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.
Knowledge of pathophysiology is the first step to address the management of a disease appropriately. It is familiar with the mechanism that the virus uses to evade host immune defense mechanisms or those that uses to harm will permit the design of appropriate strategies to neutralize the dysfunctions or disbalances generated either by the virus or by the consequences of the infection. From the knowledge gathered, it seems that most organ damage in severe COVID-19 is done through an immune-mediated mechanism, although SARS-CoV-2 is the necessary initiator. The spectrum of disease is comprehensive, and since not all the patients will share the same evolving pattern, the search for predictive factors to promptly identify patients more prone to evolve to life-threatening disease is of the utmost importance. In severe cases, the quick evolving pattern of the disease makes early treatment imperative, at least until reliable predictive factors become widely available. The implication of viral and host-dependent mechanisms in COVID-19 pathogenesis suggests that any therapeutic strategy must combine antiviral drugs and adjuvant therapy to modulate the host's responses.
All these goals will be achieved through the broad effort of basic, translational, and clinical scientists and clinicians, and will demand a high degree of commitment from patients and their families, allied professionals, and everyone engaged in the fight against COVID-19. Among them, politicians and Health Administration Officers will play a unique role, since such a gigantic task will need the allocation of a vast amount of resources to overcome a health challenge to Mankind like none other in recent times.
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