Anti-Interleukin-23 Treatment Linked to ImprovedClostridioides difficileInfection Survival

Abstract Clostridioides difficile is a leading cause of healthcare associated infection and an unacceptably high proportion of patients with C. difficile infection die despite conventional antibiotic treatment. Host-directed immunotherapy has been proposed as an ideal treatment modality for C. difficile infection to mitigate the underlying toxin-mediated pathogenic immune response while sparing protective gut microbes. Interleukin-23 monoclonal antibody inhibitors are used extensively to control pro-inflammatory Th17 immune pathways in psoriasis and inflammatory bowel disease that are similarly important during C. difficile infection. We used a large retrospective electronic health record database to test the hypothesis that hospitalized patients with C. difficile infection who are on anti-IL-23 treatment will have improved survival compared to patients without anti-IL-23. 9,301 anti-IL-23 patients had significantly lower probability of all-cause death within 30 days (0.54%) compared with 1:1 propensity-matched control patients (3.1%). IL-23 inhibition is a promising adjunct to C. difficile treatment and further clinical trials repositioning anti-IL-23 monoclonal antibodies from psoriasis and inflammatory bowel disease to C. difficile infection are warranted. Competing Interest Statement W. A. Petri is a consultant for TechLab Inc., a company that manufactures diagnostic tests for C. difficile toxins. All other authors report no conflicts of interest relevant to this article. Funding Statement This work was supported by the National Institutes of Health (K23AI163368 to G.R.M.; 5R01AI152477 and 5R01AI124214 to W.A.P). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Use of de-identified, aggregate data was determined non-human subjects research (IRB-Non-HSR 22282) by the UVA Institutional Review Board for Health Sciences Research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Contact Information: Gregory Russell Madden, MD, MSDS, Address: Division of Infectious Diseases & International Health, P.O. Box 800545, Charlottesville, VA, USA 22908-0473, phone: (434) 982-1700, fax: (434) 924-1225, email: grm7q{at}virginia.edu Data Availability Data displayed and analyzed by the TriNetX Platform are in aggregate form or any patient-level data are de-identified due to protected health information. A detailed report of the TriNetX query and analysis (including propensity score density function plots before and after matching) are provided in the Supplementary Material. Contact R.P. (saskia.preissner{at}charite.de) for original data upon reasonable request.