The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes

Authors: Y. Chen et al Link to paper: https://www.medrxiv.org/content/10.1101/2020.03.27.20045427v1

Journal/ Pre-Print: medRxiv

Key Words: COVID-19 patients, histology, spleen, lymph nodes, ACE2, SARS-COV2 dissemination, apoptosis, lymphocytopenia

RESEARCH HIGHLIGHTS 

1. Severe cases of COVID-19 demonstrate extensive apoptosis in spleen and LNs

2. SARS-COV2 NP antigens and potentially ACE-2 receptors are detected in macrophages in LN and in the splenic RP

3. Increase Fas expression and IL-6 secretion in secondary lymphoid organs (SLOs) of covid-19 patients.

SUMMARY 

This study aims to understand the mechanism leading to the lymphopenia observed in severe SARS-COV2 infected patients. The spleens and LNs of 6 COVID-19 patients and 3 controls were examined by autopsy and compared using histology. TUNEL and H&E staining revealed highly prevalent apoptosis and disorganisation throughout the secondary lymphoid organs (SLO) of COVID-19 patients. The splenic red pulp and the subcapsular sinus macrophages in the LNs stained for SARS-COV2 NP antigens and potentially ACE-2 suggesting dissemination of SARS-CoV-2. Finally, IL-6 and Fas staining was detected in the NP+ve macrophages. The authors propose a model in which SARS-COV2 disseminates to SLOs leading to Fas upregulation and IL-6 secretion that could trigger Activation-induced cell death (AICD) in lymphocytes resulting in lymphopenia.

IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS

Understand the immune response to SARS-CoV2/COVID19

Clinical symptoms and pathogenesis of SARS-Cov2/COVID19

The impact of this paper is limited. It highlights an overall disorganisation of the SLOs that was previously reported and is probably due to the cytokine storm observed in severe Covid-19 patients.

STUDY TYPE

· Ex vivo study (immunohistochemistry on post-mortem spleen and LNs)

· Clinical Cohort study (collection of 6 post-mortem patient secondary lymphoid organs and 3 healthy donors collected from road accident induced death.)

STRENGTHS AND LIMITATIONS OF THE PAPER

Novelty: The novelty is limited as previous studies have already pointed out the SLO atrophy, the lymphocytopenia and the correlation of this phenotype with the presence of sepsis/cytokine storm.

Standing in the field: Their claim that macrophages in the spleen express ACE2 as a receptor for SARS-CoV-2 is not supported by a paper that shows limited ACE2 expression in the spleen (https://doi.org/10.1002/path.1570)

Appropriate statistics: Limited, the authors don’t indicate how many samples they use for each assay.

Viral model used: SARS-CoV-2

Translatability: Not directly translatable.

Main limitations:

- The information is limited, as all samples represent donors in whom the infection was not controlled and therefore lead to death by sepsis/cytokine storm.

-They don’t show that macrophages were infected but look at viral NP antigen staining that could highlight phagocytosis rather than infection.

-The quality of some of the staining is unreliable for ACE2, potentially NP too (control image needs lower magnification or structural delineation with B or T cell staining to show an absence of staining convincingly).

- Often not clear if image shows LN or spleen. Quantification in 4E does not match images in 4D.

-They mention the use of electron microscopy to show virions in the LN but it’s not present in the figures.