2  The pathophysiology of COVID-19 infection
Coronaviruses are the largest viruses with a positive-sense single-stranded-RNA genome. The host immune response is by one side essential for the resolution of COVID-19 infection, but it can also be crucial for the pathogenesis of major clinical manifestations of the disease. The angiotensin-converting enzyme 2 (ACE2) has been identified as the host cell-surface receptor for SARS-CoV2 envelope spike glycoprotein [12]. ACE2 is a type I membrane protein expressed on cells in the kidney, heart, gastrointestinal tract, blood vessels, and, importantly, lung AT2 alveolar epithelial cells, which are particularly prone to viral infection [13]. SARS-CoV-2 infection leads to the downregulation of ACE2 expression, thus resulting in excessive production of angiotensin II by the related enzyme ACE. It has been suggested that the stimulation of type 1a angiotensin II receptor (AGTR1A) increases pulmonary vascular permeability, thus potentially explaining the increased lung damage when the expression of ACE2 is decreased [14]. Due to this mechanism of action, it has been postulated that subjects with diabetes mellitus or hypertension using ACE-inhibitors or angiotensin receptor blockers may have an increase of both the risk of infection and the severity of COVID-19 [15]. As only scarce evidence supports this hypothesis, the European Society of Cardiology recently published a position statement that strongly recommends continuing these treatments despite the current epidemic [16]. An additional point to be clarified is also the role of the genetic predisposition for an increased risk of SARS-CoV-2 infection due to ACE2 polymorphisms that have been linked to hypertension, diabetes mellitus, and cerebral stroke, especially in Asian populations [15].
The viral RNA genome is released into the cytoplasm, and the RNA is uncoated to allow translation of the two polyproteins, transcription of the sub-genomic RNAs and replication of the viral genome [17]. Progression to ARDS is associated with the upregulation of pro-inflammatory cytokines and chemokines, known as Cytokines Release Syndrome (CRS), with a pattern very similar to that of secondary haemophagocytic lymphohistiocytosis (sHLH). In adults, sHLH is an under-recognized, hyperinflammatory syndrome characterized by a massive and fatal hypercytokinaemia with multiorgan failure, most commonly triggered by viral infections [18,19]. Main clinical features of sHLH include unremitting fever, hyperferritinaemia and cytopenias, and pulmonary involvement (including ARDS) occurring in approximately 50% of patients [20]. A cytokine profile resembling sHLH has been reported in most severe COVID-19 infections, characterized by increased levels of a number of cytokines (interleukin-1β [IL-1β], IL-2, IL-6, IL-7, IL-8, tumor necrosis factor-α [TNF]) and chemokines (CXC-chemokine ligand 10 [CXCL10] and CC-chemokine ligand 2 [CCL2]) [21,22]. The management of this cytokine storm is one of the major unmet needs regarding COVID-19 infection.