Preemptive interleukin-6 blockade in patients with COVID-19

Guillén, Lucía; Padilla, Sergio; Fernández, Marta; Agulló, Vanesa; García, José Alberto; Telenti, Guillermo; García-Abellán, Javier; Botella, Ángela; Gutiérrez, Félix; Masiá, Mar

doi:10.1038/s41598-020-74001-3

Cited by 42 publications

(38 citation statements)

References 35 publications

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“…Nevertheless, the inconsistency of the results does not allow any conclusion—mainly due to the very low number of patients [ 71 , 72 ]. Although not always reaching statistical significance, almost all studies showed improvements in survival rate, respiratory functions, reduction in ICU admission, and reduced the need for mechanical ventilation in COVID-19 patients with rather severe symptoms when treated with TCZ in addition to standard of care [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. However, in a randomised, double-blind, placebo-controlled clinical trial, tocilizumab did not show any beneficial effects in terms of mortality rate or preventing intubation in moderately ill, hospitalised COVID-19 patients [ 85 ].…”

Section: Clinical-stage Therapeuticsmentioning

confidence: 99%

Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

Pum

Ennemoser

Adage³

et al. 2021

Biomolecules

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The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences are not completely clear, the presence and involvement of specific chemokines is undoubtedly crucial for the development and progression of COVID-19. Cytokine storm and the often-resulting cytokine release syndrome (CRS) are pathophysiological hallmarks in COVID-19 infections related to its most severe and fatal cases. In this hyperinflammatory event, chemokines and other cytokines are highly upregulated and are therefore not fulfilling their beneficial function in the host response anymore but causing harmful effects. Here, we present the recent views on the involvement of chemokines and selected cytokines in COVID-19 and the therapeutics currently in clinical development targeting or interfering with them, discussing their potentials in the treatment of COVID-19 infections.

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Section: Clinical-stage Therapeuticsmentioning

confidence: 99%

Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

Pum

Ennemoser

Adage³

et al. 2021

Biomolecules

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“…), anti-pyretic (paracetamol), anti-histaminic (cetirizine,), antibiotics (cephalosporins), corticosteroids (prednisolone, methylprednisolone), monoclonal antibodies (tocilizumab, imatinib) [16]. In this context, the IL-6 antagonists are considered to have better therapeutic benefits in the symptomatic management of COVID-19, in these lines TCZ is considered as one of the most commonly used medication to suppress the cytokine storm in COVID-19 patients [17]. There are multiple case series, retrospective and prospective studies available on the therapeutic role of TCZ in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 29, 2021. ; https://doi.org/10.1101/2021.01.27.21250599 doi: medRxiv preprint IL-6 antagonists are considered to have better therapeutic benefits in the symptomatic management of COVID-19, in these lines TCZ is considered as one of the most commonly used medication to suppress the cytokine storm in COVID-19 patients [17]. There are multiple case series, retrospective and prospective studies available on the therapeutic role of TCZ in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of tocilizumab in the management of COVID-19: A systematic review and meta-analysis of observational studies

Viswanatha¹,

Male²,

Shylaja³

2021

Preprint

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BackgroundThis systematic review and meta-analysis was aimed to evaluate the therapeutic benefits and safety of tocilizumab (TCZ) in treating severe coronavirus disease 2019 (COVID-19) and associated health complications.MethodsThe electronic search was performed using PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials (RCTs), and Google scholar databases to identify the retrospective observational reports. The studies published from 01 January 2020 to 30th September 2020 involving comparison of TCZ group with SOC/control treatment group were included. The studies included in this work involve RT-PCR confirmed cases of COVID-19 (Population), having tocilizumab and corresponding SOC/control as interventions (Intervention), comparison between tocilizumab versus SOC/control (Comparison) for the parameter of interest. Mortality, incidences of ICU admission, need of mechanical ventilation (MV), length of stay in the hospital (LOS), and length of stay in the ICU (LOS-ICU), and the incidences of super-infection, bacteraemia, fugleman, pneumonia, and pulmonary thrombosis were evaluated as the primary outcomes. The comparison will be between TCZ versus standard of care (SOC)/placebo.ResultsBased on the inclusion criteria there were 24 retrospective studies involving 5686 subjects were included. The outcomes of the meta-analysis have revealed that the TCZ has reduced the mortality (Mantel-Haenszel (M-H), random effects risk difference (RE-RD) of - 0.11 (-0.18 to -0.04), at 95% CI, p = 0.001, I2 = 88%) and increased the incidences of super-infections (M-H, RE-Risk ratio (RR) of 1.49 (1.13 to 1.96) at 95% CI, p=0.004, I2 = 47%). However, there is no significant difference in ICU admissions rate (M-H, RE-RD of -0.06 (-0.23 to 0.12) at 95% CI, p=0.54, I2 = 93%), need of MV (M-H, RE-RD of 0.00 (-0.06 to 0.07) at 95% CI, p=0.96, I2 = 74%), LOS (Inverse variance (IV): -2.86 (-0.91 to 3.38) at 95% CI, p=0.37, I2 = 100%), LOS-ICU (IV: -3.93 (-12.35 to 4.48) at 95% CI, p=0.36, I2 = 100%), and incidences of pulmonary thrombosis (M-H, fixed effect odds ratio (FE-OR) of 1.01 (0.45 to 2.26) at 95% CI, p=0.99, I2 = 0%) compared to SOC/control.ConclusionThis meta-analysis was performed using retrospective clinical reports on the use of tocilizumab in COVID-19 and based on the outcomes of the meta-analysis we can conclude that administration of TCZ would reduce the risk of mortality, and however there is no much difference observed between the TCZ and SOC/control groups in other parameters such as ICU admission rate, need of mechanical ventilation and length of hospital stay (ICU and Non-ICU). On the other hand, TCZ treated subjects possess higher chances of super-infections and pneumonia compared with SOC/control group. However, there is a need for multi-centric randomized trials to determine the potential therapeutic role of TCZ in mitigating COVID-19 and associated health complications.

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“…These studies allowed the refinement of a plausible structural model for the interaction between these two proteins, which we used to perform a second in silico screening of our drug repurposing library. Effective inhibitors of this interaction would enable the selective modulation of virus-induced immune responses, as opposed to the nonspecific effects of currently explored treatment options targeting host immune and inflammatory pathways, such as IL-6 antibodies and steroids [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections

Flude

Nannetti

Mitchell

et al. 2021

Viruses

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MASP-2, mannose-binding protein-associated serine protease 2, is a key enzyme in the lectin pathway of complement activation. Hyperactivation of this protein by human coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 has been found to contribute to aberrant complement activation in patients, leading to aggravated lung injury with potentially fatal consequences. This hyperactivation is triggered in the lungs through a conserved, direct interaction between MASP-2 and coronavirus nucleocapsid (N) proteins. Blocking this interaction with monoclonal antibodies and interfering directly with the catalytic activity of MASP-2, have been found to alleviate coronavirus-induced lung injury both in vitro and in vivo. In this study, a virtual library of 8,736 licensed drugs and clinical agents has been screened in silico according to two parallel strategies. The first strategy aims at identifying direct inhibitors of MASP-2 catalytic activity, while the second strategy focusses on finding protein-protein interaction inhibitors (PPIs) of MASP-2 and coronaviral N proteins. Such agents could represent promising support treatment options to prevent lung injury and reduce mortality rates of infections caused by both present and future-emerging coronaviruses. Forty-six drug repurposing candidates were purchased and, for the ones selected as potential direct inhibitors of MASP-2, a preliminary in vitro assay was conducted to assess their interference with the lectin pathway of complement activation. Some of the tested agents displayed a dose-response inhibitory activity of the lectin pathway, potentially providing the basis for a viable support strategy to prevent the severe complications of coronavirus infections.

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Preemptive interleukin-6 blockade in patients with COVID-19

Cited by 42 publications

References 35 publications

Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

Efficacy and safety of tocilizumab in the management of COVID-19: A systematic review and meta-analysis of observational studies

Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections

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