Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context

Angriman, Federico; Ferreyro, Bruno L.; Burry, Lisa; Fan, Eddy; Ferguson, Niall D.; Husain, Shahid; Keshavjee, S.; Lupia, Enrico; Munshi, Laveena; Renzi, Samuele; Ubaldo, Onion Gerald V; Rochwerg, Bram; Sorbo, Lorenzo Del

doi:10.1016/s2213-2600(21)00139-9

Cited by 97 publications

(92 citation statements)

References 59 publications

(108 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…93 Blockade of IL-6 and the consequent reduction of downstream effects on inflammation and the innate immune response may have beneficial effects on clinical outcomes in patients with COVID-19, including those with acute hypoxemic respiratory failure. 97 Contemporary in vitro and in vivo evidence indicating a potential effect of N-acetylcysteine in IL-6 inhibition may stimulate further research to understand how the drug affects disease outcomes and maximize its benefits with concomitant…”

Section: Discussionmentioning

confidence: 99%

N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence

Wong¹,

Lee²,

Kua³

2021

JIR

View full text Add to dashboard Cite

The looming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a long-lasting pandemic of coronavirus disease 2019 around the globe with substantial morbidity and mortality. N-acetylcysteine, being a nutraceutical precursor of an important antioxidant glutathione, can perform several biological functions in mammals and microbes. It has consequently garnered a growing interest as a potential adjunctive therapy for coronavirus disease. Here, we review evidence concerning the effects of N-acetylcysteine in respiratory viral infections based on currently available in vitro, in vivo, and human clinical investigations. The repurposing of a known drug such as N-acetylcysteine may significantly hasten the deployment of a novel approach for COVID-19. Since the drug candidate has already been translated into the clinic for several decades, its established pharmacological properties and safety and side-effect profiles expedite preclinical and clinical assessment for the treatment of COVID-19. In vitro data have depicted that N-acetylcysteine increases antioxidant capacity, interferes with virus replication, and suppresses expression of pro-inflammatory cytokines in cells infected with influenza viruses or respiratory syncytial virus. Furthermore, findings from in vivo studies have displayed that, by virtue of immune modulation and anti-inflammatory mechanism, N-acetylcysteine reduces the mortality rate in influenza-infected mice animal models. The promising in vitro and in vivo results have prompted the initiation of human subject research for the treatment of COVID-19, including severe pneumonia and acute respiratory distress syndrome. Albeit some evidence of benefits has been observed in clinical outcomes of patients, precision nanoparticle design of N-acetylcysteine may allow for greater therapeutic efficacy.

show abstract

Section: Discussionmentioning

confidence: 99%

N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence

Wong¹,

Lee²,

Kua³

2021

JIR

View full text Add to dashboard Cite

show abstract

“…Several case series and controlled studies with tocilizumab were reported so far with conflicting results either showing a favorable or no effect on the outcome of severe COVID-19, mainly due to the lack of power or problems associated with the study designs affecting the patient selection, SOC or timing of the drug administration [ 14 , 15 , 23 – 26 ]. In most of these studies, tocilizumab treatment was not aimed at treating the patients selected according to the findings of cytokine storm/macrophage activation syndrome such as lymphopenia and high ferritin levels, but they targeted mainly patients with severe COVID-19 pneumonia with poor respiratory findings.…”

Section: Discussionmentioning

confidence: 99%

“…Tocilizumab, a humanized monoclonal antibody against IL-6 receptor (IL-6R), has been shown to be effective in several immune-mediated inflammatory conditions where excessive production of IL-6 was documented [ 11 ]. Similarly, following a favorable report with tocilizumab in 21 patients with severe COVID-19 pneumonia [ 13 ], several open-label or randomized controlled studies were initiated with tocilizumab and other biologic agents blocking IL-6 activity, and conflicting results were reported so far [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Tocilizumab treatment in severe COVID-19: a multicenter retrospective study with matched controls

et al. 2021

View full text Add to dashboard Cite

Coronavirus disease-2019 (COVID-19) associated pneumonia may progress into acute respiratory distress syndrome (ARDS). Some patients develop features of macrophage activation syndrome (MAS). Elevated levels of IL-6 were reported to be associated with severe disease, and anti-IL-6R tocilizumab has been shown to be effective in some patients. This retrospective multicenter case–control study aimed to evaluate the efficacy of tocilizumab in hospitalized COVID-19 patients, who received standard of care with or without tocilizumab. Primary outcome was the progression to intubation or death. PSMATCH (SAS) procedure was used to achieve exact propensity score (PS) matching. Data from 1289 patients were collected, and study population was reduced to 1073 based on inclusion–exclusion criteria. The composite outcome was observed more frequently in tocilizumab-users, but there was a significant imbalance between arms in all critical parameters. Primary analyses were carried out in 348 patients (174 in each arm) after exact PS matching according to gender, ferritin, and procalcitonin. Logistic regression models revealed that tocilizumab significantly reduced the intubation or death (OR 0.40, p = 0.0017). When intubation is considered alone, tocilizumab-users had > 60% reduction in odds of intubation. Multiple imputation approach, which increased the size of the matched patients up to 506, provided no significant difference between arms despite a similar trend for intubation alone group. Analysis of this retrospective cohort showed more frequent intubation or death in tocilizumab-users, but PS-matched analyses revealed significant results for supporting tocilizumab use overall in a subset of patients matched according to gender, ferritin and procalcitonin levels. Supplementary Information The online version contains supplementary material available at 10.1007/s00296-021-04965-6.

show abstract

“…In contrast, dexamethasone, an antiinflammatory and immunosuppressive drug, has been found effective in decreasing all-cause mortality and composite disease progression [22] . Regarding others, effectiveness of the IL6 receptor directed antibody tocilizumab has been controversial, with the drug possibly reducing the likelihood of progression to mechanical ventilation [1] , [19] , [24] . Also, a trial in hospitalized patients not receiving noninvasive or invasive ventilation has recently reported death risk or respiratory failure lowering effect of the of the JAK inhibitor tofacitinib [14] .…”

Section: Introductionmentioning

confidence: 99%

Randomized trial drug controlled compendious transcriptome analysis supporting broad and phase specific therapeutic potential of multiple candidates in COVID-19

Sharma

2021

Cytokine

View full text Add to dashboard Cite

Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed. Maladaptive hyperinflammation and excessive cytokine release underlie the disease severity, with antiinflammatory and cytokine inhibiting agents expected to exert therapeutic effects. A major present challenge is identification of appropriate phase of the illness for a given intervention to yield optimum outcomes. Considering its established disease biomarker and drug discovery potential, a compendious analysis of existing transcriptomic data is presented here toward addressing this gap. The analysis is based on COVID-19 data related to intensive care unit (ICU) and non-ICU admissions, discharged and deceased patients, ventilation and non-ventilation phases, and high oxygen supplementation. It integrates transcriptomic data related to the effects of, in various cellular treatment models, the COVID-19 randomized clinical trial (RCT) successful drug dexamethasone, and the failed drug, with a potential to harm, hydroxychloroquine/chloroquine. Similarly, effects of various COVID-19 candidate drugs/anticytokines as well as proinflammatory cytokines implicated in the illness are also examined. The underlying assumption was that compared to COVID-19, an effective drug/anticytokine and a disease aggravating agent would affect gene regulation in opposite and same direction, in that order. Remarkably, the assumption was supported with respect to both the RCT drugs. With this control validation, etanercept, followed by tofacitinib and adalimumab, showed transcriptomic effects predictive of benefits in both ventilation and non-ventilation ICU stages as well as in non-ICU phase. On the other hand, canakinumab showed potential for effectiveness in high oxygen supplementation phase. These findings may inform experimental and clinical studies toward drug repurposing in COVID-19.

show abstract

Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context

Cited by 97 publications

References 59 publications

N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence

N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence

Tocilizumab treatment in severe COVID-19: a multicenter retrospective study with matched controls

Randomized trial drug controlled compendious transcriptome analysis supporting broad and phase specific therapeutic potential of multiple candidates in COVID-19

Contact Info

Product

Resources

About