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Authors: Harvey B. Pollard, Bette S. Pollard and John R. Pollard

Link to paper: https://doi.org/10.1101/2020.04.09.034983

Journal/ Pre-Print: BioRxiv

Key Words: Digitoxin, Cytokine Storm, Influenza A Virus

RESEARCH HIGHLIGHTS 

1. Digitoxin administration to influenza A virus (IAV)-infected cotton rats lowers pro-inflammatory cytokine production in lungs associated with cytokine storm

SUMMARY 

Pollard et al. aim to show the anti-inflammatory effect of digitoxin, indicated for the treatment of heart conditions, in an influenza A Virus infection model in cotton rats. Animals were treated daily with different doses of digitoxin starting at day 1 prior to infection up until sacrifice. Protein levels of TNF𝛼, GRO/KC, MIP2, MCP1, TGFβ, and IFNy in the lungs were significantly reduced at 10 and 30µg of digitoxin administered.

IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS

Potential treatment of SARS-CoV2/COVID19 patients by digitoxin administration (although showing no data for SARS-CoV2 infection itself)

STUDY TYPE

· In vivo study (rat influenza model)

STRENGTHS AND LIMITATIONS OF THE PAPER

Novelty: Digitoxin treatment of viral respiratory tract infection reduces various pro-inflammatory cytokines and chemokines.

Standing in the field: In line with previously described digitoxin inhibitory effect on NF-kB.

Digitoxin has some antiviral properties as well and has been shown for instance to inhibit human cytomegalovirus, adenovirus and herpes simplex replication.

Appropriate statistics: pooled 2-tailed t tests, appropriate, as author are only comparing no treatment (0µg) to treatment (single concentration), but not an actual dose response.

Viral model used: Influenza A infection of cotton rats

Translatability: Potential treatment of SARS-CoV2 with digitoxin

Main limitations:

- Influenza A-H2N2 virus used instead of SARS-CoV2 model

- IL-6 not measured (major cytokine in cytokine storm in SARS-CoV2)

- Viral titers not investigated

- No route of digitoxin administration specified

- No dose response of the drug investigated, i.e. does the concentration of digitoxin have a significant role in the cytokine response

- Digitoxin was given as a pretreatment as well at Day -1 (explain why this is a limitation)

- No explanation which cells are mainly targeted by digitoxin, problematic as systemic treatment with Nf-KB inhibitor might be quite toxic

- Not experimentally shown that NF-kB is inhibited by digitoxin in their model