As of April 6, 2020, the average COVID-19 mortality rate in a selection of European and other developed countries is staggering 10%. An explanation is needed for such abysmally poor results of the medical treatment of COVID-19. One possible explanation is an inappropriate use of steroids. In Italy, corticosteroids were used to treat 30% of the COVID-19 patient as of March 17, 2020.
In this article, we share our notes taking during reading a 2003 article by Thompson (1), that addresses the use of glucocorticosteroids (synonyms: “corticosteroids”, sometimes also, steroids).
Critical illness, such as trauma, pneumonia, sepsis, and major surgery, is accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis.
Glucocorticoids
Glucocorticoids exert their effects through binding to cytoplasmic glucocorticoid receptors. These receptors modulate the transcription rates of many inflammatory response elements, including nuclear factor-B and activated protein-1 (Fig. 1) (10). Glucocorticoids thus act as natural inhibitors of proinflammatory cytokine production, such as tumor necrosis factor (TNF)-, interleukin (IL)-1, IL-1, interferon-, IL-2, IL-3, IL-5, IL-6, IL-8, IL-12, and granulocytemacrophage colony-stimulating factor (2, 5, 11). Glucocorticoids act in synergy with some anti-inflammatory cytokines, including IL-4, IL-10, and IL-13, and increase transcription of IL-1ra (11, 12). Cortisol suppresses the synthesis of phospholipase A2 , cyclo-oxygenase, and inducible nitric oxide synthase. Glucocorticoids also inhibitfibroblast proliferation and collagen deposition; stimulate T-cell, eosinophil, and monocyte apoptosis; and inhibit neutrophil activation. This indicates potential beneficial properties for the treatment of late, fibroproliferative ARDS (2, 11–13)
The HPA Axis
During stress, hypothalamus releases corticotropin-releasing hormone (CRH) in response to activation by norepinephrine and serotonergic/cholinergic neurons.
Normal activation and functioning of the HPA axis have an important role in modulating the response to critical illness and systemic inflammation (1). A deficiency in the HPA axis could lead to unchecked or ongoing activation of inflammatory mediators, cardiovascular instability, loss of vascular integrity, and, perhaps, persistent airspace inflammation and injury leading to an exuberant fibroproliferative response in the lung following injury (4). During stress, hypothalamus releases corticotropin-releasing hormone (CRH) in response to activation by norepinephrine and serotonergic/cholinergic neurons, resulting in stimulation of pituitary ACTH release. During systemic inflammation, circulating cytokines, principally TNF-, IL-1, and IL-6, also stimulate hypothalamic CRH release, which is further amplified by prostanoids and platelet activating factor (1, 2). ACTH acts on the adrenal cortex to release up to 225–440 mg/day of cortisol, which, as mentioned previously and in Figure 1, feeds back to inhibit immune-mediated hypothalamic activation (4). During immune activation of the HPA axis, diurnal variation appears to be lost (1). Interestingly, TNF-also has been reported to inhibit pituitary release of ACTH in response to CRH, suggesting a dual role for HPA modulation by this cytokine (14).
Cortisol During Critical Illness.
“The highest cortisol concentrations (30–260g/dL) generally are seen in nonsurvivors shortly before death.”
During critical illness, cortisol concentrations are roughly four tofive times those seen in normal subjects. Numerous studies have shown that higher plasma cortisol concentrations are correlated with a greater severity of illness, as measured by the Acute Physiology and Chronic Health Evaluation II score or the Trauma Injury Severity Score, and higher mortality rates (15–20). The highest cortisol concentrations (30–260g/dL) generally are seen in nonsurvivors shortly before death (15). However, a few reports of critically ill patients with “normal” plasma cortisol concentrations (generally 10g/dL) and a poor prognosis have led investigators to suggest that these individuals have relative adrenal insufficiency.
Glucocorticoids in early and late acute respiratory distress syndrome (ARDS) and sepsis.
“High doses of methylprednisolone for 1–2 days early in the course of severe sepsis or established ARDS do not prevent ARDS development or reduce mortality rate, and they may be harmful.”
High doses of methylprednisolone for 1–2 days early in the course of severe sepsis or established ARDS do not prevent ARDS development or reduce mortality rate, and they may be harmful. Lower doses of methylprednisolone in late, unresolving ARDS may be of benefit, but a large clinical trial is needed to clearly demonstrate a survival advantage that outweighs the potential risks
Selected references:
1. Thompson, S257 Crit Care Med 2003 Vol. 31, No. 4 (Suppl.).
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