In the initial phase of the pandemic, large platform trials reported the benefit of corticosteroids (mainly low/intermediate doses) in SARS-CoV-2 AHRF (1, 2). Recently, using all the available data included in a systematic review and meta-analysis (7), the Cochrane network concluded that systemic corticosteroids plus usual care probably reduces the number of deaths from any cause slightly, up to 30 days. No definite conclusion could be drawn about the number of deaths from any cause up to 120 days or on the optimal dose and duration of corticosteroids given to the patients.
In this post hoc analysis using a Bayesian approach, we first confirmed the absence of any treatment benefit on Day 60 mortality associated with high-dose DXM compared to low/intermediate doses of DXM (Table 2, Fig. 1). The Bayesian approach using concepts of probabilities of benefit or harm for a given intervention allowed us to quantify a 27% posterior probability of a more than trivial benefit and a 50.5% of a more than trivial arm of high-dose DXM in the whole sample.
This result contradicts the Bayesian secondary analysis of the COVID-STEROIDS2 study (9). The adjusted RR for 28-day mortality was 0.87 (95% CI 0.73–1.03), with probabilities of any benefit, clinically important benefit, and clinically important harm of 94.8, 80.7, and 0.9%, respectively. In addition to the difference in outcomes, many patient characteristics were very similar, i.e., time from symptoms onset and randomization (9 days in the median in both studies), IMV rate (17% and 21%), and age (mean 65 vs. 67 years). However, one-third of the patients from COVID-STEROIDS 2 were enrolled in low-income countries, with one-fifth randomized outside of the ICU. Moreover, remdesivir was used more frequently in COVID-STEROIDS2 than in COVIDICUS (26% vs. 62%).
The potential heterogeneity in the DXM20 effect according to the use of remdesivir observed in our study may explain some of the discrepancies between the effects of high-dose DXM in COVID-STEROIDS2 and COVIDICUS. Indeed, in our study, there was a 92% chance of high-dose DXM benefit in patients receiving remdesivir compared to only 21% in those who did not (Table 2). This is in agreement with the reported effect of corticosteroid therapy in delaying viral clearance: a small effect towards delayed time to viral clearance in young treated patients compared to young untreated patients was found in a large epidemiologic study (31). In the same study, viral dynamics after hospitalization was an independent predictor of mortality (HR = 1.31, p < 10 − 3). Finally, a secondary analysis of the DISCOVERY study comparing remdesivir with the standard of care found that remdesivir use was associated with a small but significant increase in viral clearance (32). We can therefore postulate that the potential benefit of high-dose DXM in the inflammatory process is offset by a detrimental effect on viral clearance. Remdesivir therapy may suppress this deleterious effect.
In a large multicentre Spanish cohort study involving 4,226 patients, Torres et al.(19) suggested that a longer therapy (≥ 10 days) was associated with the strongest benefit of corticosteroids but not the daily dose. The mean duration of corticosteroid therapy was longer in the COVIDICUS trial than in the COVID-STEROID2 study (9 vs. 7 days). This difference in the duration of DXM therapy in the low/intermediate group may also explain the higher mortality observed in the COVID-STEROID study and the more favourable impact of a high DXM dose.
In our exploratory analysis, we found that the posterior probability of a benefit of high-dose DXM was 93% when the time from symptoms onset was < 7 days, with an 90% probability of interaction between this delay and the DXM20 benefit; approximately one-quarter of both groups received remdesivir. In the RECOVERY study, a short delay between the first symptoms and randomization was associated with an insignificant impact of DXM6 on Day 28 mortality (1). Corticosteroid administration within 7 days from symptoms onset was unbeneficial or even harmful in all subgroups defined based on ICU admission data (19). In contrast, this delay did not impact the corticosteroid effect in the Outcomerea cohort (16).
The interaction between time from symptoms onset and high dose benefit was not found in the COVID-STEROID2 trial (6). One possible hypothesis is that inflammation is more important in patients whose respiratory status rapidly deteriorates with a possible higher benefit of a high dose of corticosteroids. This is in line with the 84% posterior probability of a beneficial effect in patients with high inflammation as reflected by a high ferritin level (above 3150.29 mg/L, threshold published by Tom (27)) compared to 50% in those with lower levels. Unfortunately, the inflammation characteristics of the patients included in the COVID-STEROID2 study are not available.
The relationship between inflammatory reactions and corticosteroid effects was suggested during the early phase of the pandemic, although based on observational data (26). Using a latent class variable model, the authors found significant heterogeneity in the corticosteroid effect on mortality across inflammatory phenotypes, with corticosteroid exposure associated with decreased mortality in the hyperinflammatory phenotype and increased mortality in the hypoinflammatory phenotype (26). Finally, an individualization of the corticosteroid dose based on the level of inflammation was suggested by a preliminary study but remains to be further evaluated (33). The impact of hyperinflammation on the selection of patients who may benefit from high-dose DXM requires further study.
Of course, the Bayesian analyses of DXM20 effect modifiers could be questioned. We limited our analyses to factors that have been evoked in previous studies of corticosteroid effects in SARS-CoV-2 ARF. However, the use of Bayesian analyses to unmask possible effect modifiers is considered the best way to avoid enormous inflation of the risk of drawing erroneous conclusions (34). Other unobserved effect modifiers may have been missed.