Key messages
• Overall, we did not find sufficient evidence to show that medicines that block interleukin-1 (a protein involved in immune responses) are effective treatments for people with COVID-19, or whether they cause unwanted effects.
• We found 16 studies with unpublished results. We will update this review when new data are available.
• In future, we need high-quality studies to evaluate medicines that block interleukin-1 to treat COVID-19.
What is interleukin-1 and what is its role in COVID-19?
Interleukin-1 (IL-1) is a type of protein called a cytokine, which helps to regulate the body’s immune system. In particular, IL-1 triggers inflammation to help fight infection. In COVID-19, as the immune system fights the virus, the lungs and airways become inflamed, causing breathing difficulties. However, in some people, the immune system can over-react (called a ‘cytokine storm’) and produce dangerously high levels of inflammation and tissue damage. This can lead to severe breathing difficulties, organ failure and death.
What are interleukin-1 ‘blockers’?
IL-1 blockers are medicines that stop IL-1 from working by blocking signals from IL-1 to other parts of the immune system. This reduces inflammation and may help the immune system to fight COVID-19. In turn, this may reduce the need for breathing support with a ventilator (a machine that breathes for a patient) and reduce the number of deaths from COVID-19. Three IL-1 blockers are available: anakinra, canakinumab and rilonacept.
What did we want to find out?
We wanted to know if IL-1 blockers are effective treatments for people with COVID-19, compared with standard care alone or with placebo (a dummy treatment that appears identical to the medicine being tested but without any active medicine). We were particularly interested in the effects of IL-1 blockers on:
• whether people’s symptoms got better or worse;
• how many people died; and
• any unwanted effects and serious unwanted effects.
What did we do?
We searched for studies that assessed the effects of IL-1 blockers to treat people with COVID-19 compared with standard care alone or with placebo. People in the studies could have suspected or confirmed COVID-19 of any severity (mild, moderate or severe), and be any age or sex.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found six studies with 2132 people. Four studies assessed anakinra (1633 people) and two assessed canakinumab (499 people). People in the studies were aged between 58 and 68 years old on average, and the majority were men. All the people in the studies were in hospital, mainly with moderate to critical COVID-19. The studies varied in size, from 45 to 2253 people. At the start of the studies, 67% to 100% of people were receiving oxygen, and 0% to 33% were on a ventilator.
We also found 16 studies that have not yet published their results.
Anakinra compared to usual care and placebo to treat people with COVID-19
• Anakinra probably results in little or no improvement in COVID-19 symptoms (defined as improvement on a clinical scale or discharge from hospital) at 28 days after treatment (three studies, 837 people) but we do not know if it makes a difference at 60 days (one study, 115 people).
• We do not know if anakinra makes a difference to the number of deaths at 28 days after treatment (two studies, 722 people) or at 60 days (four studies, 1633 people).
• Anakinra probably results in little or no increase in any unwanted effects at 28 days after treatment, but we are not sure about its effect on serious unwanted effects (two studies, 722 people).
Canakinumab compared to usual care and placebo to treat people with COVID-19
• Canakinumab probably results in little or no improvement in COVID-19 symptoms (defined as improvement on a clinical scale or discharge from hospital) at 28 days after treatment (two studies, 499 people).
• We do not know if canakinumab makes a difference to the number of deaths at 28 days after treatment (two studies, 499 people) or at 60 days (one study, 45 people).
• Canakinumab probably results in little or no increase in any unwanted effects (one study, 454 people), but we are not sure about its effect on serious unwanted effects (two studies, 499 people) at 28 days.
What are the limitations of the evidence?
Our confidence in the evidence is limited for several reasons. All the people in the studies were hospitalised, but some were more seriously ill than others - some studies only included people on a ventilator. Usual care also differed between studies, and studies measured and reported their results using different methods.
How up to date is this evidence?
The evidence is up to date to 5 November 2021.
Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).
Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19.
To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19.
We will update this assessment regularly.
We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021).
We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity.
We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events.
We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab.
Effectiveness of anakinra for people with COVID-19
Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence.
The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).
The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence).
Safety of anakinra for people with COVID-19
Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).
The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence).
Effectiveness of canakinumab for people with COVID-19
Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).
The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).
The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence).
Safety of canakinumab for people with COVID-19
Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence).
The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence).