Tissue-specific tolerance in fatal Covid-19

Abstract

<jats:p>Successful host defence against a pathogen can involve resistance or tolerance, with implications for prioritising either antimicrobial or immunomodulatory therapeutic approaches. Hyper-inflammation occurs in Covid-19 and is associated with worse outcomes. The efficacy of dexamethasone in preventing mortality in critical Covid-19 suggests that inflammation has a causal role in death. Whether this deleterious inflammation is primarily a direct response to the presence of SARS-CoV-2 requiring enhanced resistance, or an independent immunopathologic process necessitating enhanced tolerance, is unknown. Here we report an aberrant immune response in fatal Covid-19, principally involving the lung and reticuloendothelial system, that is not clearly topologically associated with the virus, indicating tissue-specific tolerance of SARS-CoV-2. We found that inflammation and organ dysfunction in fatal Covid-19 did not map to the widespread tissue and cellular distribution of SARS-CoV-2 RNA and protein, both between and within tissues. A monocyte/myeloid-rich vasculitis was identified in the lung, along with an influx of macrophages/monocytes into the parenchyma. In addition, stereotyped abnormal reticulo-endothelial responses (reactive plasmacytosis and iron-laden macrophages) were present and dissociated from the presence of virus in lymphoid tissues. Our results support virus-independent immunopathology being one of the primary mechanisms underlying fatal Covid-19. This supports prioritising pathogen tolerance as a therapeutic strategy in Covid-19, by better understanding non-injurious organ-specific viral tolerance mechanisms and targeting aberrant macrophage and plasma cell responses.</jats:p>

Proteomics identifies a type I IFN, prothrombotic hyperinflammatory circulating COVID-19 neutrophil signature distinct from non-COVID-19 ARDS

“…perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 18, 2020. ; https://doi.org/10.1101/2020.09.15.20195305 doi: medRxiv preprint detection of virus, supporting the concept of aberrant host immune responses as drivers of tissue injury and pulmonary disease progression (Dorward et al, 2020). A disordered myeloid response is further supported by analysis of gene clusters and surface protein expression of whole blood and peripheral blood mononuclear cell (PBMC) layers of patients with mild and severe COVID-19, identifying a suppressive myeloid cell response in severe disease (Schulte-Schrepping et al, 2020).…”

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

“…and cerebrovascular disease are associated with higher incidence of mortality in COVID-19 patients (Docherty et al, 2020;Wang, Li, Lu, & Huang, 2020). Furthermore, post-mortem examinations reveal that tissue inflammation and organ dysfunction do not map to tissue/cellular dispersal of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during fatal COVID-19 (Dorward et al, 2020). Thus it was concluded that immune-mediated as opposed to pathogen-mediated organ inflammation and injury contributed to death in COVID-19 patients (Dorward et al, 2020).…”

“…Furthermore, post-mortem examinations reveal that tissue inflammation and organ dysfunction do not map to tissue/cellular dispersal of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during fatal COVID-19 (Dorward et al, 2020). Thus it was concluded that immune-mediated as opposed to pathogen-mediated organ inflammation and injury contributed to death in COVID-19 patients (Dorward et al, 2020). COVID-19 is caused by SARS-CoV-2, which generally has a 4-to 5-day average incubation period (prior to onset of symptoms), with 97.5% of symptomatic patients experiencing symptoms within 11.5 days (Lauer et al, 2020), although patients can also be asymptomatic.…”

Pathogen Infection Recovery Probability (PIRP) Versus Proinflammatory Anti-Pathogen Species (PIAPS) Levels: Modelling and Therapeutic Strategies

“…Both pathogen and key PIAPS (e.g., IL-6) should be targeted as critical biomarkers ASAP. As an example, in the case of COVID-19, while there appears lack of evidences of organ damages directly due to SARS-cov-2 virus 23 , excess levels or presences of certain PIAPS such as macrophages, neutrophils, or inflammatory cytokines (such as IL-6) were observed in multiple damaged organs in the autopsies and biopsies of the SARS-cov-2 virus infected hosts 18,24 , i.e., the evidences imply the death of covid-19 infected hosts appears to be mainly due to immune-mediated rather than pathogen mediated organ injuries 24 . Additionally, the fact that the average viral levels of intensive care unit ICU (i.e., critically ill) patients were surprisingly lower than those non-ICU patients also seem to confirm that many ICU patients may have been already in stage II 25 .…”

“…As an example, in the case of COVID-19, while there appears lack of evidences of organ damages directly due to SARS-cov-2 virus 23 , excess levels or presences of certain PIAPS such as macrophages, neutrophils, or inflammatory cytokines (such as IL-6) were observed in multiple damaged organs in the autopsies and biopsies of the SARS-cov-2 virus infected hosts 18,24 , i.e., the evidences imply the death of covid-19 infected hosts appears to be mainly due to immune-mediated rather than pathogen mediated organ injuries 24 . Additionally, the fact that the average viral levels of intensive care unit ICU (i.e., critically ill) patients were surprisingly lower than those non-ICU patients also seem to confirm that many ICU patients may have been already in stage II 25 . Though APS/PIAPS boosters (such as interferon INF-alpha, gamma immunoglobulin, convalescent plasma containing SARS-cov-2 antibodies collected from COVID-19 recovered patients) were recommended for COVID-19 treatments 18 , based on this proposed model, such treatments should be used only for those hosts with deficient or very weak immune responses and should be administered in stage I. PIAPS suppression via a series of inflammation antagonists, or cytokine elimination via blood purification 18 appear useful for controlling CRS but they should be done after te in the stage II, i.e., the PIAPS level control are extremely critical for COVID-19 therapy.…”