Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population

  1. Ariel Israel  Is a corresponding author
  2. Alejandro A Schäffer
  3. Assi Cicurel
  4. Ilan Feldhamer
  5. Ameer Tal
  6. Kuoyuan Cheng
  7. Sanju Sinha
  8. Eyal Schiff
  9. Gil Lavie
  10. Eytan Ruppin  Is a corresponding author
  1. Clalit Health Services, Israel
  2. National Institutes of Health, United States
  3. Sheba Medical Center, Israel
  4. Tel-Aviv University, Israel

Abstract

Background: Until COVID-19 drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Towards this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members.

Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID‑19 hospitalization. Case patients were adults aged 18-95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p‑value, using Fisher's exact test. False discovery rate was used to adjust for multiple testing.

Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI (0.058 to 0.458), p<0.001), ezetimibe (OR=0.488, 95% CI ((0.377 to 0.622)), p<0.001), rosuvastatin (OR=0.673, 95% CI (0.596 to 0.758), p<0.001), flecainide (OR=0.301, 95% CI (0.118 to 0.641), p<0.001), and vitamin D (OR=0.869, 95% CI (0.792 to 0.954), p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization.

Conclusions: Ubiquinone, ezetimibe and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies.

Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.

Data availability

Data were obtained from patients' electronic health records, and IRB approval restrains its use to researchers inside Clalit Health Services. For further information regarding data availability, researchers may contact Dr. Lavie gillav@clalit.org.ilThis study is based on real-world patient drug purchases, and it cannot be made available due to patient privacy concerns. R code used to produce Figure 1 is available as Supplemental File 1.

Article and author information

Author details

  1. Ariel Israel

    Department of Research and Data, Clalit Health Services, Tel-Aviv, Israel
    For correspondence
    dr.ariel.israel@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4389-8896
  2. Alejandro A Schäffer

    Cancer Data Science Laboratory, , National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Assi Cicurel

    Department of Research and Data, Division of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Ilan Feldhamer

    Department of Research and Data, Clalit Health Services, Tel-Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Ameer Tal

    Department of Research and Data, Clalit Health Services, Tel-Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Kuoyuan Cheng

    Cancer Data Science Laboratory, , National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sanju Sinha

    Cancer Data Science Laboratory, , National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Eyal Schiff

    Tel-Aviv University, Sheba Medical Center, Ramat Gan, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Gil Lavie

    Department of Research and Data, Division of Planning and Strategy, Clalit Health Services, Tel-Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Eytan Ruppin

    Blavatnik School of Computer Science, Tel-Aviv University, Tel-Aviv, Israel
    For correspondence
    eytan.ruppin@nih.gov
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Cancer Institute (Intramural funding)

  • Alejandro A Schäffer
  • Kuoyuan Cheng
  • Sanju Sinha
  • Eytan Ruppin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Frank L van de Veerdonk, Radboudumc Center for Infectious Diseases, Netherlands

Ethics

Human subjects: This study has been approved by the CHS Institutional Review Board (IRB) with a waiver of informed consent, approval number: COM-0046-20.

Version history

  1. Preprint posted: October 14, 2020 (view preprint)
  2. Received: March 7, 2021
  3. Accepted: July 7, 2021
  4. Accepted Manuscript published: July 27, 2021 (version 1)
  5. Version of Record published: July 29, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 10,687
    views
  • 240
    downloads
  • 33
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ariel Israel
  2. Alejandro A Schäffer
  3. Assi Cicurel
  4. Ilan Feldhamer
  5. Ameer Tal
  6. Kuoyuan Cheng
  7. Sanju Sinha
  8. Eyal Schiff
  9. Gil Lavie
  10. Eytan Ruppin
(2021)
Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population
eLife 10:e68165.
https://doi.org/10.7554/eLife.68165

Share this article

https://doi.org/10.7554/eLife.68165

Further reading

    1. Medicine
    2. Microbiology and Infectious Disease
    3. Epidemiology and Global Health
    4. Immunology and Inflammation
    Edited by Jos WM van der Meer et al.
    Collection

    eLife has published articles on a wide range of infectious diseases, including COVID-19, influenza, tuberculosis, HIV/AIDS, malaria and typhoid fever.

    1. Epidemiology and Global Health
    Sean V Connelly, Nicholas F Brazeau ... Jeffrey A Bailey
    Research Article

    Background:

    The Zanzibar archipelago of Tanzania has become a low-transmission area for Plasmodium falciparum. Despite being considered an area of pre-elimination for years, achieving elimination has been difficult, likely due to a combination of imported infections from mainland Tanzania and continued local transmission.

    Methods:

    To shed light on these sources of transmission, we applied highly multiplexed genotyping utilizing molecular inversion probes to characterize the genetic relatedness of 282 P. falciparum isolates collected across Zanzibar and in Bagamoyo district on the coastal mainland from 2016 to 2018.

    Results:

    Overall, parasite populations on the coastal mainland and Zanzibar archipelago remain highly related. However, parasite isolates from Zanzibar exhibit population microstructure due to the rapid decay of parasite relatedness over very short distances. This, along with highly related pairs within shehias, suggests ongoing low-level local transmission. We also identified highly related parasites across shehias that reflect human mobility on the main island of Unguja and identified a cluster of highly related parasites, suggestive of an outbreak, in the Micheweni district on Pemba island. Parasites in asymptomatic infections demonstrated higher complexity of infection than those in symptomatic infections, but have similar core genomes.

    Conclusions:

    Our data support importation as a main source of genetic diversity and contribution to the parasite population in Zanzibar, but they also show local outbreak clusters where targeted interventions are essential to block local transmission. These results highlight the need for preventive measures against imported malaria and enhanced control measures in areas that remain receptive to malaria reemergence due to susceptible hosts and competent vectors.

    Funding:

    This research was funded by the National Institutes of Health, grants R01AI121558, R01AI137395, R01AI155730, F30AI143172, and K24AI134990. Funding was also contributed from the Swedish Research Council, Erling-Persson Family Foundation, and the Yang Fund. RV acknowledges funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 program supported by the European Union. RV also acknowledges funding by Community Jameel.