Cochrane has produced a series of reviews relevant to the COVID-19 pandemic and is keeping these up-to-date in light of new evidence. In November 2022, we published the second version of a living systematic review on systemic corticosteroids and, in this podcast, the first authors, Mirko Griesel of the University of Leipzig Medical Center and Carina Wagner of the University Hospital in Cologne in Germany, talk about the evidence they’ve found and the potential effects of these drugs.
Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. Cochrane has produced a series of reviews relevant to the COVID-19 pandemic and is keeping these up-to-date in light of new evidence. In November 2022, we published the second version of a living systematic review on systemic corticosteroids and, in this podcast, the first authors, Mirko Griesel of the University of Leipzig Medical Center and Carina Wagner of the University Hospital in Cologne in Germany, talk about the evidence they’ve found and the potential effects of these drugs.
Carina: Hi Mirko, thanks for being here today. Could you begin by telling us why this update is important and giving some background on systemic corticosteroids and COVID-19?
Mirko: Thank you, too! We are quite excited to share our findings and thoughts here again. The rationale for the use of systemic steroids is their immunomodulatory potential in the hyperinflammatory state of severe and critical COVID-19. This is because, while trying to prevent virus replication in infected cells, the body’s immune system launches an all-out attack which also harms other cells in the body. In the first version of our review, we found that the probable slight effect of systemic steroids might be limited to severely and critically ill patients, while those in the mild stages or without any symptoms might experience harm if given systemic steroids.
Carina: I remember that that was a key finding when the review was published in August 2021, so why is it important to continue to review the effectiveness of these drugs and why are we using a living systematic review approach?
Mirko: It’s because we know that other interventions for COVID-19 have failed after initial excitement and the evidence for corticosteroids in similar conditions, such as acute respiratory distress syndrome and sepsis, has been contradictory. Moreover, when we prepared the first version of the review, most of the data came from one study, the large RECOVERY trial. Many other studies had not been published or even finished enrolment by then and what was a probable slight effect on rather short-term mortality at 28 days needed more scrutiny. In using the living approach, we continuously monitor the evolving evidence through weekly update searches and regular consultations in our working group and with the Cochrane Central Editorial Unit. The goal is to avoid spending time and money on the preparation and analyses of the updated review until enough new data have been published to make a substantial difference to the conclusions. The living systematic review approach also allows us to explore sub-questions, like dosing or patient selection, in more depth. Apart from these time-dependent aspects we also made qualitative amendments to our review. For example, we decided that the platform trial designs of RECOVERY and REMAP-CAP needed more consideration as to whether their results can be used in the same way as we use results from conventional randomised trials.
Finally, based on feedback on the first version of the review, we wanted to do subgroup analyses to take a closer look at equity-related factors such as age (younger and older than 70 years), sex, ethnicity (Black, Asian or other ethnicity versus White versus unknown) and place of residence (high-income versus low- and middle-income countries).
Carina: Thanks, let’s move to the evidence that we were able to include in the November 2022 version of the review. Please, can you tell us about that?
Mirko: We could include 16 randomised trials, reporting on approximately 9600 participants, half of whom received steroids. All the studies looked at participants with moderate or severe COVID-19, which means that they had all been admitted to hospitals but needing difference levels of respiratory or other organ support.
Eleven trials compared systemic corticosteroids plus standard care to standard care, with a placebo given to the standard care group in some of these; and four trials compared different dosages of dexamethasone. There was also one trial comparing different systemic steroids, namely methylprednisolone and dexamethasone, but with just 86 participants, it‘s too small for reliable conclusions about the effects on mortality.
Carina: So, what do the other studies tell us about the effects for people with COVID-19?
Mirko: For the addition of systemic corticosteroids to standard care, the data from ten studies, which contained nearly 8000 of the participants, provided moderate-certainty evidence that steroids probably have a small effect on all-cause mortality up to 30 days after the drugs are started, but the evidence for the effect on all-cause mortality up to 120 days remains very uncertain.
For all-cause mortality up to 30 days, people younger than 70 seemed to benefit more from systemic corticosteroids compared to those aged 70 years and older. For ethnicity, the few participants from a Black, Asian, or other ethnic group showed a larger estimated effect than the many White participants; but the other subgroup analyses I mentioned showed no relevant effects.
We are particularly excited about the new comparison of different dosing of systemic steroids. But, our assessment of the risk of bias means that there is only low- and very low-certainty evidence that high doses of 12mg or more per day may lead to lower all-cause mortality at 28 days compared to 6 to 8mg, such as used in the RECOVERY trial.
Carina: What about safety? What evidence is there about any unwanted events?
Mirko: Only two studies, with 678 participants, reported serious adverse events and five trials with 660 participants provide data for hospital-acquired infections and adverse events more generally. However, the high risk of bias in these study outcomes, combined with the likelihood of publication bias, means that we refrained from meta-analyses and are not able to provide firm conclusions.
Carina: Alongside this updating of things we looked at the first review, are there other new aspects of the update of the review that are worth mentioning?
Mirko: Yes, indeed. Although we cannot quantify this, many of the participants included in the studies in this update will have been enrolled in studies before the wide-spread vaccination programmes and most of them had acquired their first infection. This introduces some indirectness to our whole body of evidence when we try to apply it to the current situation. We now also have more emphasis on the global health aspects of COVID-19 and, for example, we have discussed the possibility that, in low-resource or tropical environments, considerably more harm might come from secondary infections, which might require more caution in the use of steroids.
Carina: Thanks. In summary, what’s the main conclusion and what are our next steps?
Mirko: The take home message is that systemic corticosteroids appear to have a marginal effect on short-term mortality up to 30 days, which is the basis for their inclusion in treatment guidelines worldwide. However, they continue to be nothing like a magic bullet with the power to change the course of the pandemic. Looking to the future, we know of 23 trials that have been completed but not yet published their results, and there are at least another 42 ongoing studies. These studies might help resolve some of the remaining uncertainties and we plan to update the review when the accumulating evidence will allow us to derive more certain conclusions.
Carina: Finally, Mirko, if people would like to read the review, how can they get hold of it?
Mirko: It’s available online from Cochrane Library dot com. Typing 'corticosteroids for COVID-19' in the search box will bring up a link to the review and listeners might also be able to link straight to it from the platform from which they got this podcast.