| Summary: | <p><strong>Background.</strong> Despite substantial interest in biomarkers, their impact on clinical outcomes and variation with bacterial strain has rarely been explored using integrated databases.</p> <p><strong>Methods.</strong> From September 2006 to May 2011, strains isolated from <em>Clostridium difficile</em> toxin enzyme immunoassay (EIA)–positive fecal samples from Oxfordshire, United Kingdom (approximately 600 000 people) underwent multilocus sequence typing. Fourteen-day mortality and levels of 15 baseline biomarkers were compared between consecutive <em>C. difficile</em> infections (CDIs) from different clades/sequence types (STs) and EIA-negative controls using Cox and normal regression adjusted for demographic/clinical factors.</p> <p><strong>Results.</strong> Fourteen-day mortality was 13% in 2222 adults with 2745 EIA-positive samples (median, 78 years) vs 5% in 20 722 adults with 27 550 EIA-negative samples (median, 74 years) (absolute attributable mortality, 7.7%; 95% CI, 6.4%–9.0%). Mortality was highest in clade 5 CDIs (25% [16 of 63]; polymerase chain reaction (PCR) ribotype 078/ST 11), then clade 2 (20% [111 of 560]; 99% PCR ribotype 027/ST 1) versus clade 1 (12% [137 of 1168]; adjusted P < .0001). Within clade 1, 14-day mortality was only 4% (3 of 84) in ST 44 (PCR ribotype 015) (adjusted <em>P</em> = .05 vs other clade 1). Mean baseline neutrophil counts also varied significantly by genotype: 12.4, 11.6, and 9.5 × 10<sup>9</sup> neutrophils/L for clades 5, 2 and 1, respectively, vs 7.0 × 10<sup>9</sup> neutrophils/L in EIA-negative controls (<em>P</em> < .0001) and 7.9 × 10<sup>9</sup> neutrophils/L in ST 44 (<em>P</em> = .08). There were strong associations between <em>C. difficile</em>-type-specific effects on mortality and neutrophil/white cell counts (rho = 0.48), C-reactive-protein (rho = 0.43), eosinophil counts (rho = −0.45), and serum albumin (rho = −0.47). Biomarkers predicted 30%–40% of clade-specific mortality differences.</p> <p><strong>Conclusions.</strong> <em>C. difficile</em> genotype predicts mortality, and excess mortality correlates with genotype-specific changes in biomarkers, strongly implicating inflammatory pathways as a major influence on poor outcome after CDI. PCR ribotype 078/ST 11 (clade 5) leads to severe CDI; thus ongoing surveillance remains essential.</p>
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