Is IL-6 the Right Target in COVID-19 Severe Pneumonia?

Blot, Mathieu; Bourredjem, Abderrahmane; Binquet, Christine; Piroth, Lionel; Quenot, Jean-Pierre; Charles, Pierre‐Emmanuel; Aptel, François; Prin, Sébastien; Andreu, Pascal; Labruyère, Marie; Dargent, Auguste; Nguyen, Maxime; Bouhemad, Bélaïd; Georges, Marjolaine; Bonniaud, Philippe; Beltramo, Guillaume; Buisson, Marielle; Bonnotte, B.; Bielefeld, P.; Barben, Jérémy; Putot, Alain; Monier, Serge; Large, Audrey; Mouriès-Martin, S.; Devilliers, H.; Chavanet, P.; Guilhem, A

doi:10.1164/rccm.202007-2924le

Cited by 13 publications

(13 citation statements)

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“…At baseline respiratory severity, COVID-19 patients had a significantly longer duration of MV (15 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] vs. 4 [0-14.5]; p = 0.0049), and ICU stay (p = 0.0274) and higher rate of ventilator-acquired pneumonia (p = 0.001) than non-COVID-19 patients ( Table 1). The 30-day mortality rate was 6% (n = 2) in the non-COVID-19 group and 4% (n = 1) in the COVID-19 group (p = 1.00).…”

Section: Covid-19 Patients Had a Significantly Longer Duration Of Mecmentioning

confidence: 99%

“…11 Department of Internal Medicine and Clinical Immunology, Dijon Bourgogne University Hospital, Dijon, France. 12 Department of Internal Medicine and Systemic Diseases, Dijon Bourgogne University Hospital, Dijon, France. 13 Geriatrics Internal Medicine Department, Dijon Bourgogne University Hospital, Dijon, France.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…Second, the relevance of the cytokine storm paradigm is being questioned [10,11]. We recently reported that COVID-19 patients had lower concentrations of interleukin (IL)-6 compared to non-COVID-19 patients with severe pneumonia [12]. Others showed that mean IL-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome, 27 times higher in patients with sepsis and 12 times higher in patients with ARDS unrelated to COVID-19 [13].…”

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confidence: 99%

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The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome

Blot

Bour²,

Quenot

et al. 2020

J Transl Med

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Background Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. Methods Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. Results At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7–22] vs. 4 (0–15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. Conclusion We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

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Section: Covid-19 Patients Had a Significantly Longer Duration Of Mecmentioning

confidence: 99%

Section: Supplementary Informationmentioning

confidence: 99%

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confidence: 99%

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The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome

Blot

Bour²,

Quenot

et al. 2020

J Transl Med

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“…Hence, from our findings, it seems that the inhibition of IL-6 alone may not be adequate to mitigate the risk of mortality in patients with COVID-19, at least in certain subpopulation of patients with more severe disease [11]. Indeed, a recent prospective study by Blot et al [12], which compared the plasma concentrations of IL-6 among patients with COVID-19 associated pneumonia and patients with pneumonia other than COVID-19, reported that the plasma concentrations of IL-6 were significantly lower among the patients with COVID-19 associated pneumonia relative to the patients with pneumonia other than COVID-19 (121.0 pg/mL versus 460.4 pg/mL).…”

Section: Discussionmentioning

confidence: 72%

The effect of tocilizumab on mortality in hospitalized patients with COVID-19: a meta-analysis of randomized controlled trials

Kow

Hasan

2021

Eur J Clin Pharmacol

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Objective We aimed to perform a meta-analysis of randomized controlled trials (RCTs) to summarize the overall effect of tocilizumab on the risk of mortality among patients with coronavirus disease 2019 (COVID-19). Methods We systematically searched PubMed, Cochrane Central Register of Controlled Trials, Google Scholar, and medRxiv (preprint repository) databases (up to 7 January 2021). Pooled effect sizes with 95% confidence interval (CI) were generated using random-effects and inverse variance heterogeneity models. The risk of bias of the included RCTs was appraised using version 2 of the Cochrane risk-of-bias tool for randomized trials. Results Six RCTs were included: two trials with an overall low risk of bias and four trials had some concerns regarding the overall risk of bias. Our meta-analysis did not find significant mortality benefits with the use of tocilizumab among patients with COVID-19 relative to non-use of tocilizumab (pooled hazard ratio = 0.83; 95% CI 0.66–1.05, n = 2,057). Interestingly, the estimated effect of tocilizumab on the composite endpoint of requirement for mechanical ventilation and/or all-cause mortality indicated clinical benefits, with some evidence against our model hypothesis of no significant effect at the current sample size (pooled hazard ratio = 0.62; 95% CI 0.42–0.91, n = 749). Conclusion Despite no clear mortality benefits in hospitalized patients with COVID-19, tocilizumab appears to reduce the likelihood of progression to mechanical ventilation.

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“…Leptin is secreted by adipose tissue and acts as a central pro-inflammatory regulator of innate and adaptative immune responses, especially by increasing T-cell proliferation and Th-1 response [ 5 ]. Interestingly, we recently reported that both alveolar and plasma concentrations of CXCL10, a Th-1 chemokine, were higher in COVID-19 patients than in non-COVID-19 patients, and were independently associated with a longer duration of MV [ 8 , 12 ]. Accordingly, we tried to unravel the link between adipokines and inflammatory cytokine production in patients with severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Are adipokines the missing link between obesity, immune response, and outcomes in severe COVID-19?

et al. 2021

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Introduction Obesity is commonly reported in COVID-19 patients and is associated with poorer outcomes. It is suggested that leptin could be the missing link between obesity and severe COVID-19. Our study aimed to unravel the link between adipokines, COVID-19 status, immune response, and outcomes in severe pneumonia. Methods In this prospective observational single-center study, 63 immunocompetent patients with severe pneumonia (36 non-COVID-19 and 27 COVID-19) were enrolled, most required intensive care. Clinical and biological characteristics (glucose metabolism, plasma adipokines, and cytokine concentrations) and outcomes were compared. Results At similar baseline severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients ( p = 0.0049). Plasma concentrations of leptin and adiponectin were respectively positively and negatively correlated with BMI and glucose metabolism (glycemia and insulinemia), but not significantly different between the two groups. Leptin levels were negatively correlated with IL-1β and IL-6, but the adipokines were not correlated with most other inflammatory mediators, baseline severity (SOFA score), or the duration of mechanical ventilation. Conclusion Adipokine levels were correlated with BMI but not with most inflammatory mediators, severity, or outcomes in severe pneumonia, regardless of the origin. The link between obesity, dysregulated immune response, and life-threatening COVID-19 requires further investigation. Clinical trial ClinicalTrials.gov: NCT03505281.

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Is IL-6 the Right Target in COVID-19 Severe Pneumonia?

Cited by 13 publications

References 3 publications

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome

The effect of tocilizumab on mortality in hospitalized patients with COVID-19: a meta-analysis of randomized controlled trials

Are adipokines the missing link between obesity, immune response, and outcomes in severe COVID-19?

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