In this study, we investigated the influence of different corticosteroid doses on the overall survival of critically ill COVID-19 patients. Our real-world data study results suggest that, regardless of invasive oxygen supply, patients who are not severely critically ill in the intensive care unit may not necessarily benefit from corticosteroid therapy.
Glucocorticoids act as potent immune modulators that can prevent or attenuate hyper-inflammatory states typical of severe SARS-CoV-2 infections through genomic and/or non-genomic effects [11]. Glucocorticoids, such as dexamethasone, have shown promising results in reducing mortality rates among COVID-19 patients [3–5, 11, 12]. International guidelines universally recommend the use of glucocorticoids for hospitalized COVID-19 patients with acute respiratory failure, supported by moderate-to-high-quality evidence [2, 13]. A systematic review and meta-analysis substantiate the notion that glucocorticoids may decrease mortality and duration of mechanical ventilation in patients with ARDS, including those with COVID-19 [6]. Various glucocorticoids with different doses and durations have been studied in patients with different severities [14]. However, the appropriate dose and duration of corticosteroid therapy for patients with COVID-19 have not been clearly defined. After the RECOVERY study, it is recommended to use dexamethasone at a dosage of 6 mg once daily for a duration spanning 7 to 10 days [4]. In the RECOVERY study, patients who received 6 mg/d of dexamethasone had a decreased mortality. The difference in all patients' mortality was 22.9% in those who received dexamethasone and 25.7% in those who did not [4]. A meta-analysis also demonstrated that the use of glucocorticoids in critically ill COVID-19 patients significantly reduced the 28-day mortality [2]. However, other clinical trials observed that treatment with dexamethasone in patients with moderate ARDS and COVID-19 had no significant effect on all-cause mortality, ICU-free days or duration of mechanical ventilation at 28 days [15, 16].
Our real-world analysis of the COVID-19 cohort has now confirmed these findings demonstrating no relevant difference in 35-day in-hospital survival rates among patient groups treated without glucocorticoids, with low-dose glucocorticoids or with high-dose glucocorticoids for 10 days. Additionally, our study analyzed the survival rates of critically ill patients up to 200 days. Interestingly, we observed no relevant increase in mortality among critically ill COVID-19 patients receiving corticosteroid treatment with doses of 6 mg/d of dexamethasone, compared to patients without glucocorticoid treatment, and a 2.09-fold increase for lower doses. This effect was measured while adjusting for age, sex, invasive oxygenation or disease status upon admission such as APACHE 2, SAPS II or SOFA. Patients without corticosteroid therapy upon admission to the ICU had the lowest scores on APACHE 2, SOFA and SAPS II. The results also aligned with the analysis indicating that patients in the NoC group had the shortest duration of stay in hospital, while the LowC group stayed the longest. Our evaluations suggest that regardless of ventilation status, the decision-making process for administering corticosteroid therapy should account for the individual severity of the illness.
Our finding thus aligns with existing literature, suggesting that corticosteroid treatment in different doses may not yield benefits for all critically ill COVID-19 patients. Many recently published studies focused on the question of the effectiveness of different dosages of dexamethasone in COVID-19 patients compared to the standard dosage. The COVID STEROID 2 trial revealed no discernible difference in days survived without life support when comparing dexamethasone at 12 mg versus 6 mg [17]. Taboada et al. observed a decrease in clinical deterioration within 11 days using dexamethasone at 20 mg as opposed to the standard 6 mg dose, though without any improvement in 28-day mortality [18]. Additionally, trials by Maskin and Wu failed to demonstrate any advantages of higher dexamethasone doses concerning clinically relevant endpoints [16]. Notably, another randomized controlled trial in COVID-19 patients receiving high-flow oxygen or non-invasive ventilation found that a higher dose of dexamethasone (20 mg daily) was even associated with increased 28-day mortality [19].
Furthermore, long-term corticosteroid use has also been associated with higher mortality rates (long-term HR 1.68; [95% CI: 1.16–2.45]) in mechanically ventilated COVID-19 patients with ARDS [20, 21]. One potential explanation for the observed adverse effects of corticosteroid treatment might be their unspecific suppression of various immune response pathways against pathogens [9, 10]. Corticosteroid therapy is associated with certain adverse events, including hyperglycemia, hypernatremia, and neuromuscular weakness [3]. Differences in doses can be responsible for diverse clinical efficacy in various settings, as they critically influence the activity of the glucocorticoid receptor [22].
In our analysis, patients administered a dexamethasone dosage of less than 6 mg for 10 days showed prolonged stays in the ICU and an elevated risk of mortality. Notably, individuals in the LowC group exhibited the highest disease severity upon admission, potentially resulting in a reduced corticosteroid dosage. Nevertheless, as we systematically considered confounding factors, the observed effect appears to diminish. However, low doses of glucocorticoids gradually activate their effects, while high doses can rapidly saturate cytoplasmic glucocorticoid receptors, leading to a swift onset of anti-inflammatory action (48). A higher proportion of genomic effects is emphasized when using low-dose steroids, whereas an increasing number of non-genomic effects is typically associated with higher doses. [23].
In the literature, conflicting findings regarding the benefits of glucocorticoids can be attributed to various factors, including differences in patient cohorts, duration of corticosteroid treatment, and length of follow-up in mortality assessments conducted in respective clinical studies. The latest guidelines developed by the European Respiratory Society (ERS) and the WHO identified the need to better evaluate the optimal glucocorticoids to be used in COVID-19 in terms of formulation, dosage, timing, and the scheme of administration [13, 18].
As our understanding of the disease, progressed subsequent studies were conducted to investigate long-term survival rates and outcomes, aiming to gain a deeper understanding of prognosis and the effectiveness of various treatment approaches [24, 25]. Many of these later studies with extended observation periods, however, were observational [24–26], similar to the present real-world data (RWD) study, which complemented the findings of randomized controlled trials (RCTs).
Limitations
Our study has several limitations that should be acknowledged. Firstly, it is important to note that our study design was non-randomized, and despite adjusting for confounding factors in our multivariable Cox regression analyses, there may still be unknown confounders that have influenced our findings. Secondly, adverse events related to both high-dose and low-dose glucocorticoids were not extensively reported. Additionally, the analysis cannot make any statement regarding the severity of pneumonia. Long-term follow-up outcomes for COVID-19 survivors treated with high-dose and low-dose glucocorticoids are essential to assess potential complications, particularly in the context of ARDS and pneumonia relapse. Therefore, further studies with a sufficient follow-up length will need to be necessary to evaluate the effectiveness of different treatment strategies.