Interleukin-6 blocking agents for treating COVID-19: a living systematic review

Ghosn, Lina; Chaimani, Anna; Evrenoglou, Theodoros; Davidson, Mauricia; Graña, Carolina; Schmucker, Christine; Bollig, Claudia; Henschke, Nicholas; Sguassero, Yanina; Nejstgaard, Camilla Hansen; Menon, Sonia; Nguyen, Thu Van; Ferrand, G; Kapp, Philipp; Riveros, Carolina; Ávila, Camila; Devane, Declan; Meerpohl, Joerg J; Rada, Gabriel; Hróbjartsson, Asbjørn; Grasselli, Giacomo; Tovey, David; Ravaud, Philippe; Boutron, Isabelle

doi:10.1002/14651858.cd013881

Cited by 143 publications

(180 citation statements)

References 105 publications

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“…Indeed, IL-6 is crucial in regulating the inflammatory response, and increased IL-6 levels in COVID-19 patients have been repeatedly related to the severity and prognosis of this disease [ 4 , 5 ]. Consistent with this hypothesis, tocilizumab, a recombinant humanized antihuman IL-6 receptor monoclonal antibody, has been widely used with the aim to improve the clinical outcome and possibly reduce mortality in severe and critical COVID-19 patients [ 27 – 29 ]. Interestingly, we previously demonstrated that a low vitamin D status is associated with an enhanced acute inflammatory reaction in patients undergoing bisphosphonate treatment, that becomes particularly relevant when 25OHD levels are below 20 ng/mL [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

et al. 2021

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Background Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19. Methods We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization. Results Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0–56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0–32.0) pg/mL, p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0–99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5–45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ − 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98–1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95–0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count. Conclusion In our COVID-19 patients, low 25OHD levels were inversely correlated with high IL-6 levels and were independent predictors of COVID-19 severity and mortality.

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Section: Discussionmentioning

confidence: 99%

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

et al. 2021

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“…Indeed, IL-6 is crucial in regulating the inflammatory response, and increased IL-6 levels in COVID-19 patients have been repeatedly related to the severity and prognosis of this disease [4,5]. Consistent with this hypothesis, tocilizumab, a recombinant humanized antihuman IL-6 receptor monoclonal antibody, has been widely used with the aim to improve the clinical outcome and possibly reduce mortality in severe and critical COVID-19 patients [27][28][29]. Interestingly, we previously demonstrated that a low vitamin D status is associated with an enhanced acute inflammatory reaction in patients undergoing bisphosphonate treatment, that becomes particularly relevant when 25OHD levels are below 20 ng/mL [30].…”

Section: Discussionmentioning

confidence: 93%

Vitamin D and COVID-19 Severity and Related Mortality: A Prospective Study in Italy

et al. 2020

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Background: Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 . We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19. Methods: We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization. Results: Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0-56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0-32.0) pg/mL, p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0-99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5-45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ − 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98-1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95-0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count.

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“…We only included data from RCTs with a low or moderate risk of bias, as assessed by the living systematic review from which we based our data extraction process. [11] Further, we tried to mitigate potential biases associated with researcher degrees of freedom by pre-registering the data extraction process and part of the analysis plan, [14] and restricting our analyses to RECOV-ERY specified subgroups. Next, in contrast to P-values and confidence intervals, Bayesian analyses can provide intuitive and understandable probability estimates of each subgroup's treatment effect.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Tocilizumab in COVID-19 – A Bayesian reanalysis of RECOVERY

Albuquerque

Tramujas²,

Sewanan

et al. 2021

Preprint

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Background: Randomised Evaluation of COVID-19 Therapy (RECOVERY) demonstrated that tocilizumab reduces mortality in hospitalized COVID-19 patients. However, substantial uncertainty remains whether tocilizumab's effect is similar across clinically relevant subgroups. Whether this uncertainty can be resolved with Bayesian methods is unknown. Design, Setting, Participants, and Interventions: RECOVERY was a controlled, open-label, platform UK trial that randomized (1:1) 4116 adults with oxygen saturation <92% on room air or receiving oxygen therapy with C-reactive protein ≥75 mg/L to either usual care or tocilizumab plus usual care. Main outcome measures: Mortality and hospital discharge within 28 days. Methods: Using Bayesian methods, we combined RECOVERY with evidence-based priors incorporating previous COVID-19 tocilizumab RCTs. The probability of tocilizumab's benefit for respiratory support and corticosteroid subgroups and sensitivity analyses were performed with different prior distributions and baseline risks. Results: For all-cause mortality, the posterior probabilities of decreased deaths with tocilizumab were >99% and 19% in patients using and not using corticosteroids, respectively. In patients on simple oxygen only, non-invasive ventilation and invasive mechanical ventilation, the probabilities of decreased mortality were 96%, >99% and 77%, respectively. The probabilities for a clinically significant mortality reduction, as assessed by an absolute risk difference > 3% (number needed to treat ≤ 33), were 77%, 96%, 56%, respectively. Sensitivity analyses highlighted the uncertainty and lack of conclusive evidence for tocilizumab's effect in patients on invasive mechanical ventilation and those without concurrent corticosteroids. Posterior probabilities of benefit for hospital discharge outcome were high and consistent across most subgroups. Conclusions: In this Bayesian reanalysis, COVID-19 hospitalized patients exposed to corticosteroids or on non-invasive ventilation have a high probability of a clinically meaningful mortality benefit from tocilizumab. Tocilizumab also likely improves discharge from hospital in most subgroups. Future research should further address if patients on invasive mechanical ventilation can also benefit from tocilizumab.

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Interleukin-6 blocking agents for treating COVID-19: a living systematic review

Abstract: Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

Cited by 143 publications

References 105 publications

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy

Vitamin D and COVID-19 Severity and Related Mortality: A Prospective Study in Italy

Tocilizumab in COVID-19 – A Bayesian reanalysis of RECOVERY

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