By Paul E Marik et al.


COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.


The COVID-19 pandemic has claimed over four million lives and shows no evidence of abating. While the majority of SARS-CoV-2 infections are self-limited, approximately 20% of patients are symptomatic, with many of these patients requiring hospitalization with approximately 3% symptomatic patients having a fatal outcome.13 Furthermore, in excess of 50% of patients who recover from symptomatic infections, independent of disease severity, develop the debilitating “long-haul syndrome”4 The human and economic toll of this disease is astronomical. In order to develop effective prophylactic and therapeutic strategies against COVID-19, an accurate understanding of its pathogenesis is required. While tens of thousands of publications have explored the clinical and basic science aspects of this disease, there is lack of an integrative, all-encompassing, and clinically focused review of the pathogenetic mechanisms of this disease.

Phases of COVID-19

COVID-19 progresses through three distinct phases, namely, the incubation phase, the symptomatic phase, and the pulmonary phase (see Figure 1).5 SARS-CoV-2 is highly infectious being transmitted by droplet and aerosol spread.68 In distinction to SARS-CoV and Middle Eastern Respiratory Virus (MERS) patients infected with SARS-CoV-2 are most infectious during the late incubation/presymptomatic phase (highest viral load).9 SARS-CoV and SARS-CoV-2 infects human cells by binding to the cell-surface protein angiotensin-converting enzyme 2 (ACE-2) through the Receptor Binding Domain (RBD) of its spike protein.10,11 ACE-2 is expressed on ciliated epithelium of the nasopharynx and upper respiratory tract, bronchial epithelium, type II pneumocytes in addition to macrophages/monocytes, mast cells, and vascular endothelial cells.10 In the respiratory tract, there is a gradient of ACE-2 expression with greater expression in the upper than lower respiratory tract.12 ACE-2 receptor expression is highest in the microvasculature of the lung, fat, and brain with lower amounts in the liver, kidney, and heart.10,13 Once engaged with ACE-2, the ACE-2-bound viral spike protein undergoes proteolytic cleavage catalyzed by a host membrane-anchored protein, the transmembrane protease serine 2 (TMPRSS2).14 TMPRSS2 results in a conformational change in the spike protein that is required for host and virus membrane fusion. After this spike-mediated fusion process, the internalized virus particle releases its RNA genome and begins replication.15 More recently, a furin protease and the cellular receptor neuropilin-1 (NRP1) have been demonstrated to be involved in the infection process.

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