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Authors: Nienhold et al 

Journal/ Pre-Print:      medRxiv/bioRxiv  

Tags: Bioinformatics, Clinical, Immunology/Immunity, Inflammation 

Research Highlights 

  1. Post mortem transcriptional and cellular profiling along with histological analysis of lungs from Covid-19 patients reveadistinct sample clustering driven through high or low expression of interferon stimulated genes (ISGs)  

  1. ISGlow, in comparison to ISGhigh, lungs are characterised by low viral loads, increased CD8+ T cell and macrophage infiltrate and exacerbated pulmonary damage 

  1. ISGlow patients exhibit longer hospitalization periods, thus differences in ISGlow vs ISGhigh immunopathology may be indicative of early vs late stages of lethal SARS-CoV-2 infection 


The authors employ transcriptomic analysis and immunohistochemistry of post mortem lungs to characterise the immunopathology of lethal Covid-19. Clustering of samples based on differential immune gene expression led to the identification of 2 distinct Covid-19 sub-groups, defined by the high or low expression of interferon stimulated genes (ISGhigh or ISGlow). Histological analysis of ISGhigh vs ISGlow lungs revealed, in the latter, increased frequencies of CD8+ T cells and macrophages and exacerbated pulmonary damage. SARS-CoV-2 load correlated positively with ISG expression and inversely with CD8+ T cell activation. Hospitalization periods were notably longer in ISGlow vs ISGhigh patients. This data highlights the potential differences between early vs late stages of lethal Covid-19, which may be used to inform future therapeutic intervention strategies.  

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19  

Transcriptomic analysis coupled with immunohistochemistry details the immune response that underlies lethal Covid-19 

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19 

The authors specifically aim to define the immunopathology that underlies lethal Covid-19 

Treat of SARS-CoV2/COVID19 positive individuals 

Linking immunopathology findings with duration of hospitalization aims to inform strategies taken when treating early vs late lethal Covid-19 

Study Type  

  • Post mortem study 

  • Clinical 

Strengths and limitations of the paper 

Novelty:  First study to describe 2 distinct lung immunopathological profiles in lethal post mortem Covid-19  

Standing in the field:  Similar pathology i.e. diffuse alveolar damage with macrophage and lymphocyte infiltrate previously reported in post-mortem lungs of Covid-19 patients. Bacterial co-infection has been linked with severe Covid-19, something which is not found in this study (here, only 3/16 patients had evidence for bacterial superinfection). Sub-populations of individuals who die in early and late stages of hospitalized SARS-CoV-2 infection supported by epidemiological data (  

Appropriate statistics: Yes 

Viral model used:         Human cases of lethal SARS-CoV-2 infection, confirmed in nasopharyngeal swabs taken both when alive and, in 5 cases, post-mortem and in post mortem lung tissues 

Translatability:If verified, differences in early vs late stages of lethal Covid-19 could be used to inform therapeutic intervention strategies e.g. the use of antivirals vs immunosuppressants.  

Main limitations:  

  • Relatively small number of cases (n=16 Covid-19 patients)