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. 2023 Feb 8;76(3):e1467-e1475.
doi: 10.1093/cid/ciac624.

Stool Interleukin-1β Differentiates Clostridioides difficile Infection (CDI) From Asymptomatic Carriage and Non-CDI Diarrhea

Javier A Villafuerte Gálvez  1   2 , Nira R Pollock  2   3   4 , Carolyn D Alonso  2   3 , Xinhua Chen  1   2 , Hua Xu  1 , Lamei Wang  1   2 , Nicole White  2   3 , Alice Banz  5 , Mark Miller  5 , Kaitlyn Daugherty  1   2 , Anne J Gonzalez-Luna  6 , Caitlin Barrett  1   2 , Rebecca Sprague  1   2 , Kevin W Garey  6 , Ciaran P Kelly  1   2
Affiliations

Stool Interleukin-1β Differentiates Clostridioides difficile Infection (CDI) From Asymptomatic Carriage and Non-CDI Diarrhea

Javier A Villafuerte Gálvez et al. Clin Infect Dis. .

Abstract

Background: Despite advances in the understanding and diagnosis of Clostridioides difficile infection (CDI), clinical distinction within the colonization-infection continuum remains an unmet need.

Methods: By measuring stool cytokines and antitoxin antibodies in well-characterized cohorts of CDI (diarrhea, nucleic acid amplification test [NAAT] positive), non-CDI diarrhea (NCD; diarrhea, NAAT negative), asymptomatic carriers (ASC; no diarrhea, NAAT positive) and hospital controls (CON; no diarrhea, NAAT negative), we aim to discover novel biological markers to distinguish between these cohorts. We also explore the relationship of these stool cytokines and antitoxin antibody with stool toxin concentrations and disease severity.

Results: Stool interleukin (IL) 1β, stool immunoglobulin A (IgA), and immunoglobulin G (IgG) anti-toxin A had higher (P < .0001) concentrations in CDI (n = 120) vs ASC (n = 43), whereas toxins A, B, and fecal calprotectin did not. Areas under the receiver operating characteristic curve (ROC-AUCs) for IL-1β, IgA, and IgG anti-toxin A were 0.88, 0.83, and 0.83, respectively. A multipredictor model including IL-1β and IgA anti-toxin A achieved an ROC-AUC of 0.93. Stool IL-1β concentrations were higher in CDI compared to NCD (n = 75) (P < .0001) and NCD + ASC+ CON (CON, n = 75) (P < .0001), with ROC-AUCs of 0.83 and 0.86, respectively. Stool IL-1β had positive correlations with toxins A (ρA = +0.55) and B (ρB = +0.49) in CDI (P < .0001) but not in ASC (P > .05).

Conclusions: Stool concentrations of the inflammasome pathway, proinflammatory cytokine IL-1β, can accurately differentiate CDI from asymptomatic carriage and NCD, making it a promising biomarker for CDI diagnosis. Significant positive correlations exist between stool toxins and stool IL-1β in CDI but not in asymptomatic carriers.

Keywords: antibiotic-associated diarrhea; colonization; cytokine; fecal biomarker.

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Conflict of interest statement

Potential conflicts of interest. C. D. A. has received grant support from Merck (investigator-initiated award, paid to institution); consulting fees for advisory board from Cidara Therapeutics, Merck, and Prime Meridian Group (on behalf of AiCuris); and honoraria for presentations from the American Society of Healthcare Pharmacists. A. B. reports being an employee of bioMérieux. M. M. reports being an employee of bioMérieux and a holder of patent (Susceptibility to C. difficile infection and Fecal Immunoglobulins; bioMérieux). C. P. K. has acted as a paid consultant to Artugen, Facile Therapeutics, Ferring, First Light Biosciences, Finch, Janssen (J&J), Milky Way Life Sciences, Pfizer, Seres, Summit, RVAC Medicines, and Vedanta; has received grant support from Milky Way Life Sciences; reports participation on a data and safety monitoring board or advisory board from Finch Therapeutics (payments to self); has served as Secretary (unpaid) for the Society for the Study of Celiac Disease; and holds stock or stock options from First Light. K. W. G. has received grant support paid to the University of Houston from Acurx, Summit, Paratek Pharmaceuticals, Tetraphase Pharmaceuticals, and Seres Health, and reports consulting fees from Acurx and Summit Pharmaceuticals. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Stool concentrations of interleukin 1β across the 4 study cohorts. The y-axis is shown in logarithmic scale. *CDI vs NCD, P < .0001; **CDI vs ASC, P < .0001; ***CDI vs (NCD + ASC + CON), P < .0001. Abbreviations: ASC, asymptomatic carrier; CDI, Clostridioides difficile infection; CON, control; IL-1β, interleukin 1β; IQR, interquartile range; NCD, non–Clostridioides difficile diarrhea.
Figure 2.
Figure 2.
Correlations of stool biomarkers with stool toxins A and B by study cohort. Black cells: no significant correlation. Cell shading gradient: degree ± direction of correlation. Cell values: Spearman correlation coefficient (ρ). Abbreviations: ASC, asymptomatic carrier; CDI, Clostridioides difficile infection; G-CSF, granulocyte colony-stimulating factor; IgA, immunoglobulin A; IgG, immunoglobulin G; IL, interleukin; TNF, tumor necrosis factor.
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