An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli

Abstract

Background: Experimental human challenge models have played a major role in enhancing our understanding of infectious diseases. Primary outcomes have typically utilized overly simplistic outcomes that fail to entirely account for complex illness syndromes. We sought to characterize clinical outcomes associated with experimental infection with enterotoxigenic Escherichia coli (ETEC) and to develop a disease score.

Methods: Data were obtained from prior controlled human ETEC infection studies. Correlation and univariate regression across sign and symptom severity was performed. A multiple correspondence analysis was conducted. A 3-parameter disease score with construct validity was developed in an iterative fashion, compared to standard outcome definitions and applied to prior vaccine challenge trials.

Results: Data on 264 subjects receiving seven ETEC strains at doses from 1x105 to 1x1010 cfu were used to construct a standardized dataset. The strongest observed correlation was between vomiting and nausea (r = 0.65); however, stool output was poorly correlated with subjective activity-impacting outcomes. Multiple correspondence analyses showed covariability in multiple signs and symptoms, with severity being the strongest factor corresponding across outcomes. The developed disease score performed well compared to standard outcome definitions and differentiated disease in vaccinated and unvaccinated subjects.

Conclusion: Frequency and volumetric definitions of diarrhea severity poorly characterize ETEC disease. These data support a disease severity score accounting for stool output and other clinical signs and symptoms. Such a score could serve as the basis for better field trial outcomes and gives an additional outcome measure to help select future vaccines that warrant expanded testing in pivotal pre-licensure trials.

Conflict of interest statement

Competing Interests: Five of the authors are employees of the U.S. Government or military service members. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. There are no patents, products in development or marketed products to declare. One of the authors is employed by a commercial company: MD Biologic, LTD. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Maximum number and volume of loose stools during any 24 hour period post-inoculation.

Footnote: Rectangles represent thresholds for mild, moderate and severe diarrhea.

Fig 2. Multiple correspondence analysis of signs and symptoms of ETEC following experimental infection.

Fig 3

A: Histogram of 3 component ETEC disease score relative to traditional diarrhea severity based on fixed cut points of stool output. B: Receiver Operator Curve comparing 3 component ETEC disease score to traditional primary endpoint of moderate-severe diarrhea based on stool output.