Toxin A-predominant Pathogenic C. difficile: A Novel Clinical Phenotype

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019.
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Lin Q, Pollock NR, Banz A, Lantz A, Xu H, Gu L, Gerding DN, Garey KW, Gonzales-Luna AJ, Zhao M, Song L, Duffy DC, Kelly CP and Chen X

Clin Infect Dis. 2019 Aug 11. pii: ciz727. doi: 10.1093/cid/ciz727.

Abstract

BACKGROUND:

Most Clostridioides difficile toxinogenic strains produce both toxins A and B (A+B+), but A-B+ variants also cause disease. We report the identification of a series of pathogenic clinical C. difficile isolates that produce high amounts of toxin A with low or non-detectable toxin B.

METHODS:

An ultrasensitive, quantitative immunoassay was used to measure toxins A and B in stools from 187 CDI patients and 44 carriers. Isolates were cultured and assessed for in vitro toxin production and in vivo phenotype (mouse CDI model).

RESULTS:

7 CDI patients and 6 carriers had stools with detectable toxin A (range 23-17,422 pg/mL, 5.6% of samples overall) but toxin B below the clinical detection limit (<20 pg/mL; median TcdA:B ratio 17.93). Concentrations of toxin A far exceeded B in in vitro cultures of all 12 recovered isolates (median TcdA:B ratio 26). Of eight toxin A>>B isolates tested in mice, 4 caused diarrhea, and 3 of those 4 caused lethal disease. Ribotyping demonstrated strain diversity. TcdA-predominant samples were also identified at two other centers, with similar frequency (7.5% and 6.8%).

CONCLUSION:

We report the discovery of clinical pathogenic C. difficile strains that produce high levels of toxin A but minimal or no toxin B. This pattern of toxin production is not rare (>5% of isolates) and is consistently observed in vitro and in vivo in humans and mice. Our study highlights the significance of toxin A in human CDI pathogenesis and has important implications for CDI diagnosis, treatment and vaccine development.