Zhou
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduPR China
| | - Yu Xiang
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
| | - Pedro Gutierrez‐Castrellon
- Center for Translational Research on Health Science Hospital General Dr. Manuel Gea GonzalezMinistry of HealthMexico CityMexico
| | - Xuelei Ma
- Department of BiotherapyState Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan UniversityChengduPR China
| |
Collapse
|
|
12
|
Sivapalasingam S, Lederer DJ, Bhore R, Hajizadeh N, Criner G, Hosain R, Mahmood A, Giannelou A, Somersan-Karakaya S, O’Brien MP, Boyapati A, Parrino J, Musser BJ, Labriola-Tompkins E, Ramesh D, Purcell LA, Gulabani D, Kampman W, Waldron A, Ng Gong M, Saggar S, Sperber SJ, Menon V, Stein DK, Sobieszczyk ME, Park W, Aberg JA, Brown SM, Kosmicki JA, Horowitz JE, Ferreira MA, Baras A, Kowal B, Thomas DiCioccio A, Akinlade B, Nivens MC, Braunstein N, Herman GA, Yancopoulos GD, Weinreich DM. Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial. Clin Infect Dis 2022; 75:e380-e388. [PMID: 35219277 PMCID: PMC8903479 DOI: 10.1093/cid/ciac153] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION NCT04315298.
Collapse
Affiliation(s)
| | | | - Rafia Bhore
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Negin Hajizadeh
- Institute for Clinical Outcomes Research, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, New York, and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health, Hempstead, New York, New York, USA
| | - Gerard Criner
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Romana Hosain
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Adnan Mahmood
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | | | | | | | - Anita Boyapati
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Janie Parrino
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Bret J Musser
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | | | - Divya Ramesh
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Lisa A Purcell
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Daya Gulabani
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Wendy Kampman
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Alpana Waldron
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | | | - Suraj Saggar
- Department of Infectious Disease, Holy Name Medical Center, Teaneck, New Jersey, USA
| | - Steven J Sperber
- Department of Infectious Disease, Hackensack Meridian School of Medicine and Hackensack University Medical Center, Hackensack, New Jersey, USA
| | - Vidya Menon
- Department of Medicine, NYC Health + Hospitals/Lincoln, Bronx, New York, USA
| | - David K Stein
- Department of Medicine, Jacobi Medical Center, Bronx, New York, USA
| | | | - William Park
- Pulmonary and Sleep Disorder Clinic, Valley Medical Center, Renton, Washington, USA
| | - Judith A Aberg
- Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USAand
| | - Samuel M Brown
- Department of Internal Medicine, Intermountain Medical Center and University of Utah, Salt Lake City, Utah, USA
| | | | | | | | - Aris Baras
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Bari Kowal
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | | | | | | | - Ned Braunstein
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | - Gary A Herman
- Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA
| | | | | |
Collapse
|
|
13
|
Andaluz-Ojeda D, Vidal-Cortes P, Aparisi Sanz Á, Suberviola B, Del Río Carbajo L, Nogales Martín L, Prol Silva E, Nieto del Olmo J, Barberán J, Cusacovich I. Immunomodulatory therapy for the management of critically ill patients with COVID-19: A narrative review. World J Crit Care Med 2022; 11:269-297. [PMID: 36051937 PMCID: PMC9305685 DOI: 10.5492/wjccm.v11.i4.269] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 12/01/2021] [Accepted: 05/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. AIM To describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of hyperinflammation and abnormal immune responses to disease progression together with a complete narrative review of the different immunoadjuvant treatments used so far in COVID-19 and their indication in severe and life-threatening subsets. METHODS A comprehensive literature search was developed. Authors reviewed the selected manuscripts following the PRISMA recommendations for systematic review and meta-analysis documents and selected the most appropriate. Finally, a recommendation of the use of each treatment was established based on the level of evidence of the articles and documents reviewed. This recommendation was made based on the consensus of all the authors. RESULTS A brief rationale on the SARS-CoV-2 pathogenesis, immune response, and inflammation was developed. The usefulness of 10 different families of treatments related to inflammation and immunopathogenesis of COVID-19 was reviewed and discussed. Finally, based on the level of scientific evidence, a recommendation was established for each of them. CONCLUSION Although several promising therapies exist, only the use of corticosteroids and tocilizumab (or sarilumab in absence of this) have demonstrated evidence enough to recommend its use in critically ill patients with COVID-19. Endotypes including both, clinical and biological characteristics can constitute specific targets for better select certain therapies based on an individualized approach to treatment.
Collapse
Affiliation(s)
- David Andaluz-Ojeda
- Department of Critical Care, Hospital Universitario HM Sanchinarro, Hospitales Madrid, Madrid 28050, Spain
| | - Pablo Vidal-Cortes
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | | | - Borja Suberviola
- Department of Intensive Care, Hospital Universitario Marqués de Valdecilla, Santander 39008, Spain
| | - Lorena Del Río Carbajo
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | - Leonor Nogales Martín
- Department of Intensive Care, Hospital Clínico Universitario de Valladolid, Valladolid 47005, Spain
| | - Estefanía Prol Silva
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | - Jorge Nieto del Olmo
- Department of Intensive Care, Complejo Hospitalario Universitario de Ourense, Ourense 32005, Spain
| | - José Barberán
- Department of Internal Medicine, Hospital Universitario HM Montepríncipe, Hospitales Madrid, Boadilla del Monte 28860, Madrid, Spain
| | - Ivan Cusacovich
- Department of Internal Medicine, Hospital Clínico Universitario de Valladolid, Valladolid 47005, Spain
| |
Collapse
|
|
14
|
Scavone C, Mascolo A, Rafaniello C, Sportiello L, Trama U, Zoccoli A, Bernardi FF, Racagni G, Berrino L, Castaldo G, Coscioni E, Rossi F, Capuano A. Therapeutic strategies to fight COVID-19: Which is the status artis? Br J Pharmacol 2022; 179:2128-2148. [PMID: 33960398 PMCID: PMC8239658 DOI: 10.1111/bph.15452] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is a complex disease, and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated and evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, whereas the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. There are conflicting data on the use of convalescent plasma and vitamin D. According to the World Health Organization (WHO), many vaccines are in Phase III clinical trials, and some of them have already received marketing approval in European countries and in the United States. In conclusion, drug repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, analysis of efficacy and safety data of drugs and vaccines used in real-life context is strongly needed. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.
Collapse
Affiliation(s)
- Cristina Scavone
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Annamaria Mascolo
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Concetta Rafaniello
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Liberata Sportiello
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Ugo Trama
- Regional Pharmaceutical UnitU.O.D. 06 Politica del Farmaco e DispositiviNaplesItaly
| | - Alice Zoccoli
- Clinical Innovation OfficeUniversità Campus Bio‐MedicoRomeItaly
| | - Francesca Futura Bernardi
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
- Regional Pharmaceutical UnitU.O.D. 06 Politica del Farmaco e DispositiviNaplesItaly
| | - Giorgio Racagni
- Department of Pharmacological and Biomolecular SciencesUniversity of MilanMilanItaly
| | - Liberato Berrino
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| | - Giuseppe Castaldo
- Department of Molecular Medicine and Medical BiotechnologyUniversity of Napoli Federico IINaplesItaly
- CEINGE—Advanced Biotechnology ScarlNaplesItaly
| | | | - Francesco Rossi
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
- Clinical Innovation OfficeUniversità Campus Bio‐MedicoRomeItaly
| | - Annalisa Capuano
- Department of Experimental MedicineUniversità degli studi della Campania ‘Luigi Vanvitelli’NaplesItaly
| |
Collapse
|
|
15
|
Niedźwiedzka-Rystwej P, Majchrzak A, Kurkowska S, Małkowska P, Sierawska O, Hrynkiewicz R, Parczewski M. Immune Signature of COVID-19: In-Depth Reasons and Consequences of the Cytokine Storm. Int J Mol Sci 2022; 23:4545. [PMID: 35562935 PMCID: PMC9105989 DOI: 10.3390/ijms23094545] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023] Open
Abstract
In the beginning of the third year of the fight against COVID-19, the virus remains at least still one step ahead in the pandemic "war". The key reasons are evolving lineages and mutations, resulting in an increase of transmissibility and ability to evade immune system. However, from the immunologic point of view, the cytokine storm (CS) remains a poorly understood and difficult to combat culprit of the extended number of in-hospital admissions and deaths. It is not fully clear whether the cytokine release is a harmful result of suppression of the immune system or a positive reaction necessary to clear the virus. To develop methods of appropriate treatment and therefore decrease the mortality of the so-called COVID-19-CS, we need to look deeply inside its pathogenesis, which is the purpose of this review.
Collapse
Affiliation(s)
| | - Adam Majchrzak
- Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, 71-455 Szczecin, Poland; (A.M.); (M.P.)
| | - Sara Kurkowska
- Department of Nuclear Medicine, Pomeranian Medical University, 71-252 Szczecin, Poland;
| | - Paulina Małkowska
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (P.M.); (O.S.); (R.H.)
- Doctoral School, University of Szczecin, 71-412 Szczecin, Poland
| | - Olga Sierawska
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (P.M.); (O.S.); (R.H.)
- Doctoral School, University of Szczecin, 71-412 Szczecin, Poland
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (P.M.); (O.S.); (R.H.)
| | - Miłosz Parczewski
- Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, 71-455 Szczecin, Poland; (A.M.); (M.P.)
| |
Collapse
|
|
16
|
Elahi R, Karami P, Heidary AH, Esmaeilzadeh A. An updated overview of recent advances, challenges, and clinical considerations of IL-6 signaling blockade in severe coronavirus disease 2019 (COVID-19). Int Immunopharmacol 2022; 105:108536. [PMID: 35074571 PMCID: PMC8747952 DOI: 10.1016/j.intimp.2022.108536] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 01/01/2022] [Accepted: 01/07/2022] [Indexed: 02/07/2023]
Abstract
Since 2019, COVID-19 has become the most important health dilemma around the world. The dysregulated immune response which results in ARDS and cytokine storm has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through induction of pro-inflammatory chemokines and cytokines, is the pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, IL-6 pathway blockade is considered an emerging approach with high efficacy to reduce lung damage in COVID-19. This article aims to review the pleiotropic roles of the IL-6 pathway in lung damage and ARDS in severe COVID-19, and the rationale for IL-6 signaling blockade at different levels, including IL-6 soluble and membrane receptor pathways, IL-6 downstream signaling (such as JAK-STAT) inhibition, and non-specific anti-inflammatory therapeutic approaches. Recent clinical data of each method, with specific concentration on tocilizumab, along with other new drugs, such as sarilumab and siltuximab, have been discussed. Challenges of IL-6 signaling inhibition, such as the risk of superinfection and hepatic injury, and possible solutions have also been explained. Moreover, to achieve the highest efficacy, ongoing clinical trials and special clinical considerations of using different IL-6 inhibitors have been discussed in detail. Special considerations, including the appropriate timing and dosage, monotherapy or combination therapy, and proper side effect managment must be noticed regarding the clinical administration of these drugs. Future studies are still necessary to improve the productivity and unknown aspects of IL-6 signaling blockade for personalized treatment of severe COVID-19.
Collapse
Affiliation(s)
- Reza Elahi
- Zanjan University of Medical Sciences, Zanjan, Iran
| | - Parsa Karami
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran; Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
| |
Collapse
|
|
17
|
Zhao X, Zhou L, Kou Y, Kou J. Activated neutrophils in the initiation and progression of COVID-19: hyperinflammation and immunothrombosis in COVID-19. Am J Transl Res 2022; 14:1454-1468. [PMID: 35422922 PMCID: PMC8991139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 01/20/2022] [Indexed: 06/14/2023]
Abstract
Coronavirus disease 2019 (COVID-19) is a pandemic respiratory disease caused by a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). COVID-19 is typically associated with fever and influenza-like symptoms in its early stages. Severe cases progress to acute respiratory distress syndrome/acute lung injury (ARDS/ALI), multiple organ damage, and even death. Until now, there has been a lack of specific and definitive treatment for COVID-19, which further challenges the situation. Previous clinical and laboratory data showed that neutrophils were significantly decreased in patients who died from COVID-19 in the early stages of disease; when patients were admitted to the hospital the number of neutrophils increased dramatically from 7 to 14 days after admission, which is correlated to myocardial and liver injury, thromboembolic complications, and poor prognosis. Autopsy findings revealed abundant neutrophil infiltration in the pulmonary capillaries and exudation into the alveolar cavity. Therefore, we speculate that neutrophils may play an important role in the initiation and progression of COVID-19. In this review, the relationship among the dynamic changes in neutrophils, cytokine storms, and the release of neutrophil extracellular traps (NETs) with the progression of COVID-19 was elucidated in detail. With a better understanding of the pathogenic mechanisms this can lead to improved clinical applications which are identified and discussed in this review.
Collapse
Affiliation(s)
- Xinyi Zhao
- Department of Cardiology of The Second Hospital, Harbin Medical University Harbin 150001, Heilongjiang, China
| | - Lijin Zhou
- Department of Cardiology of The Second Hospital, Harbin Medical University Harbin 150001, Heilongjiang, China
| | - Yan Kou
- Department of Cardiology of The Second Hospital, Harbin Medical University Harbin 150001, Heilongjiang, China
| | - Junjie Kou
- Department of Cardiology of The Second Hospital, Harbin Medical University Harbin 150001, Heilongjiang, China
| |
Collapse
|
|
18
|
García-Vicuña R, Rodriguez-García SC, Abad-Santos F, Bautista Hernández A, García-Fraile L, Barrios Blandino A, Gutiérrez Liarte A, Alonso-Pérez T, Cardeñoso L, Alfranca A, Mejía-Abril G, Sanz Sanz J, González-Alvaro I. Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial. Front Med (Lausanne) 2022; 9:819621. [PMID: 35280907 PMCID: PMC8904894 DOI: 10.3389/fmed.2022.819621] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/10/2022] [Indexed: 12/15/2022] Open
Abstract
Background The use of IL-6 blockers in COVID-19 hospitalized patients has been associated with a reduction in mortality compared to standard care. However, many uncertainties remain pertaining to optimal intervention time, administration schedule, and predictors of response. To date, data on the use of subcutaneous sarilumab is limited and no randomized trial results are available. Methods Open label randomized controlled trial at a single center in Spain. We included adult patients admitted with microbiology documented COVID-19 infection, imaging confirmed pneumonia, fever and/or laboratory evidence of inflammatory phenotype, and no need for invasive ventilation. Participants were randomly assigned to receive sarilumab, a single 400 mg dose in two 200 mg subcutaneous injections, added to standard care or standard care, in a 2:1 proportion. Primary endpoints included 30-day mortality, mean change in clinical status at day 7 scored in a 7-category ordinal scale ranging from death (category 1) to discharge (category 7), and duration of hospitalization. The primary efficacy analysis was conducted on the intention-to-treat population. Results A total of 30 patients underwent randomization: 20 to sarilumab and 10 to standard care. Most patients were male (20/30, 67%) with a median (interquartile range) age of 61.5 years (56-72). At day 30, 2/20 (10%) patients died in the sarilumab arm vs. none (0/10) in standard care (Log HR 15.11, SE 22.64; p = 0.54). At day 7, no significant differences were observed in the median change in clinical status (2 [0-3]) vs. 3 [0-3], p = 0.32). Median time to discharge (days) was similar (7 [6-11] vs. 6 [4-12]; HR 0.65, SE 0.26; p = 0.27). No significant differences were detected in the rate of progression to invasive and noninvasive mechanical ventilation. Conclusions and Relevance Our pragmatic pilot study has failed to demonstrate the benefit of adding subcutaneous sarilumab to standard care for mortality by 30 days, functional status at day 7, or hospital stay. Findings herein do not exclude a potential effect of sarilumab in severe COVID-19 but adequately powered blinded randomized phase III trials are warranted to assess the impact of the subcutaneous route and a more selected target population. Trial Registration www.ClinicalTrials.gov, Identifier: NCT04357808.
Collapse
Affiliation(s)
- Rosario García-Vicuña
- Rheumatology Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain.,Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Sebastián C Rodriguez-García
- Rheumatology Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Francisco Abad-Santos
- Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,Department of Clinical Pharmacology, Clinical Research and Clinical Trials Unit (CRCTU), Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Azucena Bautista Hernández
- Division of Infectious Diseases, Internal Medicine Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Lucio García-Fraile
- Division of Infectious Diseases, Internal Medicine Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Ana Barrios Blandino
- Division of Infectious Diseases, Internal Medicine Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Angela Gutiérrez Liarte
- Division of Infectious Diseases, Internal Medicine Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Tamara Alonso-Pérez
- Pneumology Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Laura Cardeñoso
- Department of Microbiology, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Aránzazu Alfranca
- Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,Immunology Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Gina Mejía-Abril
- Department of Clinical Pharmacology, Clinical Research and Clinical Trials Unit (CRCTU), Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Jesús Sanz Sanz
- Division of Infectious Diseases, Internal Medicine Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| | - Isidoro González-Alvaro
- Rheumatology Service, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Hospital Universitario La Princesa, Madrid, Spain
| |
Collapse
|
|
19
|
Al-Hajeri H, Baroun F, Abutiban F, Al-Mutairi M, Ali Y, Alawadhi A, Albasri A, Aldei A, AlEnizi A, Alhadhood N, Al-Herz A, Alkadi A, Alkanderi W, Almathkoori A, Almutairi N, Alsayegh S, Alturki A, Bahbahani H, Dehrab A, Ghanem A, Haji Hasan E, Hayat S, Saleh K, Tarakmeh H. Therapeutic role of immunomodulators during the COVID-19 pandemic- a narrative review. Postgrad Med 2022; 134:160-179. [PMID: 35086413 PMCID: PMC8862162 DOI: 10.1080/00325481.2022.2033563] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/18/2022] [Indexed: 02/07/2023]
Abstract
The emergency state caused by COVID-19 saw the use of immunomodulators despite the absence of robust research. To date, the results of relatively few randomized controlled trials have been published, and methodological approaches are riddled with bias and heterogeneity. Anti-SARS-CoV-2 antibodies, convalescent plasma and the JAK inhibitor baricitinib have gained Emergency Use Authorizations and tentative recommendations for their use in clinical practice alone or in combination with other therapies. Anti-SARS-CoV-2 antibodies are predominating the management of non-hospitalized patients, while the inpatient setting is seeing the use of convalescent plasma, baricitinib, tofacitinib, tocilizumab, sarilumab, and corticosteroids, as applicable. Available clinical data also suggest the potential clinical benefit of the early administration of blood-derived products (e.g. convalescent plasma, non-SARS-CoV-2-specific immunoglobins) and the blockade of factors implicated in the hyperinflammatory state of severe COVID-19 (Interleukin 1 and 6; Janus Kinase). Immune therapies seem to have a protective effect and using immunomodulators alone or in combination with viral replication inhibitors and other treatment modalities might prevent progression into severe COVID-19 disease, cytokine storm and death. Future trials should address existing gaps and reshape the landscape of COVID-19 management.
Collapse
Affiliation(s)
- Hebah Al-Hajeri
- Department of Rheumatology and Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Fatemah Baroun
- Department of Rheumatology and Internal Medicine, AlJahra Hospital, Al-Jahra, Kuwait
| | - Fatemah Abutiban
- Department of Rheumatology and Internal Medicine, Jaber Al-Ahmad Hospital, South Surra, Kuwait
| | | | - Yasser Ali
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Adel Alawadhi
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Anwar Albasri
- Rheumatology Unit, Department of Internal Medicine, Jaber Al-Ahmad Hospital, South Surra, Kuwait
| | - Ali Aldei
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Ahmad AlEnizi
- Rheumatology Unit, Department of Internal Medicine, AlJahra Hospital, AlJahra, Kuwait
| | - Naser Alhadhood
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Adeeba Al-Herz
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Amjad Alkadi
- Rheumatology Unit, Department of Internal Medicine, Al-Sabah Hospital, Alsabah, Kuwait
| | - Waleed Alkanderi
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Ammar Almathkoori
- Rheumatology Unit, Department of Internal Medicine, Al-Adan Hospital, Hadiya, Kuwait
| | - Nora Almutairi
- Rheumatology Unit, Department of Internal Medicine, Al-Sabah Hospital, Alsabah, Kuwait
| | - Saud Alsayegh
- Rheumatology Unit, Department of Internal Medicine, Jaber Al-Ahmad Armed Forces, Kuwait City, Kuwait
| | - Ali Alturki
- Rheumatology Unit, Department of Internal Medicine, Al-Adan Hospital, Hadiya, Kuwait
| | - Husain Bahbahani
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Ahmad Dehrab
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Aqeel Ghanem
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Eman Haji Hasan
- Rheumatology Unit, Department of Internal Medicine, Al-Amiri Hospital, Kuwait City, Kuwait
| | - Sawsan Hayat
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Khuloud Saleh
- Rheumatology Unit, Department of Internal Medicine, Farwaneyah Hospital, AlFarwaniya, Kuwait
| | - Hoda Tarakmeh
- Rheumatology Unit, Department of Internal Medicine, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| |
Collapse
|
|
20
|
Kumar A, Sharma A, Tirpude NV, Sharma S, Padwad YS, Kumar S. Pharmaco-immunomodulatory interventions for averting cytokine storm-linked disease severity in SARS-CoV-2 infection. Inflammopharmacology 2022; 30:23-49. [PMID: 35048262 PMCID: PMC8769772 DOI: 10.1007/s10787-021-00903-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/24/2021] [Indexed: 12/15/2022]
Abstract
The year 2020 is characterised by the COVID-19 pandemic that has quelled more than half a million lives in recent months. We are still coping with the negative repercussions of COVID-19 pandemic in 2021, in which the 2nd wave in India resulted in a high fatality rate. Regardless of emergency vaccine approvals and subsequent meteoric global vaccination drives in some countries, hospitalisations for COVID-19 will continue to occur due to the propensity of mutation in SARS-CoV-2 virus. The immune response plays a vital role in the control and resolution of infectious diseases. However, an impaired immune response is responsible for the severity of the respiratory distress in many diseases. The severe COVID-19 infection persuaded cytokine storm that has been linked with acute respiratory distress syndrome (ARDS), culminates into vital organ failures and eventual death. Thus, safe and effective therapeutics to treat hospitalised patients remains a significant unmet clinical need. In that state, any clue of possible treatments, which save patients life, can be treasured for this time point. Many cohorts and clinical trial studies demonstrated that timely administration of immunomodulatory drugs on severe COVID-19 patients may mitigate the disease severity, hospital stay and mortality. This article addresses the severity and risk factors of hypercytokinemia in COVID-19 patients, with special emphasis on prospective immunomodulatory therapies.
Collapse
Affiliation(s)
- Arbind Kumar
- COVID-19 Testing facility, CSIR-Institute of Himalayan Bioresource Technology (IHBT), Palampur, Himachal Pradesh India
| | - Aashish Sharma
- COVID-19 Testing facility, CSIR-Institute of Himalayan Bioresource Technology (IHBT), Palampur, Himachal Pradesh India
| | - Narendra Vijay Tirpude
- Animal Facility, CSIR-Institute of Himalayan Bioresource Technology (IHBT), Palampur, Himachal Pradesh India
| | - Suresh Sharma
- COVID-19 Testing facility, CSIR-Institute of Himalayan Bioresource Technology (IHBT), Palampur, Himachal Pradesh India
| | - Yogendra S. Padwad
- Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology (IHBT), Palampur, Himachal Pradesh India
| | - Sanjay Kumar
- CSIR-Institute of Himalayan Bioresource Technology (IHBT), Palampur, Himachal Pradesh India
| |
Collapse
|
|
21
|
Yin J, Li C, Ye C, Ruan Z, Liang Y, Li Y, Wu J, Luo Z. Advances in the development of therapeutic strategies against COVID-19 and perspectives in the drug design for emerging SARS-CoV-2 variants. Comput Struct Biotechnol J 2022; 20:824-837. [PMID: 35126885 PMCID: PMC8802458 DOI: 10.1016/j.csbj.2022.01.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/18/2022] [Accepted: 01/27/2022] [Indexed: 12/15/2022] Open
Abstract
Since Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was identified in late 2019, the coronavirus disease 2019 (COVID-19) pandemic has challenged public health around the world. Currently, there is an urgent need to explore antiviral therapeutic targets and effective clinical drugs. In this study, we systematically summarized two main therapeutic strategies against COVID-19, namely drugs targeting the SARS-CoV-2 life cycle and SARS-CoV-2-induced inflammation in host cells. The development of above two strategies is implemented by repurposing drugs and exploring potential targets. A comprehensive summary of promising drugs, especially cytokine inhibitors, and traditional Chinese medicine (TCM), provides recommendations for clinicians as evidence-based medicine in the actual clinical COVID-19 treatment. Considering the emerging SARS-CoV-2 variants greatly impact the effectiveness of drugs and vaccines, we reviewed the appearance and details of SARS-CoV-2 variants for further perspectives in drug design, which brings updating clues to develop therapeutical agents against the variants. Based on this, the development of broadly antiviral drugs, combined with immunomodulatory, or holistic therapy in the host, is prior to being considered for therapeutic interventions on mutant strains of SARS-CoV-2. Therefore, it is highly acclaimed the requirements of the concerted efforts from multi-disciplinary basic studies and clinical trials, which improves the accurate treatment of COVID-19 and optimizes the contingency measures to emerging SARS-CoV-2 variants.
Collapse
Key Words
- ACE2, Angiotensin-converting enzyme 2
- ARDS, acute respiratory distress syndrome
- CEP, Cepharanthine
- COVID-19 pandemic
- COVID-19, coronavirus disease 2019
- CRS, cytokine release syndrome
- CTD, C-terminal domain
- Drug target
- EMA, European Medicines Agency
- ERGIC, endoplasmic reticulum-Golgi intermediate compartment
- FDA, U.S. Food and Drug Administration
- JAK, Janus kinase
- MODS, multiple organ dysfunction syndrome
- NMPA, National Medical Products Administration
- NTD, N-terminal domain
- Nbs, nanobodies
- RBD, receptor-binding domain
- RdRp, RNA dependent RNA polymerase
- SARS-CoV-2
- SARS-CoV-2 variants
- SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2
- STAT, Signal Transducer and Activator of Transcription
- TCM, traditional Chinese medicine
- TCZ, Tocilizumab
- Therapeutic strategies
- VOC, variants of concern
- VOI, variants of interest
- VUM, variants under monitoring
- mAb, monoclonal antibody
- α1AT, alpha-1 antitrypsin
Collapse
Affiliation(s)
- Jialing Yin
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
| | - Chengcheng Li
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
| | - Chunhong Ye
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
| | - Zhihui Ruan
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
- Foshan Institute of Medical Microbiology, Foshan 528315, PR China
| | - Yicong Liang
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
| | - Yongkui Li
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
| | - Jianguo Wu
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
- Foshan Institute of Medical Microbiology, Foshan 528315, PR China
| | - Zhen Luo
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou 510632, PR China
- Foshan Institute of Medical Microbiology, Foshan 528315, PR China
| |
Collapse
|
|
22
|
Talwar D, Kumar S, Acharya S, Raisinghani N, Madaan S, Hulkoti V, Akhilesh A, Khanna S, Shah D, Nimkar S. Interleukin 6 and Its Correlation with COVID-19 in Terms of Outcomes in an Intensive Care Unit of a Rural Hospital: A Cross-sectional Study. Indian J Crit Care Med 2022; 26:39-42. [PMID: 35110842 PMCID: PMC8783243 DOI: 10.5005/jp-journals-10071-24075] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background Methods Result Conclusion How to cite this article
Collapse
Affiliation(s)
- Dhruv Talwar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Sunil Kumar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
- Sunil Kumar, Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India, e-mail:
| | - Sourya Acharya
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Nitin Raisinghani
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Sparsh Madaan
- Department of Obstetrics and Gynaecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Vidyashree Hulkoti
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Annadatha Akhilesh
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Shivam Khanna
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Divit Shah
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| | - Shubham Nimkar
- Department of Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India
| |
Collapse
|
|
23
|
Raina R, Sethi SK, Chakraborty R, Singh S, Teo S, Khooblall A, Montini G, Bunchman T, Topaloglu R, Yap HK. Blood Filters in Children with COVID-19 and AKI: A Review. Ther Apher Dial 2022; 26:566-582. [PMID: 34997670 DOI: 10.1111/1744-9987.13793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/11/2021] [Accepted: 01/03/2022] [Indexed: 11/28/2022]
Abstract
COVID-19 has challenged the global healthcare system through rapid proliferation and lack of existing treatment resulting in over 180 million cases and 3.8 million deaths since December 2019. Although pediatric patients only comprise 1-2% of diagnosed cases, their incidence of acute kidney injury ranges from 8.2% to 18.2% compared to 49% in adults. Severe infection, initiated by dysregulated host response, can lead to multiorgan failure. In this review, we focus on the use of various blood filters approved for use in pediatric kidney replacement therapy to mitigate adverse effects of severe illness. Therapeutic effects of these blood filters range from cytokine removal (CytoSorb, HA330, HCO/MCO), endotoxin removal (Toraymyxin, CPFA), both cytokine and endotoxin removal (oXiris), and non-specific removal of proteins (PMMA) that have already been established and can be used to mitigate the various effects of the cytokine storm syndrome in COVID-19.
Collapse
Affiliation(s)
- Rupesh Raina
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH.,Department of Nephrology, Akron Children's Hospital, Akron, OH
| | - Sidharth Kumar Sethi
- Pediatric Nephrology, Kidney Institute, Medanta, The Medicity Hospital, Gurgaon, Haryana, India
| | - Ronith Chakraborty
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH.,Department of Nephrology, Akron Children's Hospital, Akron, OH
| | - Siddhartha Singh
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH.,Department of Nephrology, Akron Children's Hospital, Akron, OH
| | - Sharon Teo
- Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore, Singapore
| | - Amrit Khooblall
- Akron Nephrology Associates/Cleveland Clinic Akron General Medical Center, Akron, OH.,Department of Nephrology, Akron Children's Hospital, Akron, OH
| | - Giovanni Montini
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione Ca' Granda IRCCS, Policlinico di Milano, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy
| | - Timothy Bunchman
- Pediatric Nephrology & Transplantation, Children's Hospital of Richmond at VCU, Richmond, VA
| | - Rezan Topaloglu
- Department of Pediatric Nephrology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Hui Kim Yap
- Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore, Singapore.,Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
24
|
Rezabakhsh A, Sadat‐Ebrahimi S, Ala A, Nabavi SM, Banach M, Ghaffari S. A close-up view of dynamic biomarkers in the setting of COVID-19: Striking focus on cardiovascular system. J Cell Mol Med 2022; 26:274-286. [PMID: 34894069 PMCID: PMC8743667 DOI: 10.1111/jcmm.17122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 10/15/2021] [Accepted: 12/01/2021] [Indexed: 01/08/2023] Open
Abstract
Based on the recent reports, cardiovascular events encompass a large portion of the mortality caused by the COVID-19 pandemic, which drawn cardiologists into the management of the admitted ill patients. Given that common laboratory values may provide key insights into the illness caused by the life-threatening SARS-CoV-2 virus, it would be more helpful for screening, clinical management and on-time therapeutic strategies. Commensurate with these issues, this review article aimed to discuss the dynamic changes of the common laboratory parameters during COVID-19 and their association with cardiovascular diseases. Besides, the values that changed in the early stage of the disease were considered and monitored during the recovery process. The time required for returning biomarkers to basal levels was also discussed. Finally, of particular interest, we tended to abridge the latest updates regarding the cardiovascular biomarkers as prognostic and diagnostic criteria to determine the severity of COVID-19.
Collapse
Affiliation(s)
- Aysa Rezabakhsh
- Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Alireza Ala
- Emergency Medicine Research TeamTabriz University of Medical SciencesTabrizIran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research CenterBaqiyatallah University of Medical SciencesTehranIran
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and HypertensionMedical University of LodzLodzPoland
- Polish Mother’s Memorial Hospital Research Institute (PMMHRI)LodzPoland
| | - Samad Ghaffari
- Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
| |
Collapse
|
|
25
|
Wanhella KJ, Fernandez-Patron C. Biomarkers of ageing and frailty may predict COVID-19 severity. Ageing Res Rev 2022; 73:101513. [PMID: 34838734 PMCID: PMC8611822 DOI: 10.1016/j.arr.2021.101513] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/11/2021] [Accepted: 11/09/2021] [Indexed: 01/08/2023]
Abstract
Coronavirus Disease 2019 (COVID-19) is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) - the culprit of an ongoing pandemic responsible for the loss of over 3 million lives worldwide within a year and a half. While the majority of SARS-CoV-2 infected people develop no or mild symptoms, some become severely ill and may die from COVID-19-related complications. In this review, we compile and comment on a number of biomarkers that have been identified and are expected to enhance the detection, protection and treatment of individuals at high risk of developing severe illnesses, as well as enable the monitoring of COVID-19 prognosis and responsiveness to therapeutic interventions. Consistent with the emerging notion that the majority of COVID-19 deaths occur in older and frail individuals, we researched the scientific literature and report the identification of a subset of COVID-19 biomarkers indicative of increased vulnerability to developing severe COVID-19 in older and frail patients. Mechanistically, increased frailty results from reduced disease tolerance, a phenomenon aggravated by ageing and comorbidities. While biomarkers of ageing and frailty may predict COVID-19 severity, biomarkers of disease tolerance may predict resistance to COVID-19 with socio-economic factors such as access to adequate health care remaining as major non-biomolecular influencers of COVID-19 outcomes.
Collapse
|
|
26
|
Zou H, Yang Y, Dai H, Xiong Y, Wang JQ, Lin L, Chen ZS. Recent Updates in Experimental Research and Clinical Evaluation on Drugs for COVID-19 Treatment. Front Pharmacol 2021; 12:732403. [PMID: 34880750 PMCID: PMC8646041 DOI: 10.3389/fphar.2021.732403] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/13/2021] [Indexed: 12/17/2022] Open
Abstract
Since the outbreak of corona virus disease 2019 (COVID-19) in Wuhan (China) in December 2019, the epidemic has rapidly spread to many countries around the world, posing a huge threat to global public health. In response to the pandemic, a number of clinical studies have been initiated to evaluate the effect of various treatments against COVID-19, combining medical strategies and clinical trial data from around the globe. Herein, we summarize the clinical evaluation about the drugs mentioned in this review for COVID-19 treatment. This review discusses the recent data regarding the efficacy of various treatments in COVID-19 patients, to control and prevent the outbreak.
Collapse
Affiliation(s)
| | - Yuqi Yang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Huiqiang Dai
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Yunchuang Xiong
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Jing-Quan Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| | - Lusheng Lin
- Cell Research Center, Shenzhen Bolun Institute of Biotechnology, Shenzhen, China
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States
| |
Collapse
|
|
27
|
Veenith T, Fisher BA, Slade D, Rowe A, Sharpe R, Thickett DR, Whitehouse T, Rowland M, Scriven J, Parekh D, Bowden SJ, Savage JS, Richards D, Bion J, Kearns P, Gates S. CATALYST trial protocol: a multicentre, open-label, phase II, multiarm trial for an early and accelerated evaluation of the potential treatments for COVID-19 in hospitalised adults. BMJ Open 2021; 11:e050202. [PMID: 34764169 PMCID: PMC8587583 DOI: 10.1136/bmjopen-2021-050202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 10/18/2021] [Indexed: 01/08/2023] Open
Abstract
INTRODUCTION Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. METHODS AND ANALYSIS The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. ETHICS AND DISSEMINATION The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBERS EudraCT2020-001684-89, ISRCTN40580903.
Collapse
Affiliation(s)
- Tonny Veenith
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Department of Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Benjamin A Fisher
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Rheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Daniel Slade
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Anna Rowe
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Rowena Sharpe
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - David R Thickett
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Tony Whitehouse
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Department of Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Matthew Rowland
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - James Scriven
- Department of Infectious Diseases, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Dhruv Parekh
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Department of Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Department of Respiratory Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Sarah J Bowden
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Joshua S Savage
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Duncan Richards
- Oxford Clinical Trials Research Unit, Botnar Research Centre, University of Oxford, Oxford, UK
| | - Julian Bion
- Department of Critical Care Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Pamela Kearns
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon Gates
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| |
Collapse
|
|
28
|
Efficacy and Safety of Sarilumab in COVID-19: A Systematic Review. Interdiscip Perspect Infect Dis 2021; 2021:8903435. [PMID: 34721573 PMCID: PMC8556127 DOI: 10.1155/2021/8903435] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/21/2021] [Accepted: 10/06/2021] [Indexed: 12/29/2022] Open
Abstract
Background It has been found that there is overactivation of immune response in patients with COVID-19. Several studies are going on to assess the role of immunomodulation. IL-6 antibodies such as tocilizumab have been found to have efficacy in the treatment of COVID-19. We aim to assess the role of sarilumab in the treatment of COVID-19 through this review. Main Body. Functional outcomes were assessed on the basis of PaO2/FiO2 ratio, mortality, and ventilation. Adverse events of studies were also noted. Five studies were included in the study. There was improvement in PaO2/FiO2 ratio, reduction in the mortality of the patients, and less number of patients were on ventilation, but there were no significant differences among the comparison and sarilumab group. Sarilumab did not have notable adverse events and can be considered a safe drug. Conclusion Sarilumab is a safe drug with good clinical outcomes in patients with COVID-19 and, hence, could be used as an alternative regimen for the treatment. Further prospective studies exploring the relations with baseline biomarkers of inflammation commonly measured such as C-reactive protein and IL-6 would be necessary for a correlation with the treatment.
Collapse
|
|
29
|
Maraolo AE, Crispo A, Piezzo M, Di Gennaro P, Vitale MG, Mallardo D, Ametrano L, Celentano E, Cuomo A, Ascierto PA, Cascella M. The Use of Tocilizumab in Patients with COVID-19: A Systematic Review, Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Studies. J Clin Med 2021; 10:jcm10214935. [PMID: 34768455 PMCID: PMC8584705 DOI: 10.3390/jcm10214935] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/21/2021] [Accepted: 10/23/2021] [Indexed: 12/22/2022] Open
Abstract
Background: Among the several therapeutic options assessed for the treatment of coronavirus disease 2019 (COVID-19), tocilizumab (TCZ), an antagonist of the interleukine-6 receptor, has emerged as a promising therapeutic choice, especially for the severe form of the disease. Proper synthesis of the available randomized clinical trials (RCTs) is needed to inform clinical practice. Methods: A systematic review with a meta-analysis of RCTs investigating the efficacy of TCZ in COVID-19 patients was conducted. PubMed, EMBASE, and the Cochrane COVID-19 Study Register were searched up until 30 April 2021. Results: The database search yielded 2885 records; 11 studies were considered eligible for full-text review, and nine met the inclusion criteria. Overall, 3358 patients composed the TCZ arm, and 3131 the comparator group. The main outcome was all-cause mortality at 28–30 days. Subgroup analyses according to trials’ and patients’ features were performed. A trial sequential analysis (TSA) was also carried out to minimize type I and type II errors. According to the fixed-effect model approach, TCZ was associated with a better survival odds ratio (OR) (0.84; 95% confidence interval (CI): 0.75–0.94; I2: 24% (low heterogeneity)). The result was consistent in the subgroup of severe disease (OR: 0.83; 95% CI: 0.74–0.93; I2: 53% (moderate heterogeneity)). However, the TSA illustrated that the required information size was not met unless the study that was the major source of heterogeneity was omitted. Conclusions: TCZ may represent an important weapon against severe COVID-19. Further studies are needed to consolidate this finding.
Collapse
Affiliation(s)
- Alberto Enrico Maraolo
- First Division of Infectious Diseases, Cotugno Hospital, AORN dei Colli, 80131 Naples, Italy;
| | - Anna Crispo
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (P.D.G.); (E.C.)
- Correspondence:
| | - Michela Piezzo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy;
| | - Piergiacomo Di Gennaro
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (P.D.G.); (E.C.)
| | - Maria Grazia Vitale
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto NazionaleTumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (M.G.V.); (D.M.); (P.A.A.)
| | - Domenico Mallardo
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto NazionaleTumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (M.G.V.); (D.M.); (P.A.A.)
| | - Luigi Ametrano
- Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, 80131 Naples, Italy;
| | - Egidio Celentano
- Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (P.D.G.); (E.C.)
| | - Arturo Cuomo
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.C.); (M.C.)
| | - Paolo A. Ascierto
- Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto NazionaleTumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (M.G.V.); (D.M.); (P.A.A.)
| | - Marco Cascella
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Naples, Italy; (A.C.); (M.C.)
| |
Collapse
|
|
30
|
Vitrone M, Mele F, Durante-Mangoni E, Zampino R. Drugs and liver injury: a not to be overlooked binomial in COVID-19. J Chemother 2021; 34:207-220. [PMID: 34644236 DOI: 10.1080/1120009x.2021.1988203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
SARS-CoV-2 infection (COVID-19) results predominantly in pulmonary involvement but a direct, virus-induced liver damage may also occur, whose mechanisms are being actively investigated. Accordingly, it appears of utmost importance to monitor liver function and carefully evaluate hepatic safety of the various drugs administered during COVID-19. In this respect, many drugs, biological agents and novel molecules, whose efficacy in COVID-19 is under scrutiny, have also been shown to potentially cause or worsen liver damage. In this article, we review safety data of established as well as promising agents for COVID-19.
Collapse
Affiliation(s)
- M Vitrone
- Department of Advanced Medical & Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - F Mele
- Department of Advanced Medical & Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy
| | - E Durante-Mangoni
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy.,Unit of Infectious and Transplant Medicine, AORN Ospedali dei Colli - Monaldi Hospital, Naples, Italy
| | - R Zampino
- Department of Advanced Medical & Surgical Sciences, University of Campania "L. Vanvitelli", Naples, Italy.,Unit of Infectious and Transplant Medicine, AORN Ospedali dei Colli - Monaldi Hospital, Naples, Italy
| |
Collapse
|
|
31
|
Cao X, Wang X, Wang H, Xu G, Yu H. Systemic Inflammation Status Relates to Anti-Inflammatory Drug Benefit and Survival in Rectal Cancer. J Surg Res 2021; 269:249-259. [PMID: 34624724 DOI: 10.1016/j.jss.2021.08.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/17/2021] [Accepted: 08/27/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Systemic inflammation status has been recognized as a sensitive marker associated with survival in cancers and anti-inflammatory treatment outcomes in inflammation-derived diseases. This study aimed to investigate the role of systemic inflammation status as a predictive marker for survival and anti-inflammatory treatment benefit in rectal cancer patients. METHODS A total of 475 patients with stage I-III rectal cancer receiving curative resection were prospectively enrolled. The platelet-neutrophils to lymphocytes ratio (PNLR) that integrates neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios was applied to enable a comprehensive evaluation of systemic inflammation status and investigate its association with survival and nonsteroidal anti-inflammatory drugs (NSAIDs) benefit. Patients were grouped according to baseline PNLR and perioperative use of NSAIDs. RESULTS The high-PNLR group had worse 5-y disease-free survival (DFS) compared with the low-PNLR group (61.2% versus 70.9%, P = 0.014). Multivariate analyses confirmed that PNLR was an independent predictor for DFS (hazard ratio [HR] 1.42, 95% CI: 1.03-1.97, P = 0.031). A nomogram including PNLR and other independent prognostic factors was developed and validated to predict DFS. In the high-PNLR subset, NSAIDs group had a 21.3% lower risk of recurrence than non-NSAIDs group (P = 0.009), and multivariate analysis confirmed the independently significant association of perioperative NSAIDs use with better DFS (hazard ratio 0.36, 95% CI 0.16-0.78, P = 0.010). However, this association was not significant in the low-PLR subset. CONCLUSIONS Baseline PNLR could be used to predict DFS and NSAIDs benefit in rectal cancer patients. This study highlights the potential survival benefit from the anti-inflammatory treatment in the patients with elevated systemic inflammation status in cancer patients.
Collapse
Affiliation(s)
- Xue Cao
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China; Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaolin Wang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Heng Wang
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Gaopo Xu
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huichuan Yu
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
| |
Collapse
|
|
32
|
Esmaeilzadeh A, Rostami S, Yeganeh PM, Tahmasebi S, Ahmadi M. Recent advances in antibody-based immunotherapy strategies for COVID-19. J Cell Biochem 2021; 122:1389-1412. [PMID: 34160093 PMCID: PMC8427040 DOI: 10.1002/jcb.30017] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 01/09/2023]
Abstract
The emergence of a new acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the cause of the 2019-nCOV disease (COVID-19), has caused a pandemic and a global health crisis. Rapid human-to-human transmission, even from asymptomatic individuals, has led to the quick spread of the virus worldwide, causing a wide range of clinical manifestations from cold-like symptoms to severe pneumonia, acute respiratory distress syndrome (ARDS), multiorgan injury, and even death. Therefore, using rapid and accurate diagnostic methods to identify the virus and subsequently select appropriate and effective treatments can help improvement of patients and control the pandemic. So far, various treatment regimens along with prophylactic vaccines have been developed to manage COVID-19-infected patients. Among these, antibody-based therapies, including neutralizing antibodies (against different parts of the virus), polyclonal and monoclonal antibodies, plasma therapy, and high-dose intravenous immunoglobulin (IVIG) have shown promising outcomes in accelerating and improving the treatment process of patients, avoiding the viral spreading widely, and managing the pandemic. In the current review paper, different types and applications of therapeutic antibodies in the COVID-19 treatment are comprehensively discussed.
Collapse
Affiliation(s)
- Abdolreza Esmaeilzadeh
- Department of Immunology, School of MedicineZanjan University of Medical SciencesZanjanIran
- Immunotherapy Research and Technology GroupZanjan University of Medical SciencesZanjanIran
| | - Samaneh Rostami
- Department of immunology, School of medicineZanjan University of Medical SciencesZanjanIran
| | - Pegah M. Yeganeh
- Department of immunology, School of medicineZanjan University of Medical SciencesZanjanIran
| | - Safa Tahmasebi
- Department of Immunology, School of Public HealthTehran University of Medical SciencesTehranIran
| | - Majid Ahmadi
- Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
| |
Collapse
|
|
33
|
Tan LY, Komarasamy TV, RMT Balasubramaniam V. Hyperinflammatory Immune Response and COVID-19: A Double Edged Sword. Front Immunol 2021; 12:742941. [PMID: 34659238 PMCID: PMC8515020 DOI: 10.3389/fimmu.2021.742941] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 09/10/2021] [Indexed: 12/14/2022] Open
Abstract
The coronavirus disease-19 (COVID-19) elicited by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastating health, economic and social impact worldwide. Its clinical spectrum ranges from asymptomatic to respiratory failure and multi-organ failure or death. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response. It involves activation of multiple inflammatory pathways leading to hyperinflammation and cytokine storm, resulting in tissue damage, acute respiratory distress syndrome (ARDS) and multi-organ failure. Accumulating evidence has raised concern over the long-term health effects of COVID-19. Importantly, the neuroinvasive potential of SARS-CoV-2 may have devastating consequences in the brain. This review provides a conceptual framework on how the virus tricks the host immune system to induce infection and cause severe disease. We also explore the key differences between mild and severe COVID-19 and its short- and long-term effects, particularly on the human brain.
Collapse
Affiliation(s)
- Li Yin Tan
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
- Greenslopes Private Hospital, Greenslopes, QLD, Australia
| | - Thamil Vaani Komarasamy
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Vinod RMT Balasubramaniam
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Malaysia
| |
Collapse
|
|
34
|
Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy. Eur J Cancer 2021; 157:214-224. [PMID: 34536945 DOI: 10.1016/j.ejca.2021.08.031] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/15/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. METHODS Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. RESULTS Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8-786) and from irAE onset to tocilizumab 32 days (range 1-192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1-93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3-99), at the onset of irAE 49.5 mg/L (range 0.3-251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3-18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9-18.8) and median overall survival was not reached. CONCLUSIONS Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required.
Collapse
|
|
35
|
Gowda P, Patrick S, Joshi SD, Kumawat RK, Sen E. Repurposing Methotrexate in Dampening SARS-CoV2-S1-Mediated IL6 Expression: Lessons Learnt from Lung Cancer. Inflammation 2021; 45:172-179. [PMID: 34480250 PMCID: PMC8415921 DOI: 10.1007/s10753-021-01536-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/12/2021] [Accepted: 08/05/2021] [Indexed: 10/28/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) is associated with uncontrolled inflammatory responses. Loss of pulmonary angiotensin-converting enzyme 2 (ACE2) function has been associated with SARS-CoV-2 infection. The aberrant signalling and dysregulated inflammation characteristic of lung cancer have marked similarities with SARS-CoV-2 infection. Spearman's correlation analysis of The Cancer Genome Atlas (TCGA) datasets indicated an inverse correlation between ACE2 and IL6 in lung adenocarcinoma. qRT-PCR analysis revealed CoV-2-SRBD-mediated diminished ACE2 expression in lung cancer cells that was concomitant with increased IL6 expression. Western blot and qRT-PCR analysis suggested that treatment with methotrexate (MTx) dampened CoV-2-SRBD-mediated increase in JAK1/STAT3 phosphorylation, gp130, IL6, and folate-binding protein (FBP) expressions. MTx also rescued the diminished expression of ACE2 in CoV-2-SRBD transfected cells. As lung tissue injury in severely affected COVID-19 patients is characterised by aberrant inflammatory response, repurposing MTx as an effective therapy against critical regulators of inflammation in SARS-CoV-2 infection warrants investigation.
Collapse
Affiliation(s)
- Pruthvi Gowda
- National Brain Research Centre, Manesar, Gurgaon, Haryana, 122 052, India
| | - Shruti Patrick
- National Brain Research Centre, Manesar, Gurgaon, Haryana, 122 052, India
| | - Shanker Datt Joshi
- National Brain Research Centre, Manesar, Gurgaon, Haryana, 122 052, India
| | | | - Ellora Sen
- National Brain Research Centre, Manesar, Gurgaon, Haryana, 122 052, India. .,National Brain Research Centre, Manesar, Gurgaon, Haryana, 122 052, India.
| |
Collapse
|
|
36
|
Huang K, Zhang P, Zhang Z, Youn JY, Wang C, Zhang H, Cai H. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms. Pharmacol Ther 2021; 225:107843. [PMID: 33811957 PMCID: PMC8011334 DOI: 10.1016/j.pharmthera.2021.107843] [Citation(s) in RCA: 286] [Impact Index Per Article: 71.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/27/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023]
Abstract
COVID-19 has remained an uncontained, worldwide pandemic. While battling for the disease in China, six Traditional Chinese Medicine (TCM) recipes have been shown to be remarkably effective for treating patients with COVID-19. The present review discusses principles of TCM in curing infectious disease, and clinical evidence and mechanisms of the 6 most effective TCM recipes used in treating COVID-19 in 92% of all of the confirmed cases in China. Applications of TCM and specific recipes in the treatment of other viral infections, such as those caused by SARS-CoV, MERS-CoV, hepatitis B virus, hepatitis C virus, influenza A virus (including H1N1 and H7N9), influenza B, dengue virus as well as Ebola virus, are also discussed. Among the 6 TCM recipes, Jinhua Qinggan (JHQG) granules and Lianhua Qingwen (LHQW) capsules are recommended during medical observation; Lung Cleansing and Detoxifying Decoction (LCDD) is recommended for the treatment of both severe and non-severe patients; Xuanfeibaidu (XFBD) granules are recommended for treating moderate cases; while Huashibaidu (HSBD) and Xuebijing (XBJ) have been used in managing severe cases effectively. The common components and the active ingredients of the six TCM recipes have been summarized to reveal most promising drug candidates. The potential molecular mechanisms of the active ingredients in the six TCM recipes that target ACE2, 3CLpro and IL-6, revealed by molecular biological studies and/or network pharmacology prediction/molecular docking analysis/visualization analysis, are fully discussed. Therefore, further investigation of these TCM recipes may be of high translational value in enabling novel targeted therapies for COVID-19, potentially via purification and characterization of the active ingredients in the effective TCM recipes.
Collapse
Affiliation(s)
- Kai Huang
- Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States of America
| | - Pan Zhang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Zhenghao Zhang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Ji Youn Youn
- Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States of America
| | - Chen Wang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China; Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China.
| | - Hongchun Zhang
- Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
| | - Hua Cai
- Department of Anesthesiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States of America.
| |
Collapse
|
|
37
|
Dayaramani C, De Leon J, Reiss AB. Cardiovascular Disease Complicating COVID-19 in the Elderly. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:833. [PMID: 34441038 PMCID: PMC8399122 DOI: 10.3390/medicina57080833] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 12/20/2022]
Abstract
SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). The highly transmissible virus gains entry into human cells primarily by the binding of its spike protein to the angiotensin-converting enzyme 2 receptor, which is expressed not only in lung tissue but also in cardiac myocytes and the vascular endothelium. Cardiovascular complications are frequent in patients with COVID-19 and may be a result of viral-associated systemic and cardiac inflammation or may arise from a virus-induced hypercoagulable state. This prothrombotic state is marked by endothelial dysfunction and platelet activation in both macrovasculature and microvasculature. In patients with subclinical atherosclerosis, COVID-19 may incite atherosclerotic plaque disruption and coronary thrombosis. Hypertension and obesity are common comorbidities in COVID-19 patients that may significantly raise the risk of mortality. Sedentary behaviors, poor diet, and increased use of tobacco and alcohol, associated with prolonged stay-at-home restrictions, may promote thrombosis, while depressed mood due to social isolation can exacerbate poor self-care. Telehealth interventions via smartphone applications and other technologies that document nutrition and offer exercise programs and social connections can be used to mitigate some of the potential damage to heart health.
Collapse
Affiliation(s)
| | | | - Allison B. Reiss
- Department of Medicine and Biomedical Research Institute, NYU Long Island School of Medicine, Mineola, NY 11501, USA; (C.D.); (J.D.L.)
| |
Collapse
|
|
38
|
Madonna G, Sale S, Capone M, De Falco C, Santocchio V, Di Matola T, Fiorentino G, Pirozzi C, D’Antonio A, Sabatino R, Atripaldi L, Atripaldi U, Raffone M, Curvietto M, Grimaldi AM, Vanella V, Festino L, Scarpato L, Palla M, Spatarella M, Perna F, Cerino P, Botti G, Parrella R, Montesarchio V, Ascierto PA, Atripaldi L. Clinical Outcome Prediction in COVID-19 Patients by Lymphocyte Subsets Analysis and Monocytes' iTNF-α Expression. BIOLOGY 2021; 10:735. [PMID: 34439967 PMCID: PMC8389652 DOI: 10.3390/biology10080735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/24/2021] [Accepted: 07/28/2021] [Indexed: 12/24/2022]
Abstract
In December 2019, a novel coronavirus, "SARS-CoV-2", was recognized as the cause of coronavirus disease 2019 (COVID-19). Several studies have explored the changes and the role of inflammatory cells and cytokines in the immunopathogenesis of the disease, but until today, the results have been controversial. Based on these premises, we conducted a retrospective assessment of monocyte intracellular TNF-α expression (iTNF-α) and on the frequencies of lymphocyte sub-populations in twenty-five patients with moderate/severe COVID-19. We found lymphopenia in all COVID-19 infected subjects compared to healthy subjects. On initial observation, in patients with favorable outcomes, we detected a high absolute eosinophil count and a high CD4+/CD8+ T lymphocytes ratio, while in the Exitus Group, we observed high neutrophil and CD8+ T lymphocyte counts. During infection, in patients with favorable outcomes, we observed a rise in the lymphocyte count, in the monocyte and in Treg lymphocyte counts, and in the CD4+ and in CD8+ T lymphocytes count but a reduction in the CD4+/CD8+ T lymphocyte ratio. Instead, in the Exitus Group, we observed a reduction in the Treg lymphocyte counts and a decrease in iTNF-α expression. Our preliminary findings point to a modulation of the different cellular mediators of the immune system, which probably play a key role in the outcomes of COVID-19.
Collapse
Affiliation(s)
- Gabriele Madonna
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Silvia Sale
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Mariaelena Capone
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Chiara De Falco
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Valentina Santocchio
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Tiziana Di Matola
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Giuseppe Fiorentino
- UOC Fisiopatologia e Riabilitazione Respiratoria, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy;
| | - Caterina Pirozzi
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Anna D’Antonio
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Rocco Sabatino
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| | - Lidia Atripaldi
- Dipartimento di Scienze Mediche Traslazionali, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (L.A.); (U.A.)
| | - Umberto Atripaldi
- Dipartimento di Scienze Mediche Traslazionali, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (L.A.); (U.A.)
| | - Marcello Raffone
- UOC Microbiologia e Virologia, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy;
| | - Marcello Curvietto
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Antonio Maria Grimaldi
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Vito Vanella
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Lucia Festino
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Luigi Scarpato
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Marco Palla
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Michela Spatarella
- UOSD di Farmacia, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy;
| | - Francesco Perna
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli “Federico II”, 80131 Naples, Italy;
| | - Pellegrino Cerino
- Istituto Zooprofilattico Sperimentale del Mezzogiorno, 80055 Portici, Italy;
| | - Gerardo Botti
- Scientific Direction, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy;
| | - Roberto Parrella
- UOC Malattie Infettive ad Indirizzo Respiratorio, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy;
| | | | - Paolo Antonio Ascierto
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, 80131 Napoli, Italy; (G.M.); (M.C.); (M.C.); (A.M.G.); (V.V.); (L.F.); (L.S.); (M.P.)
| | - Luigi Atripaldi
- UOC Biochimica Clinica, AORN Ospedali dei Colli—Monaldi—Cotugno—CTO, 80131 Napoli, Italy; (S.S.); (C.D.F.); (V.S.); (T.D.M.); (C.P.); (A.D.); (R.S.); (L.A.)
| |
Collapse
|
|
39
|
Yang L, Xie X, Tu Z, Fu J, Xu D, Zhou Y. The signal pathways and treatment of cytokine storm in COVID-19. Signal Transduct Target Ther 2021; 6:255. [PMID: 34234112 PMCID: PMC8261820 DOI: 10.1038/s41392-021-00679-0] [Citation(s) in RCA: 357] [Impact Index Per Article: 89.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/22/2021] [Accepted: 06/12/2021] [Indexed: 02/07/2023] Open
Abstract
The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.
Collapse
Affiliation(s)
- Lan Yang
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Xueru Xie
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Zikun Tu
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Jinrong Fu
- General Department, Children's Hospital of Fudan University, Shanghai, China
| | - Damo Xu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen University, Shenzhen Key Laboratory of Allergy and Immunology, Shenzhen University School of Medicine, Shenzhen, China.
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| | - Yufeng Zhou
- Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
- National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
| |
Collapse
|
|
40
|
Nissen CB, Sciascia S, de Andrade D, Atsumi T, Bruce IN, Cron RQ, Hendricks O, Roccatello D, Stach K, Trunfio M, Vinet É, Schreiber K. The role of antirheumatics in patients with COVID-19. THE LANCET. RHEUMATOLOGY 2021; 3:e447-e459. [PMID: 33817665 PMCID: PMC8009617 DOI: 10.1016/s2665-9913(21)00062-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19.
Collapse
Affiliation(s)
- Christoffer B Nissen
- Danish Hospital for Rheumatic Diseases, University of Southern Denmark, Sønderborg, Danmark
| | - Savino Sciascia
- Center of Research of Immunopathology and Rare Diseases, Coordinating Center of Piemonte and Aosta Valley Network for Rare Diseases, Nephrology and Dialysis, Department of Clinical and Biological Sciences, University of Turin, Italy
| | - Danieli de Andrade
- Department of Rheumatology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Hokkaido University, Kita-ku, Sapporo, Japan
| | - Ian N Bruce
- Centre for Epidemiology Versus Arthritis, Medicine and Health, NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre Manchester, Manchester, UK
| | - Randy Q Cron
- Division of Rheumatology, Children's of Alabama and Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Oliver Hendricks
- Danish Hospital for Rheumatic Diseases, University of Southern Denmark, Sønderborg, Danmark
- Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
| | - Dario Roccatello
- Center of Research of Immunopathology and Rare Diseases, Coordinating Center of Piemonte and Aosta Valley Network for Rare Diseases, Nephrology and Dialysis, Department of Clinical and Biological Sciences, University of Turin, Italy
| | - Ksenija Stach
- Fifth Department of Medicine and European Center for Angioscience, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
| | - Mattia Trunfio
- Department of Medical Sciences, University of Torino at Infectious Diseases Unit, Amedeo di Savoia Hospital, Torino, Italy
| | - Évelyne Vinet
- Division of Rheumatology, McGill University Health Centre, Montreal, QC, Canada
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Karen Schreiber
- Danish Hospital for Rheumatic Diseases, University of Southern Denmark, Sønderborg, Danmark
- Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
- Thrombosis and Haemostasis, Guy's and St Thomas' NHS Foundation Trust, London, UK
| |
Collapse
|
|
41
|
Dettorre GM, Patel M, Gennari A, Pentheroudakis G, Romano E, Cortellini A, Pinato DJ. The systemic pro-inflammatory response: targeting the dangerous liaison between COVID-19 and cancer. ESMO Open 2021; 6:100123. [PMID: 33932622 PMCID: PMC8026271 DOI: 10.1016/j.esmoop.2021.100123] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammation is an established driver of severe SARS-CoV-2 infection and a mechanism linked to the increased susceptibility to fatal COVID-19 demonstrated by patients with cancer. As patients with cancer exhibit a higher level of inflammation compared with the general patient population, patients with cancer and COVID-19 may uniquely benefit from strategies targeted at overcoming the unrestrained pro-inflammatory response. Targeted and non-targeted anti-inflammatory therapies may prevent end-organ damage in SARS-CoV-2-infected patients with cancer and decrease mortality. Here, we review the clinical role of selective inhibition of pro-inflammatory interleukins, tyrosine kinase modulation, anti-tumor necrosis factor agents, and other non-targeted approaches including corticosteroids in their roles as disease-modulating agents in patients with COVID-19 and cancer. Investigation of these therapeutics in this highly vulnerable patient group is posited to facilitate the development of tailored therapeutics for this patient population, aiding the transition of systemic inflammation from a prognostic domain to a source of therapeutic targets.
Collapse
Affiliation(s)
- G M Dettorre
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - M Patel
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - A Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale and Maggiore della Carità Hospital, Novara, Italy
| | - G Pentheroudakis
- Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Chief Medical Officer, European Society for Medical Oncology, Lugano, Switzerland
| | - E Romano
- Department of Medical Oncology, Center for Cancer Immunotherapy, Institut Curie, Paris, France
| | - A Cortellini
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK; Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
| | - D J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale and Maggiore della Carità Hospital, Novara, Italy.
| |
Collapse
|
|
42
|
Torrente-López A, Hermosilla J, Navas N, Cuadros-Rodríguez L, Cabeza J, Salmerón-García A. The Relevance of Monoclonal Antibodies in the Treatment of COVID-19. Vaccines (Basel) 2021; 9:557. [PMID: 34073559 PMCID: PMC8229508 DOI: 10.3390/vaccines9060557] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/18/2021] [Accepted: 05/22/2021] [Indexed: 12/14/2022] Open
Abstract
Major efforts have been made in the search for effective treatments since the outbreak of the COVID-19 infection in December 2019. Extensive research has been conducted on drugs that are already available and new treatments are also under development. Within this context, therapeutic monoclonal antibodies (mAbs) have been the subject of widespread investigation focusing on two target-based groups, i.e., non-SARS-CoV-2 specific mAbs, that target immune system responses, and SARS-CoV-2 specific mAbs, designed to neutralize the virus protein structure. Here we review the latest literature about the use of mAbs in order to describe the state of the art of the clinical trials and the benefits of using these biotherapeutics in the treatment of COVID-19. The clinical trials considered in the present review include both observational and randomized studies. We begin by presenting the studies conducted using non-SARS-CoV-2 specific mAbs for treating different immune disorders that were already on the market. Within this group of mAbs, we focus particularly on anti-IL-6/IL-6R. This is followed by a discussion of the studies on SARS-CoV-2 specific mAbs. Our findings indicate that SARS-CoV-2 specific mAbs are significantly more effective than non-specific ones.
Collapse
Affiliation(s)
- Anabel Torrente-López
- Department of Analytical Chemistry, Science Faculty, Biohealth Research Institute (ibs.GRANADA), University of Granada, E-18071 Granada, Spain; (A.T.-L.); (J.H.); (L.C.-R.)
| | - Jesús Hermosilla
- Department of Analytical Chemistry, Science Faculty, Biohealth Research Institute (ibs.GRANADA), University of Granada, E-18071 Granada, Spain; (A.T.-L.); (J.H.); (L.C.-R.)
| | - Natalia Navas
- Department of Analytical Chemistry, Science Faculty, Biohealth Research Institute (ibs.GRANADA), University of Granada, E-18071 Granada, Spain; (A.T.-L.); (J.H.); (L.C.-R.)
| | - Luis Cuadros-Rodríguez
- Department of Analytical Chemistry, Science Faculty, Biohealth Research Institute (ibs.GRANADA), University of Granada, E-18071 Granada, Spain; (A.T.-L.); (J.H.); (L.C.-R.)
| | - José Cabeza
- Department of Clinical Pharmacy, Biohealth Research Institute (ibs.GRANADA), San Cecilio University Hospital, E-18012 Granada, Spain; (J.C.); (A.S.-G.)
| | - Antonio Salmerón-García
- Department of Clinical Pharmacy, Biohealth Research Institute (ibs.GRANADA), San Cecilio University Hospital, E-18012 Granada, Spain; (J.C.); (A.S.-G.)
| |
Collapse
|
|
43
|
Liu H, Hu T, Zhang C, Chen X, Zhang S, Li M, Jing H, Wang C, Hu T, Shi J. Mechanisms of COVID-19 thrombosis in an inflammatory environment and new anticoagulant targets. Am J Transl Res 2021; 13:3925-3941. [PMID: 34149990 PMCID: PMC8205677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 02/25/2021] [Indexed: 06/12/2023]
Abstract
COVID-19 is widely epidemic in the world and poses a great threat to our life. Coagulopathy is one of the major characteristics in the COVID-19 patients. A growing number of studies have found that the severe COVID-19 patients have thrombotic microangiopathy and thromboembolism. Coagulopathy associated with increased risk of death in the patients. Unfortunately, the mechanism of coagulopathy is not clearly addressed. Understanding the pathophysiological mechanism of COVID-19 thrombosis and improving the coagulopathy through efficient treatment may help to stop disease progression, reduce mortality and sequelae. In severe COVID-19 patients, inflammation, cytokine storm, and coagulation are closely related, which together cause blood congestion and thrombosis. Many cytokines activate blood cells, expressing activating factors or releasing activated microparticles, and then accelerating thrombosis. However, the role of blood cells is not well understood in COVID-19 patients. In addition, cytokines stimulate endothelial cells, transforming them into a procoagulant phenotype. Therefore, determine their role and propose new strategies for the prevention and treatment of thrombosis in severe COVID-19 patients. We outline the major events of coagulopathies, discuss the role of blood and endothelial cells in thrombosis, to formulate a new anticoagulation protocol.
Collapse
Affiliation(s)
- Huan Liu
- Department of Stomatology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Tianshui Hu
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Cong Zhang
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Xiaojing Chen
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Shuoqi Zhang
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Mengdi Li
- Department of Stomatology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Haijiao Jing
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Chunxu Wang
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Tenglong Hu
- Department of Stomatology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
| | - Jialan Shi
- Department of Hematology, The First Hospital of Harbin, Harbin Medical UniversityHarbin, China
- Department of Research and Medicine, VA Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical SchoolBoston, MA, USA
| |
Collapse
|
|
44
|
Djokovic N, Ruzic D, Djikic T, Cvijic S, Ignjatovic J, Ibric S, Baralic K, Buha Djordjevic A, Curcic M, Djukic‐Cosic D, Nikolic K. An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease. Mol Inform 2021; 40:e2000187. [PMID: 33787066 PMCID: PMC8250230 DOI: 10.1002/minf.202000187] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 02/15/2021] [Indexed: 12/25/2022]
Abstract
Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro ). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association. Through presented approach, we selected the most promising FDA approved drugs for further COVID-19 drug development campaigns and analysed them in context of available experimental data. To the best of our knowledge, this is unique in silico study which integrates structure-based molecular modeling of Mpro inhibitors with predictions of their tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.
Collapse
Affiliation(s)
- Nemanja Djokovic
- Department of Pharmaceutical ChemistryFaculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Dusan Ruzic
- Department of Pharmaceutical ChemistryFaculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Teodora Djikic
- Department of Pharmaceutical ChemistryFaculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Sandra Cvijic
- Department of Pharmaceutical Technology and CosmetologyUniversity of BelgradeFaculty of PharmacyVojvode Stepe 45011221BelgradeSerbia
| | - Jelisaveta Ignjatovic
- Department of Pharmaceutical Technology and CosmetologyUniversity of BelgradeFaculty of PharmacyVojvode Stepe 45011221BelgradeSerbia
| | - Svetlana Ibric
- Department of Pharmaceutical Technology and CosmetologyUniversity of BelgradeFaculty of PharmacyVojvode Stepe 45011221BelgradeSerbia
| | - Katarina Baralic
- Department of Toxicology “Akademik Danilo Soldatovic”Faculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Aleksandra Buha Djordjevic
- Department of Toxicology “Akademik Danilo Soldatovic”Faculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Marijana Curcic
- Department of Toxicology “Akademik Danilo Soldatovic”Faculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Danijela Djukic‐Cosic
- Department of Toxicology “Akademik Danilo Soldatovic”Faculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| | - Katarina Nikolic
- Department of Pharmaceutical ChemistryFaculty of PharmacyUniversity of BelgradeVojvode Stepe 45011221BelgradeSerbia
| |
Collapse
|
|
45
|
Premkumar M, Kedarisetty CK. Cytokine Storm of COVID-19 and Its Impact on Patients with and without Chronic Liver Disease. J Clin Transl Hepatol 2021; 9:256-264. [PMID: 34007808 PMCID: PMC8111101 DOI: 10.14218/jcth.2021.00055] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/11/2021] [Accepted: 04/01/2021] [Indexed: 01/08/2023] Open
Abstract
The coronavirus pandemic has resulted in increased rates of hepatic decompensation, morbidity and mortality in patients suffering from existing liver disease, and deranged liver biochemistries in those without liver disease. In patients with cirrhosis with coronavirus disease 2019 (COVID-19), new onset organ failures manifesting as acute-on-chronic liver failure have also been reported. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) also directly binds to enterocytes and cholangiocytes via the angiotensin converting enzyme receptor 2, although the lung remains the portal of entry. Superadded with the COVID-19 related bystander hepatitis, a systemic inflammatory response is noted due to unregulated macrophage activation syndrome and cytokine storm. However, the exact definition and diagnostic criteria of the 'cytokine storm' in COVID-19 are yet unclear. In addition, inflammatory markers like C-reactive protein, ferritin, D-dimer and procalcitonin are frequently elevated. This in turn leads to disease progression, activation of the coagulation cascade, vascular microthrombi and immune-mediated injury in different organ systems. Deranged liver chemistries are also noted due to the cytokine storm, and synergistic hypoxic or ischemic liver injury, drug-induced liver injury, and use of hepatotoxic antiviral agents all contribute to deranged liver chemistry. Control of an unregulated cytokine storm at an early stage may avert disease morbidity and mortality. Several immunomodulator drugs and repurposed immunosuppressive agents have been used in COVID-19 with varying degrees of success.
Collapse
Affiliation(s)
- Madhumita Premkumar
- Departments of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Chandan Kumar Kedarisetty
- Department of Hepatology and Liver transplantation, Gleneagles Global Hospital, Hyderabad, India
- Correspondence to: Chandan Kumar Kedarisetty, Department of Hepatology and Liver Transplantation, Gleneagles Global Hospital, Lakdikapul, Hyderabad 500004, India. ORCID: https://orcid.org/0000-0002-7239-0293. Tel: +91-040-4592-8500, E-mail:
| |
Collapse
|
|
46
|
Khani E, Khiali S, Entezari‐Maleki T. Potential COVID-19 Therapeutic Agents and Vaccines: An Evidence-Based Review. J Clin Pharmacol 2021; 61:429-460. [PMID: 33511638 PMCID: PMC8014753 DOI: 10.1002/jcph.1822] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Since the early days of 2020, the severe acute respiratory syndrome coronavirus 2 pandemic has become a global health concern. Currently, some therapies and vaccines have received US Food and Drug Administration approval or emergency use authorization for the management of coronavirus disease 2019. According to the pathophysiology of the disease, several medications have been evaluated in different clinical conditions of the disease. Evidence-based reviewing and categorizing these medications can guide the clinicians to select the proper medications according to each patient's condition. Therefore, we performed this review to categorize the coronavirus disease 2019 potential therapeutics and vaccines.
Collapse
Affiliation(s)
- Elnaz Khani
- Department of Clinical PharmacyFaculty of PharmacyTabriz University of Medical SciencesTabrizIran
| | - Sajad Khiali
- Department of Clinical PharmacyFaculty of PharmacyTabriz University of Medical SciencesTabrizIran
| | - Taher Entezari‐Maleki
- Department of Clinical PharmacyFaculty of PharmacyTabriz University of Medical SciencesTabrizIran
- Cardiovascular Research CenterTabriz University of Medical SciencesTabrizIran
| |
Collapse
|
|
47
|
Ascierto PA, Fu B, Wei H. IL-6 modulation for COVID-19: the right patients at the right time? J Immunother Cancer 2021; 9:e002285. [PMID: 33837054 PMCID: PMC8042594 DOI: 10.1136/jitc-2020-002285] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/23/2021] [Indexed: 01/08/2023] Open
Abstract
The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.
Collapse
Affiliation(s)
- Paolo Antonio Ascierto
- Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
| | - Binqing Fu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center; Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center; Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
48
|
Kim SB, Ryoo S, Huh K, Joo EJ, Kim YJ, Choi WS, Kim YJ, Yoon YK, Heo JY, Seo YB, Jeong SJ, Park DA, Yu SY, Lee HJ, Kim J, Jin Y, Park J, Peck KR, Choi M, Yeom JS. Revised Korean Society of Infectious Diseases/National Evidence-based Healthcarea Collaborating Agency Guidelines on the Treatment of Patients with COVID-19. Infect Chemother 2021; 53:166-219. [PMID: 34409790 PMCID: PMC8032920 DOI: 10.3947/ic.2021.0303] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the global effort to mitigate the spread, coronavirus disease 2019 (COVID-19) has become a pandemic that took more than 2 million lives. There are numerous ongoing clinical studies aiming to find treatment options and many are being published daily. Some effective treatment options, albeit of variable efficacy, have been discovered. Therefore, it is necessary to develop an evidence-based methodology, to continuously check for new evidence, and to update recommendations accordingly. Here we provide guidelines on pharmaceutical treatment for COVID-19 based on the latest evidence.
Collapse
Affiliation(s)
- Sun Bean Kim
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Seungeun Ryoo
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Kyungmin Huh
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Jeong Joo
- Division of Infectious Diseases, Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung hospital, Seoul, Korea
| | - Youn Jeong Kim
- Division of Infectious Diseases, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Won Suk Choi
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yae Jean Kim
- Division of Infectious Diseases and Immunodeficiency. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Kyung Yoon
- Division of Infectious Diseases, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jung Yeon Heo
- Department of Infectious Diseases, Ajou University school of Medicine, Suwon, Korea
| | - Yu Bin Seo
- Division of Infectious Diseases, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Su Jin Jeong
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Ah Park
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Su Yeon Yu
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Hyeon Jeong Lee
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Jimin Kim
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Yan Jin
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Jungeun Park
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea
| | - Kyong Ran Peck
- Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Miyoung Choi
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency, Seoul, Korea.
| | - Joon Sup Yeom
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
49
|
Barberis E, Vanella VV, Falasca M, Caneapero V, Cappellano G, Raineri D, Ghirimoldi M, De Giorgis V, Puricelli C, Vaschetto R, Sainaghi PP, Bruno S, Sica A, Dianzani U, Rolla R, Chiocchetti A, Cantaluppi V, Baldanzi G, Marengo E, Manfredi M. Circulating Exosomes Are Strongly Involved in SARS-CoV-2 Infection. Front Mol Biosci 2021; 8:632290. [PMID: 33693030 PMCID: PMC7937875 DOI: 10.3389/fmolb.2021.632290] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Knowledge of the host response to the novel coronavirus SARS-CoV-2 remains limited, hindering the understanding of COVID-19 pathogenesis and the development of therapeutic strategies. During the course of a viral infection, host cells release exosomes and other extracellular vesicles carrying viral and host components that can modulate the immune response. The present study used a shotgun proteomic approach to map the host circulating exosomes’ response to SARS-CoV-2 infection. We investigated how SARS-CoV-2 infection modulates exosome content, exosomes’ involvement in disease progression, and the potential use of plasma exosomes as biomarkers of disease severity. A proteomic analysis of patient-derived exosomes identified several molecules involved in the immune response, inflammation, and activation of the coagulation and complement pathways, which are the main mechanisms of COVID-19–associated tissue damage and multiple organ dysfunctions. In addition, several potential biomarkers—such as fibrinogen, fibronectin, complement C1r subcomponent and serum amyloid P-component—were shown to have a diagnostic feature presenting an area under the curve (AUC) of almost 1. Proteins correlating with disease severity were also detected. Moreover, for the first time, we identified the presence of SARS-CoV-2 RNA in the exosomal cargo, which suggests that the virus might use the endocytosis route to spread infection. Our findings indicate circulating exosomes’ significant contribution to several processes—such as inflammation, coagulation, and immunomodulation—during SARS-CoV-2 infection. The study’s data are available via ProteomeXchange with the identifier PXD021144.
Collapse
Affiliation(s)
- Elettra Barberis
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy.,ISALIT, Novara, Italy
| | - Virginia V Vanella
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Medical School, Curtin University, Perth, WA, Australia
| | - Valeria Caneapero
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Giuseppe Cappellano
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy.,Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Davide Raineri
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy.,Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Marco Ghirimoldi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Veronica De Giorgis
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Chiara Puricelli
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Rosanna Vaschetto
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Pier Paolo Sainaghi
- Internal and Emergency Medicine Departments, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Azienda Ospedaliero-Universitaria "Maggiore della Carità", Novara, Italy
| | - Stefania Bruno
- Città della Salute e della Scienza and Molecular Biotechnology Center, Torino, Italy
| | - Antonio Sica
- Department of Pharmaceutical Sciences, University of Piemonte Orientale, Novara, Italy.,Humanitas Clinical and Research Center, IRCCS, Milan, Italy
| | - Umberto Dianzani
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Roberta Rolla
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Annalisa Chiocchetti
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Gianluca Baldanzi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
| | - Emilio Marengo
- Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy.,Department of Sciences and Technological Innovation, University of Piemonte Orientale, Alessandria, Italy.,ISALIT, Novara, Italy
| | - Marcello Manfredi
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.,Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy.,ISALIT, Novara, Italy
| |
Collapse
|
|
50
|
Nagoor Meeran M, Javed H, Sharma C, Goyal SN, Kumar S, Jha NK, Ojha S. Can Echinacea be a potential candidate to target immunity, inflammation, and infection - The trinity of coronavirus disease 2019. Heliyon 2021; 7:e05990. [PMID: 33585706 PMCID: PMC7870107 DOI: 10.1016/j.heliyon.2021.e05990] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/18/2020] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing public health emergency. The pathogenesis and complications advanced with infection mainly involve immune-inflammatory cascade. Therefore, the therapeutic strategy relies on immune modulation, reducing infectivity and inflammation. Given the interplay of infection and immune-inflammatory axis, the natural products received attention for preventive and therapeutic usage in COVID-19 due to their potent antiviral and anti-immunomodulatory activities. Recently, Echinacea preparations, particularly E. purpurea, have been suggested to be an important antiviral agent to be useful in COVID-19 by modulating virus entry, internalization and replication. In principle, the immune response and the resultant inflammatory process are important for the elimination of the infection, but may have a significant impact on SARS-CoV-2 pathogenesis and may play a role in the clinical spectrum of COVID-19. Considering the pharmacological effects, therapeutic potential, and molecular mechanisms of Echinacea, we hypothesize that it could be a reasonably possible candidate for targeting infection, immunity, and inflammation in COVID-19 with recent recognition of cannabinoid-2 (CB2) receptors and peroxisome proliferator-activated receptor gamma (PPARγ) mediated mechanisms of bioactive components that make them notable immunomodulatory, anti-inflammatory and antiviral agent. The plausible reason for our hypothesis is that the presence of numerous bioactive agents in different parts of plants that may synergistically exert polypharmacological actions in regulating immune-inflammatory axis in COVID-19. Our proposition is to scientifically contemplate the therapeutic perspective and prospect of Echinacea on infection, immunity, and inflammation with a potential in COVID-19 to limit the severity and progression of the disease. Based on the clinical usage for respiratory infections, and relative safety in humans, further studies for the evidence-based approach to COVID-19 are needed. We do hope that Echinacea could be a candidate agent for immunomodulation in the prevention and treatment of COVID-19.
Collapse
Affiliation(s)
- M.F. Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Hayate Javed
- Department of Anatomy, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Sameer N. Goyal
- Shri Vile Parle Kelvani Mandal's Institute of Pharmacy, Dhule 424001, Maharashtra, India
| | - Sanjay Kumar
- Division of Hematology/Nephrology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA
- Department of Life Sciences, School of Basic Science and Research, Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201310, India
| | - Niraj Kumar Jha
- Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Knowledge Park III, Greater Noida, Uttar Pradesh 201310, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, PO Box - 17666, United Arab Emirates University, Al Ain, United Arab Emirates
| |
Collapse
|