Tissue-Specific Immunopathology in Fatal COVID-19
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Abstract
Rationale
In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.
Objectives
To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.
Methods
Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.
Measurements and Main Results
Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.
Conclusions
Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.
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SciScore for 10.1101/2020.07.02.20145003: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The patients had a mean age of 77 years (range 64–97), 10/11 were male, and four received invasive mechanical ventilation during their hospital admission. Table 2: Resources
Antibodies Sentences Resources For immunophenotyping, multiplexed immunofluorescence on de-paraffinised rehydrated FFPE slides was performed using combinations of primary antibodies against CD34, CD68, MRP8, CD4, CD8 and CD20, labelled with TSA-conjugated fluorophores, with antibody removal between steps. CD34suggested: NoneCD68suggested: NoneMRP8suggested: NoneCD4suggested: NoneCD8s…SciScore for 10.1101/2020.07.02.20145003: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The patients had a mean age of 77 years (range 64–97), 10/11 were male, and four received invasive mechanical ventilation during their hospital admission. Table 2: Resources
Antibodies Sentences Resources For immunophenotyping, multiplexed immunofluorescence on de-paraffinised rehydrated FFPE slides was performed using combinations of primary antibodies against CD34, CD68, MRP8, CD4, CD8 and CD20, labelled with TSA-conjugated fluorophores, with antibody removal between steps. CD34suggested: NoneCD68suggested: NoneMRP8suggested: NoneCD4suggested: NoneCD8suggested: NoneCD20suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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