Lancet E Bio Medicine 1st August 2020

Summary
The pathogenesis of coronavirus disease 2019 (COVID-19) may be envisaged as the dynamic interaction between four vicious feedback loops chained or happening at once.

These are the viral loop, the hyperinflammatory loop, the non-canonical renin-angiotensin system (RAS) axis loop, and the hypercoagulation loop.

Severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 lights the wick by infecting alveolar epithelial cells (AECs) and downregulating the angiotensin converting enzyme-2 (ACE2)/angiotensin (Ang-1–7)/Mas1R axis.

The viral feedback loop includes evading the host’s innate response, uncontrolled viral replication, and turning on a hyperactive adaptative immune response.

The inflammatory loop is composed of the exuberant inflammatory response feeding back until exploding in an actual cytokine storm.
Downregulation of the ACE2/Ang-(1–7)/Mas1R axis leaves the lung without a critical defense mechanism and turns the scale to the inflammatory side of the RAS.

The coagulation loop is a hypercoagulable state caused by the interplay between inflammation and coagulation in an endless feedback loop.

The result is a hyperinflammatory and hypercoagulable state producing acute immune-mediated lung injury and eventually, adult respiratory distress syndrome.