The DOI matches its Crossref record; 29 of the 31 references it cites were found in a registry or an index; none of the 11 sources its claims cite is checked for support yet.
Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis
Open accessAbstract
Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.
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Claims the paper makes
78 Own result · 31 Own method · 7 Not checked yet · 6 Own interpretation · 4 No basis given
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding summary ORs for sarilumab (8 trials, 2406 patients, and 538 deaths) were 1.18 (95% CI, 0.88-1.58)and 0.92 (95% CI, 0.61-1.38),respectively.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021
plainn = 2,406- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The summary OR for the association with mortality for tocilizumab (15 trials, 7490 patients, and 1951 deaths) was 1.06 (95% CI, 0.85-1.33) in patients not receiving corticosteroids at randomization and was 0.77 (95% CI, 0.68-0.87) in patients receiving corticosteroids at randomization.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
plainn = 7,490- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By 28 days after randomization, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
plainn = 6,449- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In 19 trials that randomized 4299 patients to tocilizumab (960 deaths) and 3749 patients to usual care or placebo (1023 deaths), the summary OR was 0.83 (95% CI, 0.74-0.92;P < .001).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
plaincorrelationaln = 4,299 ·- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The inverse association with 28-day all-cause mortality appeared more marked for tocilizumab than for sarilumab (ratio of ORs, 0.76 [95% CI, 0.59-0.98],P = .04for interaction; Figure 1 and Table 2).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
hedgedcorrelationaln = 4,299 ·- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was little inconsistency between the trial results (I 2 = 18% overall, I 2 = 3% for tocilizumab, and I 2 = 0% for sarilumab).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
plainn = 4,299- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The summary ORs for 28-day all-cause mortality comparing IL-6 antagonists with usual care or placebo were 1.09 (95% CI, 0.91-1.30)for 3637 patients (830 deaths) not receiving corticosteroids and 0.78 (95% CI, 0.69-0.88)for 6316 patients (1665 deaths) receiving corticosteroids (Figure 2).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
plainn = 3,637- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87)for tocilizumab and 0.92 (95% CI, 0.61-1.38)for sarilumab.”
- Also stated in: § Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021 · plain
“The corresponding summary ORs for sarilumab (8 trials, 2406 patients, and 538 deaths) were 1.18 (95% CI, 0.88-1.58)and 0.92 (95% CI, 0.61-1.38),respectively.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021 · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“0.95 (95% CI, 0.78-1.16) in 2017 patients (801 deaths) receiving IMV or ECMO at randomization (P = .71for the differences between associations across these subgroups; Table 2).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021
plainn = 2,017- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 31
- The quote only partly states this claim. 1
- Probably not a substantial claim. 23
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no clear association between administration of IL-6 antagonists and all-cause mortality at 90 days or in the duration of IMV among patients who required IMV at randomization; however, the data were limited.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After excluding the large RECOVERY trial, the ORs comparing tocili- zumab with usual care or placebo were 0.82 (95% CI, 0.68- 0.98) for 28-day all-cause mortality and 0.71 (95% CI, 0.59- 0.84) for progression to IMV or death within 28 days (consistent with the primary analyses).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Additional Analyses
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding ORs were 0.85 (95% CI, 0.69-1.05)for tocilizumab and 0.92 (95% CI, 0.74-1.16)for sarilumab.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Other Secondary Outcomes
plaincorrelationaln = 4,651- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The fixed-effect summary OR was 0.99 (95% CI, 0.85-1.16)and there was little inconsistency between the trial results (I 2 = 0%, P = .49for heterogeneity; Figure 3).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Infections by 28 Days
plainn = 3,428- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Fifth, larger trials were mainly conducted in highincome settings; 65.9% of the tocilizumab data were provided by participants in the RECOVERY trial 9 and 71.0% of the sarilumab data were provided by participants in the Regeneron trial (NCT04315298).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Limitations
What the sources say
- Not checked yetcites [9] Abani, 2021, Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial., Lancet source
- Not checked yetcites NCT04315298
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The majority of patients in trials of sarilumab were not receiving corticosteroids at randomization, whereas the majority of patients in trials of tocilizumab were receiving corticosteroids at randomization.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The association of IL-6 antagonists with lower 28-day all-cause mortality was more marked among patients who did not require IMV at randomization, consistent with the inverse association of progression to IMV or death among these patients.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ORs restricted to trials published in peer-reviewed journals were consistent with the overall ORs for tocilizumab but were imprecisely estimated for sarilumab because of exclusion of the largest trial.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Additional Analyses
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding ORs were 1.30 (95% CI, 1.18-1.43)for tocilizumab and 0.95 (95% CI, 0.79-1.15)for sarilumab.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Other Secondary Outcomes
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ORs were 0.95 (95% CI, 0.77-1.16)for tocilizumab and 1.03 (95% CI, 0.80-1.32)for sarilumab”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Infections by 28 Days
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ORs were similar for open-label and placebo-controlled trials; however, the association of sarilumab compared with usual care for sec- ondary infections appeared more marked in open-label trials (1.97 [95% CI, 0.89-4.34]) than in placebo-controlled trials (0.96 [95% CI, 0.74-1.24]).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Additional Analyses
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding absolute risks of progression to IMV or death were 28% for all IL-6 antagonists, 27% for tocilizumab, and 33% for sarilumab compared with an assumed risk of 33% for usual care or placebo.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Progression to IMV or Death
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- The authors state this as an assumption: The assumed risk of progression to invasive mechanical ventilation or death in the usual care or placebo group is 33%.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The summary OR comparing IL-6 antagonists with usual care or placebo was 0.89 (95% CI, 0.76-1.04).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Other Secondary Outcomes
plaincorrelationaln = 4,651- Asserted: passes — The authors put it forward as true.
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The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding summary ORs for tocilizumab (17 trials, 6608 patients, and 2104 progressed) were 0.95 (95% CI, 0.76-1.20)and 0.69 (95% CI, 0.61-0.78),respectively”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Progression to IMV or Death
plaincorrelationaln = 6,608- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The corresponding summary ORs for sarilumab (7 trials, 1362 patients, and 298 progressed) were 0.98 (95% CI, 0.67-1.44)and 1.08 (95% CI, 0.67-1.75),respectively”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and Progression to IMV or Death
plainn = 1,362- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In 1 trial judged as high risk, comprising 0.65% of the weight, the usual procedures were not in place to ensure that the allocation sequence was concealed; however, there was no reason to suspect that the concealed allocation was not implemented as intended.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“For each trial, the risk of bias (low risk, some concerns, or high risk) was assessed using version 2 of the Cochrane Risk of Bias Assessment Tool.15”
- Also stated in: § Risk of Bias Assessment · plain
“Risk of bias assessments were done independently by 3 of the investigators (J.P.T.H., F.S., J.S.) with disagreements resolved through discussion.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Risk of Bias Assessment
What the sources say
- Not checked yetcites [15] Sterne, 2019, RoB 2: a revised tool for assessing risk of bias in randomised trials., BMJ source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § Risk of Bias Assessment · plain
In the paper
“The PICO (patient problem or population, intervention, comparison or control, and outcome) framework, definitions of outcomes, and subgroups of interest were agreed upon prior to collection of outcome data.6”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Development of Prospective Meta-analysis Protocol
What the sources say
- Not checked yetcites [6] Tierney, 2021, A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials., PLoS Med source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Risk of Bias Assessment
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Outcome data were supplied for 10 930 patients, representing 95.4% of all patients randomized in eligible trials (eFigure 1 in Supplement 1).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plainn = 10,930- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The primary outcome was missing for 183 patients (1.6%).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plainn = 183- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Six trials were judged to have some concerns, mainly due to small numbers of patients being excluded from the data set because they did not receive their assigned intervention.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The prospective meta-analysis protocol was registered on the PROSPERO database on January 14, 2021, and regularly updated.”
- Also stated in: § Development of Prospective Meta-analysis Protocol · plain
“The final version of the prospective meta-analysis protocol was registered before analyses started on March 29, 2021.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Development of Prospective Meta-analysis Protocol
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Also stated in: § Development of Prospective Meta-analysis Protocol · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For secondary infections, results from open-label trials were judged to have some concerns over bias in determining whether such infections had occurred due to the subjective nature of the decision (eFigure 2 and eTable 4 in Supplement 1).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Concurrent treatments at randomization varied substantially among the trials.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“the prospective metaanalysis protocol specified that a threshold for statistical significance would not be used.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Data Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Because of the diversity of classification of race/ethnicity among different trials, the subgroup analyses according to race/ethnicity are not reported.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All trials had secured institutional review board approval, but approval was not required for secondary analyses.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Development of Prospective Meta-analysis Protocol
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A greater proportion of patients in the sarilumab trials received IMV (31% [873/3136 patients]) compared with patients in the tocilizumab trials (15% [1211/8134 patients]) and a smaller proportion received corticosteroids (35% [890/3136 patients] vs 66% [5317/8134 patients], respectively; Table 1).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plaincorrelationaln = 3,136- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Concurrent administration of IL-6 antagonists 5 and corticosteroids, 26 which both have anti-inflammatory effects, may provide greater improvement than either type of drug given individually.8,9”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
What the sources say
- Not checked yetcites [8] Gordon, 2021, Interleukin-6 receptor antagonists in critically ill patients with Covid-19., N Engl J Med source
- Not checked yetcites [9] Abani, 2021, Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial., Lancet source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Trial investigators were asked to complete baseline and outcome data collection forms that were subsequently verified by trial teams.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Development of Prospective Meta-analysis Protocol
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data on respiratory support at randomization were available in 21 trials (9835 patients and 2493 deaths).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021
plainn = 9,835- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Both drugs were IL-6 receptor antagonists, but there may be differences between tocilizumab and sarilumab in receptor binding or lung concentrations.25”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
What the sources say
- Not checked yetcites [25] Xu, 2021, Differential binding of sarilumab and tocilizumab to IL-6Ra and effects of receptor occupancy on clinical parameters., J Clin Pharmacol source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Queries regarding eligibility for inclusion were resolved by consensus.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Identification and Eligibility of Trials
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In general, associations with improved outcomes were more marked for tocilizumab than for sarilumab, although comparisons between tocilizumab and sarilumab were indirect (made between trials).”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Due to limited data (including outcome events), associations for siltuximab within predefined subgroups were not estimated.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Fourth, the definitions and reporting of serious adverse events were not consistent across the trials and therefore a meta-analysis for this secondary end point was not conducted.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Among 72 potentially eligible trials, 27 (37.5%)met study selection criteria.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Searches were not restricted by trial status (ongoing or completed), publication status, or language.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Identification and Eligibility of Trials
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For tocilizumab, the results from other trials were similar to those from the large RECOVERY trial, supporting generalizability of the findings across settings.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The tendency for more marked inverse associations among patients receiving corticosteroids appeared broadly consistent across respiratory support subgroups; however, the associations were not estimated precisely.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because data were shared based on standardized definitions of outcomes and subgroups agreed upon in advance, these aggregate data meta-analyses had many of the advantages of individual-patient data meta-analyses while avoiding the need to establish formal data sharing agreements.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“However, the trials of sarilumab were generally done earlier in the pandemic than those of tocilizumab and before corticosteroids became the standard of care.7”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
What the sources say
- Not checked yetcites [7] Sterne, 2020, Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis., JAMA source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these differences between subgroups may have arisen due to sampling variation.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This limitation was addressed in the sensitivity analyses and the results were consistent with the primary analyses.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Limitations
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Because outcome data were generally complete or nearly complete across trials, we restricted the analyses to trial participants with outcomes recorded.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Data Analyses
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is possible that lack of participation or participation by some of the ongoing trials may be based on knowledge of their interim results.”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Limitations
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The authors state this as an assumption.
The assumed risk of progression to invasive mechanical ventilation or death in the usual care or placebo group is 33%.
“compared with an assumed risk of 33% for usual care or placebo”
“compared with an assumed risk of 33% for progression to IMV or death for usual care or placebo”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Clinical trials have been conducted with the IL6-blocking agent tocilizumab in patients with COVID-19 (78), and clinical studies have demonstrated efficacy in lowering all-cause mortality (79).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [79]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Association Between IL-6 Antagonists and 28-Day All-Cause Mortality
“In 9 trials that randomized 2073 patients to sarilumab (473 deaths) and 753 patients to usual care or placebo (139 deaths)”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Downloaded From: https://jamanetwork.com/ by a University of Gent / UZGent Kenniscentrum User on 07/16/2021
“17.51 139/753 437/2073 Subgroup I 2 = 0% 1.08 (0.86-1.36)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“35% [890/3136 patients]”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
Reported 35 · recomputed 28.380102
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“31% [873/3136 patients]”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
Reported 31 · recomputed 27.83801
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
“those treated with usual care or placebo (330/1787; 17.6%)”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Serious Adverse Events or Reactions
Reported 17.6 · recomputed 18.466704
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
“Risk of bias was assessed to be low in 22 of the trials contributing to the meta-analysis of 28-day all-cause mortality, comprising 78% of the weight in the analysis.Six trials were judged to have some concerns, mainly due to small numbers of patients being excluded from the data set because they did not receive their assigned intervention.In 1 trial judged as high risk”
§ Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 A Meta-analysis > Results
“Among the 27 trials included in the meta-analyses”
Citations
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Metadata
- Authors
- The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Domingo, P., Mur, I., Mateo, G. M., Gutierrez, M. D. M., Pomar, V., de Benito, N., Corbacho, N., Herrera, S., Millan, L., Muñoz, J., Malouf, J., Molas, M. E., Asensi, V., Horcajada, J. P., Estrada, V., Gutierrez, F., Torres, F., Perez-Molina, J. A., Fortun, J., Villar, L. M., Hohenthal, U., Marttila, H., Vuorinen, T., Nordberg, M., Valtonen, M., Frigault, M. J., Mansour, M. K., Patel, N. J., Fernandes, A., Harvey, L., Foulkes, A. S., Healy, B. C., Shah, R., Bensaci, A. M., Woolley, A. E., Nikiforow, S., Lin, N., Sagar, M., Shrager, H., Huckins, D. S., Axelrod, M., Pincus, M. D., Fleisher, J., Lampa, J., Nowak, P., Vesterbacka, J. C., Rasmuson, J., Skorup, P., Janols, H., Niward, K. F., Chatzidionysiou, K., Asgeirsson, H., Parke, Å., Blennow, O., Svensson, A.-K., Aleman, S., Sönnerborg, A., Henter, J.-I., Horne, A. C., Al-Beidh, F., Angus, D., Annane, D., Arabi, Y., Beane, A., Berry, S., Bhimani, Z., Bonten, M., Bradbury, C., Brunkhorst, F., Buxton, M., Cheng, A., Cove, M., De Jong, M., Derde, L., Estcourt, L., Goossens, H., Gordon, A., Green, C., Haniffa, R., Ichihara, N., Lamontagne, F., Lawler, P., Litton, E., Marshall, J., McArthur, C., McAuley, D., McGuinness, S., McVerry, B., Montgommery, S., Mouncey, P., Murthy, S., Nichol, A., Parke, R., Parker, J., Reyes, F., Rowan, K., Saito, H., Santos, M., Seymour, C., Shankar-Hari, M., Turgeon, A., Turner, A., van Bentum-Puijk, W., van de Veerdonk, F., Webb, S., Zarychanski, R., Baillie, J. K., Beasley, R., Cooper, N., Fowler, R., Galea, J., Hills, T., King, A., Morpeth, S., Netea, M., Ogungbenro, K., Pettila, V., Tong, S., Uyeki, T., Youngstein, T., Higgins, A., Lorenzi, E., Berry, L., Salama, C., Rosas, I. O., Ruiz-Antorán, B., Muñez Rubio, E., Ramos Martínez, A., Campos Esteban, J., Avendaño Solá, C., Pizov, R., Sanz Sanz, J., Abad-Santos, F., Bautista-Hernández, A., García-Fraile, L., Barrios, A., Gutiérrez Liarte, Á., Alonso Pérez, T., Rodríguez-García, S. C., Mejía-Abril, G., Prieto, J. C., Leon, R., VEIGA, V. C., SCHEINBERG, P., FARIAS, D. L. C., PRATS, J. G., CAVALCANTI, A. B., MACHADO, F. R., ROSA, R. G., BERWANGER, O., AZEVEDO, L. C. P., LOPES, R. D., DOURADO, L. K., CASTRO, C. G., ZAMPIERI, F. G., AVEZUM, A., LISBOA, T. C., ROJAS, S. S. O., COELHO, J. C., LEITE, R. T., CARVALHO, J. C., ANDRADE, L. E. C., SANDES, A. R., PINTÃO, M. C. T., SANTOS, S. V., ALMEIDA, T. M. L., COSTA, A. N., GEBARA, O. C. E., FREITAS, F. G. R., PACHECO, E. S., MACHADO, D. J. B., MARTIN, J., CONCEIÇÃO, F. G., SIQUEIRA, S. R. R., DAMIANI, L. P., ISHIHARA, L. M., SCHNEIDER, D., DE SOUZA, D., Hermine, O., Mariette, X., Tharaux, P. L., Resche Rigon, M., Porcher, R., Ravaud, P., Azoulay, E., Cadranel, J., Emmerich, J., Fartoukh, M., Guidet, B., Humbert, M., Lacombe, K., Mahevas, M., Pene, F., Pourchet-Martinez, V., Schlemmer, F., Tibi, A., Yazdanpanah, Y., Dougados, M., Bureau, S., Horby, P. W., Landray, M. J., Baillie, K. J., Buch, M. H., Chappell, L. C., Day, J. N., Faust, S. N., Haynes, R., Jaki, T., Jeffery, K., Juszczak, E., Lim, W. S., Mafham, M., Montgomery, A., Mumford, A., Thwaites, G., Kamarulzaman, A., Syed Omar, S. F., Ponnampalavanar, S., Raja Azwa, R. I. S., Wong, P. L., Kukreja, A., Ong, H. C., Sulaiman, H., Basri, S., Ng, R. X., Megat Johari, B., Rajasuriar, R., Chong, M. L., Neelamegam, M., Syed Mansor, S. M., Zulhaimi, N. S., Lee, C. S., Altice, F., Price, C., Malinis, M., Hasan, M. S., Wong, C. K., Chidambaram, S., Misnan, N. A., Mohd Thabit, A. A., Sim, B., Bidin, F. N., Mohd Abd Rahim, M. A. H., Saravanamuttu, S., Tuang, W. X., Mohamed Gani, Y., Thangavelu, S., Tay, K. H., Ibrahim, N. M., Halid, L. A., Tan, K. T., Mukri, M. N. A., Arip, M., Koh, H. M., Syed Badaruddin, S. N. A., Raja Sureja, L., Chun, G. Y., TORRE-CISNEROS, J., MERCHANTE, N., LEON, R., CARCEL, S., GARRIDO, J. C., Galun, E., Soriano, A., Martínez, J. A., Castán, C., Paredes, R., Dalmau, D., Carbonell, C., Espinosa, G., Castro, P., Muñóz, J., Almuedo, A., Prieto, S., Pacheco, I., Ratain, M., Pisano, J., Strek, M., Adegunsoye, A., Karrison, T., Jozefien, D., Karel F.A., V. D., Elisabeth, D. L., Cedric, B., Bastiaan, M., Shankar-Hari, M., Vale, C. L., Godolphin, P. J., Fisher, D., Higgins, J. P. T., Spiga, F., Savovic, J., Tierney, J., Baron, G., Benbenishty, J. S., Berry, L. R., Broman, N., Cavalcanti, A. B., Colman, R., De Buyser, S. L., Derde, L. P. G., Domingo, P., Omar, S. F., Fernandez-Cruz, A., Feuth, T., Garcia, F., Garcia-Vicuna, R., Gonzalez-Alvaro, I., Gordon, A. C., Haynes, R., Hermine, O., Horby, P. W., Horick, N. K., Kumar, K., Lambrecht, B. N., Landray, M. J., Leal, L., Lederer, D. J., Lorenzi, E., Mariette, X., Merchante, N., Misnan, N. A., Mohan, S. V., Nivens, M. C., Oksi, J., Perez-Molina, J. A., Pizov, R., Porcher, R., Postma, S., Rajasuriar, R., Ramanan, A. V., Ravaud, P., Reid, P. D., Rutgers, A., Sancho-Lopez, A., Seto, T. B., Sivapalasingam, S., Soin, A. S., Staplin, N., Stone, J. H., Strohbehn, G. W., Sunden-Cullberg, J., Torre-Cisneros, J., Tsai, L. W., van Hoogstraten, H., van Meerten, T., Veiga, V. C., Westerweel, P. E., Murthy, S., Diaz, J. V., Marshall, J. C., & Sterne, J. A. C.
- Affiliations
- The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
- St. Michael's Hospital (CA)
- MRC Clinical Trials Unit at UCL (GB)
- University of Bristol (GB)
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
- Inserm (FR)
- Hadassah Medical Center (IL)
- Berry Consultants, Austin, Texas
- Turku University Hospital (FI)
- BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil
- Ghent University (BE)
- Department of Public Health and Primary Care, Ghent University, Ghent, Belgium
- Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
- Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
- Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain
- Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain
- Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England
- Medanta The Medicity (IN)
- Regeneron (United States) (US)
- Genentech, South San Francisco, California
- University Medical Center Groningen (NL)
- Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
- University of Oxford (GB)
- Massachusetts General Hospital (US)
- Karolinska University Hospital (SE)
- Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
- Genentech (US)
- Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey
- Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands
- University of British Columbia (CA)
- Corresponding author
- Seymour, Chris
- ORCID
- Mur, Isabel
- Pomar, Virginia
- Malouf, Jorge
- Molas, Maria Ema
- Horcajada, Juan Pablo
- Estrada, Vicente
- Villar, Luisa M
- Hohenthal, Ulla
- Vuorinen, Tytti
- Nordberg, Marika
- Frigault, Matthew J
- Mansour, Michael K
- Patel, Naomi J
- Fernandes, Ana
- Foulkes, Andrea S
- Healy, Brian C
- Woolley, Ann E.
- Nikiforow, Sarah
- Lin, Nina
- Sagar, Manish
- Fleisher, Jorge
- Lampa, Jon
- Nowak, Piotr
- Rasmuson, Johan
- Skorup, Paul
- Janols, Helena
- Niward, Katarina F
- Chatzidionysiou, Katerina
- Parke, Åsa
- Blennow, Ola
- Aleman, Soo
- Sönnerborg, Anders
- Henter, Jan-Inge
- Al-Beidh, Farah
- Angus, Derek
- Annane, Djillali
- Arabi, Yaseen
- Berry, Scott
- Bonten, Marc
- Bradbury, Charlotte
- Brunkhorst, Frank
- Buxton, Meredith
- Estcourt, Lise
- Goossens, Herman
- Green, Cameron
- Haniffa, Rashan
- Ichihara, Nao
- Lawler, Patrick
- McArthur, Colin
- McAuley, Daniel
- McGuinness, Shay
- McVerry, Bryan
- Mouncey, Paul
- Nichol, Alistair
- Rowan, Kathryn
- Saito, Hiroki
- Turgeon, Alexis
- Turner, Anne
- Beasley, Richard
- Cooper, Nichola
- Fowler, Robert
- Galea, James
- Hills, Thomas
- King, Andrew
- Morpeth, Susan
- Netea, Mihai
- Ogungbenro, Kayode
- Youngstein, Taryn
- Higgins, Alisa
- García-Fraile, Lucio
- Barrios, Ana
- Rodríguez-García, Sebastian C
- Mejía-Abril, Gina
- SCHEINBERG, PHILLIP
- FARIAS, DANIELLE L.C.
- AZEVEDO, LUCIANO C.P.
- ZAMPIERI, FERNANDO G.
- LISBOA, THIAGO C.
- ROJAS, SALOMÓN S.O.
- COELHO, JULIANA C.
- PINTÃO, MARIA CAROLINA T.
- COSTA, ANDRÉ N.
- MACHADO, DAVID J.B.
- CONCEIÇÃO, FABIO G.
- SIQUEIRA, SUELLEN R.R.
- DAMIANI, LUCAS P.
- ISHIHARA, LUCIANA M.
- SCHNEIDER, DANIEL
- Tharaux, Pierre Louis
- Cadranel, Jacques
- Emmerich, Joseph
- Fartoukh, Muriel
- Guidet, Bertrand
- Humbert, Marc
- Lacombe, Karine
- Schlemmer, Frédéric
- Yazdanpanah, Yazdan
- Dougados, Maxime
- Buch, Maya H
- Chappell, Lucy C
- Day, Jeremy N
- Faust, Saul N
- Jaki, Thomas
- Jeffery, Katie
- Juszczak, Edmund
- Lim, Wei Shen
- Mafham, Marion
- Montgomery, Alan
- Mumford, Andrew
- Thwaites, Guy
- Kamarulzaman, Adeeba
- Ponnampalavanar, Sasheela
- Wong, Pui Li
- Kukreja, Anjanna
- Sulaiman, Helmi
- Basri, Sazali
- Ng, Rong Xiang
- Neelamegam, Malinee
- Altice, Frederick
- Price, Christina
- Malinis, Maricar
- Hasan, Mohd Shahnaz
- Wong, Chee Kuan
- Chidambaram, Suresh
- Sim, Benedict
- Tay, Kim Heng
- Arip, Masita
- Koh, Hui Moon
- Paredes, Roger
- Dalmau, David
- Carbonell, Cristina
- Espinosa, Gerard
- Castro, Pedro
- Muñóz, José
- Prieto, Sergio
- Ratain, Mark
- Pisano, Jennifer
- Strek, Mary
- Adegunsoye, Ayodeji
- Karrison, Theodore
- Vale, Claire L.
- Godolphin, Peter J.
- Fisher, David
- Higgins, Julian P. T.
- Spiga, Francesca
- Tierney, Jayne
- Baron, Gabriel
- Benbenishty, Julie S.
- Broman, Niklas
- Colman, Roos
- Feuth, Thijs
- Horick, Nora K.
- Lambrecht, Bart N.
- Leal, Lorna
- Lederer, David J.
- Oksi, Jarmo
- Ramanan, Athimalaipet V.
- Reid, Pankti D.
- Rutgers, Abraham
- Seto, Todd B.
- Sivapalasingam, Sumathi
- Staplin, Natalie
- Stone, John H.
- Strohbehn, Garth W.
- Tsai, Larry W.
- Westerweel, Peter E.
- Diaz, Janet V.
- Marshall, John C.
- Sterne, Jonathan A. C.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2021-08-10
- Volume
- 326
- Issue
- 6
- Pages
- 499
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC8261689
- OpenAlex
- W3181530483
- Semantic Scholar
- eb99d2480fe8ca5efe5a708d37ca25946541e1e2
- Cited by
- 678
- References
- 31
- Citations by year
- 2026: 25 · 2025: 43 · 2024: 105 · 2023: 147 · 2022: 263 · 2021: 92
- FWCI
- 48.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- HAL (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- GlaxoSmithKline
- Sanofi
- World Health Organization (COVID-19)
- Massachusetts General Hospital
- Gilead Sciences (COVID-19)
- Biogen
- Alexion Pharmaceuticals
- Celgene
- University of Chicago
- Regeneron Pharmaceuticals
- ViiV Healthcare
- Innovative Medicines Canada
- UK Research and Innovation
- Argenx
- Roche España
- Cancer Research UK (16896)
- National Institute for Health and Care Research (NIHR201409, NIHR202424, COVID-19, NF-SI-0617-10145, RP-2015-06-018, COVID-19-RECPLAS)
- European Commission (COVID-19)
- University of Bristol
- Institut National de la Santé et de la Recherche Médicale (UMR1153, UMR1184)
- Hebrew University of Jerusalem
- University of Toronto
- Karolinska Institutet
- Vetenskapsrådet
- Universiteit Gent
- Universiti Malaya
- Ministerio de Ciencia e Innovación
- Universitair Medisch Centrum Groningen
- Shionogi
- Institut National de la Recherche Agronomique
- Université Paris-Saclay (UMR1184)
- Universidad de Córdoba
- Assistance publique-Hôpitaux de Paris
- Swedish Orphan Biovitrum
- PharmaMar
- European Society of Intensive Care Medicine
- Aspen
- National Institutes of Health (2kl2tr002387-06)
- Genentech
- Biomedical Advanced Research and Development Authority
- Sanofi Genzyme
- Canadian Institutes of Health Research (COVID-19)
- Medical Research Council (MC_UU_00004/06, MC_PC_20062)
- Instituto de Salud Carlos III
- European Regional Development Fund
- Center for Innovative Medicine
- Belgian Health Care Knowledge Centre
- National Institute of Allergy and Infectious Diseases (UM1AI144295)
- National Center for Advancing Translational Sciences (KL2‐TR002387)
- Institute of Infection and Immunity
- Cilag
- Health Data Research UK
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- IL-6 inhibitors, COVID-19 pandemic, tocilizumab, sarilumab, 28-day all-cause mortality, hospitalized patients, immunomodulatory therapy, secondary infection, invasive mechanical ventilation, corticosteroids, risk of bias
- MeSH terms
- COVID-19, Interleukin-6 Inhibitors, COVID-19 Drug Treatment, Aged, Cause of Death, Drug Therapy, Combination, Female, Glucocorticoids, Hospitalization, Humans, Male, Middle Aged, Prospective Studies, Respiration, Artificial, Randomized Controlled Trials as Topic, Disease Progression, Coinfection, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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