Indication of glucocorticoid pulses for patients with SARS-CoV-2 infection

Dear Editor

Concerning the article published by Callejas et al.,¹ I would first of all like to thank our colleagues for their efforts in the search for an effective treatment for COVID-19, although on this occasion I have to disagree on the use of glucocorticoid (GC) pulses.

The approach of this article is not new. CGs have been used in other virus-related ARDS, such as SARS, MERS, or influenza A, as already reported in the article by Russell et al.,² showing no benefit on mortality at 90 days and evidencing a worse outcome in patients admitted to the ICU. The authors should be aware that these conclusions are in line with the data they provide, the reading of which shows us 83 young patients (median age of 63.9 years) treated with GC pulses, of which, in a follow-up of only 11 days, 12% died or ended up in the ICU and 28% required salvage with tocilizumab; that is, 40% of the treated patients had a poor response. To put this in context, in our series of 96 patients (median age 69.8 years) in a follow-up of 28 days we had a mortality of 14.7% (we included patients in the ICU), 85% were discharged and only 16% of the patients required treatment with tocilizumab or interferon. Obviously, we do not know if both groups are comparable. If we take into account ferritin levels, our patients had a maximum average ferritin concentration of 820 mg/dl, similar to the value described in their study. Without a multivariate analysis that includes variables such as age (the main factor associated with survival), sex, patients who were not treated, or vascular risk factors, it is difficult to establish that GCs increase survival.

Treating this inflammatory response on the assumptions used in autoimmune processes in the case of macrophage activation syndrome with uncontrolled proliferation of T cells is a conceptual error. What happens in coronavirus infection, with significant lymphopenia in the most severe cases, has little to do with this syndrome. The study authors use ferritin and IL-6 levels as parameters to predict cytokine storm, without taking into account that both molecules, and especially IL-6, are high in most viral infections (influenza, hemorrhagic fevers, HIV, HCV, HBV, coronavirus).³ It has been observed that an increase in the production of IL-6 can be detrimental to the cellular immune response during viral infections, and this is taken advantage of by some viral strains that use the stimulation of IL-6 secretion as an evasion strategy that slows down the humoral response and as a result there is an increase in viral loads.⁴ The higher the IL-6 level, the higher the viral load. Liu et al.⁵ found that the viral load is up to 60 times higher in people with a more severe course of COVID-19 infection. The established concept of viral and inflammatory phase is also erroneous, as these patients maintain high viral loads for weeks.

The response to viral infections is a humoral immune response mediated by the activation of T cells. The inflammatory effect of GCs is linked to the inhibition of IL-2, which causes T cell apoptosis. We should not slow down lymphocyte activity in patients with severe lymphopenia.

All of the above would explain why a high percentage of patients treated with GC required tocilizumab. An increase in viral load is to be expected in all of them. It would have been interesting if the authors had reported the viral load and IL-6 levels after the steroid pulses.

In such a short follow-up, it remains to be clarified if any patient has had a recurrence, a reactivation of TB, or how many of these patients had septic shock. Based on the above assumptions, we are against the systematic use (most of them meet the criteria set out by the authors) of GC pulses in patients with COVID-19 pneumonia, as not only do they not show a clear benefit on mortality, but they also entail an increased risk of shock and, contrary to what they state in their article, they lead to a worse outcome and a greater need for tocilizumab.