Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and Progression

Abstract

The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Although the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying disease severity and progression remain unclear. This review highlights key mechanisms that have been proposed to contribute to COVID-19 progression from viral entry to multisystem organ failure, as well as the central role of the immune response in successful viral clearance or progression to death.

Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury

“…The unprecedented nature of the SARS-CoV-2/COVID-19 pandemic has highlighted multiple unmet medical needs including the glaring absence of effective FDA–approved targeted pharmacotherapies. 5 This has created urgency within basic science, translational, and clinical research communities, particularly as immunity-derived protection against the novel coronaviruses such as SARS (severe acute respiratory syndrome, 2002-2004), and MERS (Middle East respiratory syndrome, 2012-2015) proved to be inefficient and unpredictable. 6 , 7 The availability of effective SARS-CoV-2 vaccines and anti-SARS-CoV-2 drugs are imminent and of obvious utility, however, neither therapeutic strategy addresses the pathobiology of COVID-19-ARDS i.e.…”

“… 16 , 17 In addition, SARS-CoV-2 infectivity peaks before the onset of symptoms, a stark contrast to SARS-CoV-1, 3 , 18 reflecting current understanding of longer SARS-CoV-2 incubation periods and higher rates of transmission compared to other coronaviruses. 5 Potential mechanisms for the significant differences in the host immune response to SARS-CoV-2 infection include viral escape from innate sensing, hyper-inflammatory responsiveness referable to inflammatory myeloid subpopulations, and lymphopenia marked by T cell and Natural Killer cell dysfunction among other alterations such as hypercoagulability. 4 , 19 , 20 Clearly, additional studies are needed to more fully define immune responses to specific coronavirus infections, including SARS-CoV-2, that dictate disease severity.…”

“… 26 The dependence on ACE2 for viral entry contributes to the tropism for nasal ciliated epithelium and alveolar type II pneumocytes. 5 Increased infectivity and novel clinical features of SARs-CoV-2 have been associated with the tropism for other ACE2-expressing cells such as endothelial cells which is conferred by acquisition of a furin cleavage site on the S-protein. 24 …”

“…A key feature of patients who progress from Stage I COVID-19 disease to increasingly severe Stage II and Stage III disease is blood biomarker evidence of the maladaptive DAMP-mediated loss of innate immunity regulation with excessive levels of circulating proinflammatory cytokines and chemokines (IL-6, IL-2, IL-7, IL-10, G-CSF, CXCL-10, MCP1, IFNγ, MIP1α, TNFα). 5 Traditional biomarkers of acute systemic inflammation include C-reactive protein (CRP) and ferritin which positively correlate with severity of COVID-19 disease, 52 , 53 but are of limited utility as they lack specificity and do not inform therapeutic decisions. In addition to dysregulated cytokine release, excessive secretion of proteases and generation of reactive oxygen species (ROS) by infiltrating immune cells contribute to the hyperinflammation characteristic of severe COVID-19 disease ( Figure 2 ).…”

Persistence of COVID-19 Symptoms after Recovery in Mexican Population

“…Likewise, clinical cases of multisystemic inflammation syndrome have been reported, both in children and adults, in post-COVID-19 patients [ 50 , 51 ]. Agreeing that it is a much more complex multisystem disorder, and refuted what was initially believed, that COVID-19 was a respiratory disease, but now we know that this is not the case [ 52 , 53 ].…”