Glucocorticoid excess and COVID-19 disease

Abstract

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing's syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.

Keywords: Cortisol; Cushing’s syndrome; Glucocorticoid; Immune system; Infections; SarsCoV2.

Fig. 1

Role of glucocorticoid (GC) excess in immune system dysregulation and covid sars 2 infection. SARS-CoV2 achieves cell entry through an S high-affinity protein binding to the catalytic domain of the ACE 2 receptor that is highly expressed in cells in the respiratory tract. In innate immune response GC reduce natural killer (NK) cytotoxic action and classical activation of macrophages (M1) whereas intermediate and nonclassical monocyte levels, and macrophage alternatively activated (M2) characterized by a lower phagocytic activity are increased. GCs reduce antigen presentation and can also significantly influence the Th1/Th2 balance and induce apoptosis in mature T lymphocytes, producing a significant shift towards Th2 differentiation. Furthermore, GCs reduce the differentiation of Th17 cells favouring infection development. COVID-19 infection is associated with marked pro-inflammatory cytokine production and pro-inflammatory macrophage and granulocyte recruitment, resulting in a “cytokine storm” leading to a multiorgan failure. In addition adipose tissue is able to secrete pro-inflammatory cytokines, including IL-6 and TNF-α, that are therefore increased in obese patients. Similarly to CS patients in COVID-19 infection there is an increase in procoagulant factor levels including fibrinogen and D-dimers, mainly related to the excessive cytokine release, to the abnormal activation and recruitment of monocytes, macrophages, neutrophils and NET (Neutrophil Extracellular Traps) formation. Abbreviations: Baff: B cell activating factor; Baff-r: Baff receptor; CS: Cushing syndrome; DC: Dendritic cell; GCs: Glucocorticoids; GCR; glucocorticoid receptor; GM-CSF: Granulocyte-macrophage Colony-stimulating factor; H2O2: Hydrogen peroxide IL-: Interleukin-; MICA: MHC class I chain-related a; MPO: Myeloperoxidase; NO: Nitric oxide; TF: Tissue factor; Th: Thelper; TNF-α: Tumor necrosis factor-α

Fig. 2

Hypothetical stages of evolution of Covid-19 infection. The initial phase is characterized by the entry of the virus, through the respiratory tract. There is an increase of CRP and CBC may reveal lymphopenia and neutrophilia. In the second stage there is viral multiplication and localized pulmonary infection with abnormal radiological findings. Blood test reveal lymphopenia and elevated transaminases. In a minority of patients there is a transition to a third phase characterized by systemic inflammation induced by the cytokine storm with a respiratory distress pattern, cytopenia, coagulopathy and multiorgan failure. Abbreviations: CBC: Complete blood count; CRP: C reactive protein; GM-CSF: Granulocyte-macrophage Colony-stimulating factor; IL- interleukin-; MØ: Macrophage; TNF-α: Tumor necrosis factor-α