title: Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection.
abstract: BACKGROUND
  Despite substantial interest in biomarkers, their impact on clinical outcomes and variation with bacterial strain has rarely been explored using integrated databases.
  
  
  METHODS
  From September 2006 to May 2011, strains isolated from Clostridium difficile 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 C. difficile infections (CDIs) from different clades/sequence types (STs) and EIA-negative controls using Cox and normal regression adjusted for demographic/clinical factors.
  
  
  RESULTS
  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 P = .05 vs other clade 1). Mean baseline neutrophil counts also varied significantly by genotype: 12.4, 11.6, and 9.5 × 10(9) neutrophils/L for clades 5, 2 and 1, respectively, vs 7.0 × 10(9) neutrophils/L in EIA-negative controls (P < .0001) and 7.9 × 10(9) neutrophils/L in ST 44 (P = .08). There were strong associations between C. difficile-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.
  
  
  CONCLUSIONS
  C. difficile 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.
authors: NIHR Biomedical Research Centre, Oxford, UK. sarah.walker@ndm.ox.ac.uk
authors: A Sarah
authors: AS
authors: Walker
authors: David W
authors: DW
authors: Eyre
authors: David H
authors: DH
authors: Wyllie
authors: Kate E
authors: KE
authors: Dingle
authors: David
authors: D
authors: Griffiths
authors: Brian
authors: B
authors: Shine
authors: Sarah
authors: S
authors: Oakley
authors: Lily
authors: L
authors: O'Connor
authors: John
authors: J
authors: Finney
authors: Alison
authors: A
authors: Vaughan
authors: Derrick W
authors: DW
authors: Crook
authors: Mark H
authors: MH
authors: Wilcox
authors: Tim E A
authors: TE
authors: Peto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D016360:Clostridioides difficile / Q000145:classification / Q000235:genetics / Q000302:isolation & purification*; D003015:Clostridium Infections / Q000453:epidemiology / Q000382:microbiology* / Q000401:mortality*; D005243:Feces / Q000382:microbiology; D005260:Female; D005838:Genotype; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D058885:Multilocus Sequence Typing; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015415:Biomarkers
keywords: C. difficile; biomarkers; mortality; strain-specific variation