In the epidemics of SARS and Middle East Respiratory Syndrome (MERS) the use of GC has been widely discussed, however, the safety and efficacy of this pharmacological class is still controversial. Evidence found in systematic reviews suggests that the administration of GC in patients with SARS is associated with increased plasma viral load and slower viral clearance, contributing to immunosuppression states (27–30). In patients with MERS, although no association was found between the use of GCs and increased mortality, there was a delay in the clearance of MERS-CoV RNA (27,29,30). Studies still indicate that in addition to the use of corticosteroids, it did not have an impact on reducing the number of deaths, the use led to prolonged hospital stay, ICU admission rate and / or the use of mechanical ventilation, as well as the appearance of important adverse effects (30).
A cohort found that all patients had a significant increase in the viral load of SARS-CoV in the body, however, there was a considerable reduction in IL-6, IL-8 and IL-10 in patients with 7-10 days of treatment with corticosteroids, coinciding with the improvement of the clinical and radiological situation (31). Another cohort identified a higher mortality rate in patients treated with corticosteroids with no lung damage, indicating that the early use of this pharmacological class would significantly increase the viral load (32).
In a clinical trial in which two groups of patients with MERS were compared, corticosteroid therapy was applied in one and not in another, it was observed that in the corticoid group, mechanical ventilation, administration of nitric oxide, the use of neuromuscular blockers, vasopressors, blood transfusion and renal replacement therapy, in addition to having delayed viral clearance (33). Loutfy et al observed that among 13 patients diagnosed with SARS who were treated with single corticosteroid therapy, 5 were transferred to the ICU, 3 were intubated and underwent mechanical ventilation and one patient died (34). Lee et al observed the early administration (<7 days) of hydrocortisone in 9 patients with SARS and concluded that the expression of SARS-CoV RNA was significantly higher in the hydrocortisone group than in the placebo group (35).
Our analysis of studies using GC in the treatment of COVID-19 patients must be interpreted with great caution. Due to the emergency of immediate responses that can guide medical conduct, we collected as much data as possible on this subject, which leads to a grouping of studies with significant differences regarding the status of the selected patients, GC dosage, period of use, outcome and analyzes used in relation to the data obtained. Another important fact is that all studies obtained are observational and retrospective, preventing the careful choice of who will or will not receive the medication. As GC tend to be used for more severe patients, the interpretation of such outcomes may be subject to selection bias. Thus, it is impossible to ensure that the criteria for administration of GC were pre-established or based on a worsening of the clinical status, admission to the ICU, changes in laboratory or radiological data.
By stratifying the interpretation of results according to the type of outcome, we can draw more secure conclusions associated with a careful individual analysis of the articles. Eight articles evaluated mortality as an outcome (13,16,18,19,22,24–26), of these, two did not present statistical analysis and, therefore, were not included in this discussion (18,24). Two cohorts, in spite of expressing the p value attached to the table, did not show significance between the variables, thereby they were not inserted as well (13,19). Among the remaining four, two included patients in any disease state and found results against the use of GC (16,26). Cruz et al included only critically ill patients and used GC administration as exposure, bringing a stronger conclusion, in addition to having the highest note in the NOS score among those included (25). In this study, mortality was lower in the group that used CG. Wu et al observed the development of ARDS and mortality in the hospitalized patients and concluded that the use of Methylprednisolone was greater in the group that developed ARDS and in this group the use was larger among those who survived, but this latter result did not obtain statistical significance (22).
Four articles analyzed the time to viral clearance (14,15,17,23). Of these, only one obtained a significant result (23). The cohort included patients in any condition and concluded that the use of GC was greater in the group that took longer to certify viral clearance. Finally, two articles analyzed clinical changes (20,21). Wang et al included only critically ill patients and observed results in favor of the use of Methylprednisolone. Shang et al included patients in any condition and used three different GC and observed, among the survivors, longer hospital stay in the group that received GC, but also a significant recovery in the lymphocyte count among those who received the medication and survived.
Recently, the multinational guideline Surviving Sepsis for COVID-19 recommended the use of steroids in patients with severe conditions and on mechanical ventilation, the purpose of which is to reduce the destructive risk, based on immunological evidence (36). The most discerning evidence to date, the RECOVERY study, brings in primary analyzes a reduction in mortality and length of hospital stay with the use of Dexamethasone (37).
The use of GC has shown a direct relationship with the development of hypercortisolism, especially in patients with individual hypersensitivity or hypoadrenalism after discontinuation of the drug. In addition, it is known that most patients are treated with antiretroviral drugs, such as Ritonavir, which acts as an inhibitor of cytochrome P4503A enzymes. By increasing the concentrations of a drug metabolized by the same route, such as GCs, this enzyme inhibitor can promote a hypercortisolemic condition (38,39).
Chronic use of high-dose GC followed by abrupt interruption can trigger tertiary adrenal insufficiency. Thus, the therapeutic use of these drugs must be done with care (40). Finally, it is important to remember the hyperglycemic potential of GC, which can be crucial in the care of diabetic patients with COVID-19 The prospective RECOVERY study, however, found no evidence that GCs induce hyperglycemia more than standard therapy (37).
This systematic review has important limitations. Due to the emergency of the study, we selected articles with notable differences in terms of their base populations, clinical status of the participants, analyzed outcome and corticotherapy used. The lack of more careful studies such as prospective cohorts or randomized controlled trials also limits the data gathered in our study.