Pathogenesis of COVID-19 from the Perspective of the Damage-Response Framework

Abstract

<jats:title>ABSTRACT</jats:title> <jats:p>The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents the medical community with a significant challenge. COVID-19 is an entirely new disease with disparate clinical manifestations that are difficult to reconcile with a single pathogenic principle. Here, we explain how the flexible paradigm of the “damage-response framework” (DRF) of microbial pathogenesis can organize the varied manifestations of COVID-19 into a synthesis that accounts for differences in susceptibility of vulnerable populations as well as for differing manifestations of COVID-19 disease. By focusing on mechanisms of host damage, particularly immune-mediated damage, the DRF provides a lens to understand COVID-19 pathogenesis and to consider how potential therapies could alter the outcome of this disease.</jats:p>

Transcriptional and proteomic insights into the host response in fatal COVID-19 cases

“…The finding that these fatal cases had a low viral load in the setting of massive transcriptional changes is suggestive that patient deaths may be more related to an overexuberant and uncontrolled host response rather than unabated viral replication. This observation is consistent with what was seen in patients who died of SARS-CoV-1 and MERS-CoV infections and fits within the damage-response framework (37,38), which holds that ongoing host damage may be the result of the host immune response rather than persistent microbial interactions. Moreover, our findings of a low viral burden at the time of fatal outcome may help explain why direct antivirals, such as remdesivir (39), are more effective in patients with less severe disease and dexamethasone, an immunosuppressant, is associated with reduced mortality in severely ill patients late in disease (40).…”

Cutaneous manifestations of COVID-19 in children (and adults): A virus that does not discriminate

“… 3 , 4 Transmission is via respiratory droplets (and possibly aerosols), although there is recent evidence of fecal-oral transmission in children. 5 , 6 SARS-CoV-2 enters cells by attaching to angiotensin-converting enzyme-2 (ACE-2) receptors. 4 , 7 , 8 This receptor is found on numerous mucosal sites, 9 , 10 including the endothelium of dermal blood vessels and epithelial cells in eccrine glands, which may account for the cutaneous manifestations of COVID-19.…”

Cell-Free DNA in Blood Reveals Significant Cell, Tissue and Organ Specific injury and Predicts COVID-19 Severity

“…We first assayed 52 serial samples collected at short time intervals from five adult patients with COVID-19 that were treated at University of California, San Francisco (UCSF) Medical Center (median of 8 samples per patient [range [6][7][8][9][10][11][12][13][14][15][16][17][18]). These plasma samples were residual from clinical testing and were collected from this group of patients over a treatment time-period of up to 14 days with up to four samples collected within 24 hours (median time between consecutive collections of 13 hours [range 5-64]).…”

“…However, there are emerging data that SARS-CoV-2 infection may also be accompanied by hematological derangements [ 10 ]–[ 13 ]. In addition, a dysregulated immune response to SARS-CoV-2 can occur, contributing to the development of ARDS, systemic tissue injury, and multi-organ failure [ 14 ]. A strong association between increased cytokine profiles and the severe deterioration of some patients has been observed [ 15 ].…”