Background
It has been more than a year since the devastating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak occurred, which emerged in Wuhan (China) on December 2019, and the global health issue is still a concern to resolve. As of July 2021, the World Health Organization reported more than 180 million cases and four million deaths worldwide due to coronavirus disease 2019 (COVID-19) [
1]. The clinical presentation ranges from asymptomatic or mild-to-severe pneumonia in which the most critical cases develop life-threatening acute respiratory distress syndrome (ARDS), requiring admission to the intensive care unit (ICU) with high rates of invasive mechanical ventilation and mortality [
2].
Worldwide, corticosteroids have become the standard of care (SOC) for severe COVID-19 patients, especially in mechanically ventilated patients since the results of the RECOVERY trial [
3] and the subsequent meta-analysis [
4] from seven randomized clinical trials (RCTs) revealed a reduction in 28-day mortality. However, several questions remain unanswered regarding the effectiveness of corticosteroids [
5,
6]. It is unclear if there are particular subsets of COVID-19 patients under mechanical ventilation with different severity of illness or ARDS degree in whom corticosteroids perhaps had less pronounced effect and caution in the use of corticosteroids should be exercised. Clinical effectiveness of corticosteroid treatment in COVID-19 patients with ARDS is still limited and conflicted by the results from some meta-analysis [
7,
8] and observational data [
9‐
11].
We hypothesize that corticosteroid use may have to be individualized for corticosteroid-responsiveness COVID-19-associated ARDS patients, recognizing patient heterogeneity according to patient characteristics, severity of the disease, timing of the illness and other complications that occur during mechanical ventilation. Therefore, the aim of this study was to determine the association of corticosteroid treatment and ICU mortality among mechanically ventilated COVID-19-associated ARDS patients.
Discussion
In this study, corticosteroid treatment did not reduce ICU mortality rates among mechanically ventilated COVID-19-associated ARDS. However, our findings suggested that corticosteroids at ICU admission had time-dependent effects based on the short-term benefit of survival in the first 2 weeks, but an increased risk of mortality thereafter. Subgroups of patients aged less than 60 years, severe ARDS and tocilizumab plus corticosteroids showed short-term protective effects without deleterious long-term effects on mortality suggesting that not all mechanically ventilated COVID-19-associated ARDS patients might be corticosteroid-responsiveness. These results have been observed in a large cohort of ICU patients after controlling for observational-related biases and competing risks, thereby the benefit or potential harm of corticosteroids should be taken into account.
Data regarding the effectiveness of corticosteroids in COVID-19-associated ARDS remain limited. A recent meta-analysis (18 RCTs enrolling 2826 patients) evaluating the use of corticosteroids in ARDS (due to COVID-19 and non-COVID-19) concluded that corticosteroids probably reduce mortality in patients with ARDS of any aetiology [
23]. However, the pooled estimate data of COVID-19-associated ARDS either using the ARDS criteria (risk ratio 0.92, 95% CI 0.76–1.11) and data from mechanically ventilated patients (risk ratio 0.89, 95% CI 0.71–1.12) did not reach statistical significance for 28-day mortality in the random-effects model. Different meta-analysis of COVID-19 patients with high heterogeneity on illness severity reported beneficial effects on mortality with corticosteroid treatment [
7,
24,
25]. It should be pointed out that in most meta-analysis, the weight of the RECOVERY trial [
3] made important contribution to overall pooled data. Conversely, conflicting results from other meta-analysis did not report benefits on mortality with corticosteroid treatment [
8,
26].
The results of the RECOVERY trial [
3] indicate that moderate dose of dexamethasone reduces 28-day mortality among patients with COVID-19 that require oxygen support, with more pronounced effect in those receiving invasive mechanical ventilation (rate ratio 0.64; 95% CI 0.51–0.81). This landmark trial has changed clinical practice worldwide for severe COVID-19 patients. Nonetheless, some uncertain issues deserve discussion and they must to be accounted for [
6]. One major concern is that at day 28 of treatment allocation, 75% of patients were still hospitalized and investigating long-term outcomes could impact on the observed results [
27]. Several factors affecting the outcome such as the level of respiratory support and the degree of hypoxemia were not measured, for instance, we found that corticosteroids may have higher benefit among severe ARDS, whereas patients with mild ARDS were not corticosteroid-responders. Additionally, there were 1707 (15%) patients who were not considered suitable for randomization but reasons for exclusion were not adequately disclosed. Physicians may exclude those patients because observed contraindications in whom corticosteroids might have detrimental consequences, which constitutes an important selection bias. Likewise, centre effect was not evaluated and there might be some imbalance in group allocation, especially in the subset of ventilated patients in which an average of only six patients were included per centre. Also in the stratified analysis, there was no benefit from dexamethasone in some subgroups, even in those with higher baseline risk (≥ 45%) which involves one half of the study patients. Therefore, the beneficial effect of corticosteroids among whole mechanically ventilated patients may be questionable.
The CoDEX trial performed in 299 ventilated COVID-19 moderate-to-severe ARDS assigned to received dexamethasone plus SOC versus SOC alone, did not find significant differences on all-cause 28-day mortality [
28]. A randomized double-blind placebo-controlled trial conducted in 393 COVID-19 patients allocated to receive methylprednisolone 0.5 mg/kg twice daily for 5 days or placebo found no differences in 28-day mortality between groups, whereas lower mortality with corticosteroids was observed in post hoc analysis among patients over 60 years old (HR 0.63, 95% CI 0.41–0.97) [
29]. Nonetheless, the rate of invasive mechanical ventilation was low and information regarding the degree of respiratory support or ARDS severity are lacking.
Results from retrospective also reported survival benefit for critically ill patients with COVID-19. In a multicentre cohort including 882 patients and high rates of invasive mechanical ventilation, it was observed that early corticosteroid treatment (within the first 48 h of ICU admission) was associated with a reduction in ICU mortality compared with delayed use or none after inverse probability weighting, although competing risks were not accounted for [
30]. Retrospectives studies with robust statistical approach also showed positive effects with corticosteroids on mortality in severe [
31] or COVID-19-associated ARDS [
32], albeit smaller sample sizes and lower rates of invasive mechanical ventilation were recognized and these results might not be applicable to all COVID-19-associated ARDS. On the contrary, conflicting data from multicentre studies in COVID-19-associated ARDS [
9,
10] and critical cases [
11] suggested that corticosteroid treatment might be associated even with higher mortality, after carefully controlling for biases.
All this controversy on the evidence may be due to the heterogeneity of patients leading to conflicting data and it is unclear whether the use of corticosteroids is adequate for overall mechanically ventilated COVID-19 patients. We focused on mechanically ventilated patients with COVID-19-associated ARDS and observed that corticosteroid treatment at ICU admission had time-dependent effects. While corticosteroids seemed to be protective within the first 2 weeks of severe illness, the likelihood of survival changes beyond this timeframe and corticosteroid exposure at ICU admission appeared to be harmful. The possible explanations for the observed long-term negative effects from corticosteroids must be evaluated in further research as data regarding side effects are still lacking, since evidence from a recent meta-analysis suggested that there is no association between corticosteroids and superinfections [
33], although a trend toward higher rates of delayed viral shedding and venous thromboembolism have been observed in some data [
7,
26,
34‐
36].
Our results have been observed in a representative cohort of COVID-19-associated ARDS, with close similarities from other studies in terms of severity degree of hypoxemia, ventilatory parameters, and respiratory support management [
37,
38]. The survival benefit from dexamethasone in mechanically ventilated patients in the RECOVERY trial [
3] might be due to the capacity of corticosteroids to dampen both inflammation and late-onset fibrosis [
39] in some cases that leads to severe lung injury in ARDS. Actually, in the present study, the subgroup of severe ARDS could benefit from corticosteroids over time without experimenting detrimental effects in long-term. Conversely, in patients with mild ARDS, corticosteroids had no significant effect on mortality questioning the need to treat such subgroup. These short-term protective effects have also been found for the subgroup of patients aged < 60 years, similar findings as those observed in the RECOVERY trial which showed protective effects of corticosteroids for patients younger than 70 years. However, a multicentre study conducted in 303 critically ill COVID-19 patients found opposite results to ours, reporting that early corticosteroid administration was associated with a lower mortality rate in patients aged ≥ 60 years [
40]. The contradictory results might be due to a different population than ours with only one-third of included patients under invasive mechanical ventilation.
Regarding the duration of corticosteroid treatment, we found that a shorter course of treatment did not have protective effects, similar results as reported in the Metcovid trial [
29]. Indeed, a meta-analysis found that ARDS patients (COVID-19 and non-COVID-19) who received a longer course of corticosteroids (over 7 days) had higher survival rates compared with a shorter course of treatment [
23]. Despite the short-term benefit on survival with a longer course of treatment, possible long-term negative effects could arise; albeit, these results would need confirmation.
The use of tocilizumab plus corticosteroids at ICU admission seem to have also short-term protective effects on survival without presenting long-term deleterious effects on mortality. These findings coincide with a recent RCT conducted in hospitalized COVID-19 patients with hypoxia and systemic inflammation, in which the allocation to tocilizumab was associated with a significant reduction in 28-day mortality compared with usual care alone (with corticosteroid use up to 80% with systemic corticosteroids in both arms) [
41].
Moreover, different phenotypes of COVID-19 critically ill patients with different host response patterns and impact on outcomes have been recently reported [
42,
43]. Indeed, a retrospective study conducted in 428 critically ill COVID-19 patients reported that corticosteroids had significant survival benefits only in hyperinflammatory phenotype (HR 0.51; 95% CI 0.34–0.78) compared with the hypoinflammatory phenotype [
44]. The subgroup analysis in our study showed that these time-dependent effects of corticosteroids on survival could be present in different subsets suggesting that patients’ response to corticosteroids may vary depending on distinct baseline conditions, although the exploratory nature of the sensitivity analysis requires that these results should be evaluated in further clinical research.
To our knowledge, this is one of the largest multicentre observational study of mechanically ventilated COVID-19-associated ARDS evaluating the effectiveness of corticosteroids on ICU mortality and results pointed out the possible time-dependent pattern of corticosteroids with likely opposite short and long-term effects on mortality. These findings support the hypothesis that not all mechanically ventilated patients with COVID-19-associated ARDS treated with corticosteroids have survival benefit over time. Our approach sought to account for selection bias and confounding, immortal time bias, and competing risks. In addition, performing subgroup sensitivity analysis made our results to be robust. As corticosteroids have become the SOC for severe COVID-19 patients, to randomize patients allocated to receive or not corticosteroids to investigate knowledge gaps would entail some ethical issues. This study attempted to make causal effects between corticosteroids and mortality from observational data. Hence, it provides real-world evidence on this topic currently under debate and new insights for a better personalization of care among mechanically ventilated patients with COVID-19-associated ARDS.
Nevertheless, our study had some limitations. First, as it was a retrospective study and some biases can arise from the observational design. Although RCTs are known to be the “gold standard” for research in investigating the effectiveness of interventions, methodological tools applied to observational data can decrease bias and confounding caused by the lack of randomization and could provide data from usual clinical practice. However, unmeasured confounders may persist. Second, our study was based on mechanically ventilated COVID-19-associated ARDS patients. Therefore, results may not be generalized to other settings such us hospitalized or outpatients. Third, we could not assess the established dosage of corticosteroids, although we deemed that suggested recommendations were followed using moderate doses of methylprednisolone, as all included patients in this study were diagnosed with ARDS [
45]. Preferably, we focused on the effect of the exposure to corticosteroids at ICU admission. Nonetheless, dosage should be also a point of discussion in further research. Likewise, the safety profile and side effects such as hyperglycaemia, secondary superinfections different from respiratory source, or myopathy could not be evaluated. Fourth, different treatment approaches were used during the first wave, in accordance with current guidance [
46], which could affect outcomes. Nevertheless, to avoid confounding by indication, all treatments received at admission were included within the adjusted Cox model after propensity score matching. Fifth, we did not collect data regarding the causes of death and the possibility of withdrawal of therapy beyond the 17th day of ICU admission. The population potentially at risk for life support withdrawal could be larger among corticosteroids users, therefore, some residual confounding may exist. Intensivists are used to facing to ethical concerns in their daily practice [
47], and our ARDS patients died under invasive mechanical ventilation and other life support therapies in both groups, meaning that the most probable cause of death was persistent organ failure, mainly terminal respiratory failure [
48]. Indeed, therapeutic withdrawal decisions in such critical care patients usually are taken under refractory/irreversibility stages of the disease. Further, we found that among non-survivors, the time to death was significantly larger in those who received corticosteroids compared with the non-corticosteroid users, suggesting that withdrawal life support rates might be lower in patients who received corticosteroids. Sixth, although two hundred and fifty-five patients without corticosteroids were not retained after matching, a sub-analysis revealed that no significant differences were found regarding demographic characteristics, severity of the disease, comorbidities and mortality, compared with those patients without corticosteroids included in the matching model. Nonetheless, propensity score matching yielded well balanced groups in terms of several observed confounders and, therefore eliminating selection bias. Seventh, conducting multiple testing for subgroup analysis may result in multiplicity. However, the sensitivity subgroup analysis was performed with an exploratory rather than confirmatory nature and these results aimed to yield consistency to the primary analysis and also to generate new hypothesis on corticosteroid-responsive subgroups for future research. Likewise, we accounted for multiplicity with the Benjamini–Hochberg approach to avoid the potential inflation of type I error. Eight, we could not evaluate the impact on outcomes of the ICU demand in periods of inundated critical care system. Finally, we did not collect data about viral shedding. The possibility of delay in viral clearance due to corticosteroid administration is an area for concern and more data are required to address this issue.
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