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0 0.5 1 1.5 2+ Ventilation 50% Improvement Relative Risk ICU admission 51% Metformin for COVID-19  Cousins et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 64,349 patients in the USA Lower ventilation (p=0.014) and ICU admission (p<0.0001) Cousins et al., Cell Reports Methods, Jul 2022 Favors metformin Favors control

Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19

Cousins et al., Cell Reports Methods, doi:10.1016/j.crmeth.2023.100503 (date from preprint)
Jul 2022  
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PSM retrospective 64,349 COVID-19 patients in the USA, showing metformin associated with lower ICU admission and mechanical ventilation.
This study includes metformin and spironolactone.
risk of mechanical ventilation, 50.0% lower, OR 0.50, p = 0.01, treatment 2,463, control 2,463, propensity score matching, RR approximated with OR.
risk of ICU admission, 51.0% lower, OR 0.49, p < 0.001, treatment 2,463, control 2,463, propensity score matching, RR approximated with OR.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Cousins et al., 6 Jul 2022, retrospective, propensity score matching, USA, peer-reviewed, 10 authors.
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Integrative analysis of viral entry networks and clinical outcomes identifies a protective role for spironolactone in severe COVID-19
Henry Cousins, Adrienne Sarah Kline, Chengkun Wang, Yuanhao Qu, Mengdi Wang, Russ Altman, Yuan Luo, Le Cong
Treatment strategies that target host entry factors have proven an effective means of impeding viral entry in HIV and may be more robust to viral evolution than drugs targeting viral proteins directly. High-throughput functional screens provide an unbiased means of identifying genes that influence the infection of host cells, while retrospective cohort analysis can measure the real-world, clinical potential of repurposing existing therapeutics as antiviral treatments. Here, we combine these two powerful methods to identify drugs that alter the clinical course of COVID-19 by targeting host entry factors. We demonstrate that integrative analysis of genomewide CRISPR screening datasets enables network-based prioritization of drugs modulating viral entry, and we identify three common medications (spironolactone, quetiapine, and carvedilol) based on their network proximity to putative host factors. To understand the drugs' real-world impact, we perform a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients and show that spironolactone use is associated with improved clinical prognosis, measured by both ICU admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in a human lung epithelial cell line. Our results suggest that spironolactone may improve clinical outcomes in COVID-19 through tissue-dependent inhibition of viral entry. Our work further provides a potential approach to integrate functional genomics with real-world evidence for drug repurposing.
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