Clostridium difficile is a formidable nosocomial and community-acquired pathogen, causing clinical presentations ranging from asymptomatic colonization to self-limiting diarrhea to toxic megacolon and fulminant colitis. Since the early 2000s, the incidence of C. difficile disease has increased dramatically, and this is thought to be due to the emergence of new strain types. For many years, the mainstay of C. difficile disease diagnosis was enzyme immunoassays for detection of the C. difficile toxin(s), although it is now generally accepted that these assays lack sensitivity. A number of molecular assays are commercially available for the detection of C. difficile. This review covers the history and biology of C. difficile and provides an in-depth discussion of the laboratory methods used for the diagnosis of C. difficile infection (CDI). In addition, strain typing methods for C. difficile and the evolving epidemiology of colonization and infection with this organism are discussed. Finally, considerations for diagnosing C. difficile disease in special patient populations, such as children, oncology patients, transplant patients, and patients with inflammatory bowel disease, are described. As detection of C. difficile in clinical specimens does not always equate with disease, the diagnosis of C. difficile infection continues to be a challenge for both laboratories and clinicians.

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Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians and for Clinical Laboratories

Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%-51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%-60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13-40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

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Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials.

Identifying patients who are at high risk for severe Clostridium difficile–associated disease (CDAD) early in the course of their infection may help clinicians improve outcomes. Therefore, we compared clinical features associated with severe versus nonsevere CDAD by retrospectively reviewing records of hospitalized patients whose fecal assays were positive for C. difficile toxin. Of 336 patients, 12.2% had severe disease and 10.1% died from all causes. Regression modeling showed the following to be significantly associated with severe CDAD (p 70 years (odds ratio [OR] 3.35), maximum leukocyte count >20,000 cells/mL (OR 2.77), minimum albumin level 2 mg/dL (OR 2.47), small bowel obstruction or ileus (OR 3.06), and computed tomography scan showing colorectal inflammation (OR 13.54). These clinical and laboratory markers for severe disease may be useful for identifying patients at risk for serious outcomes or death.

Clinical risk factors for severe Clostridium difficile-associated disease.

https://www.cell.com/cell-host-microbe/pdf/S1931-3128(15)00259-0.pdf

Innate Immune Defenses Mediated by Two ILC Subsets Are Critical for Protection against Acute Clostridium difficile Infection.

Clostridium difficile infection (CDI) is a leading cause of nosocomial infections, with disease severity ranging from mild diarrhea to fulminant colitis. The incidence and severity of CDI has been on the rise over the last 10-20 years, with CDI being increasingly described outside healthcare settings and in populations previously thought to be at low risk. There has also been an increase in the morbidity, mortality and economic burden associated with CDI in the last several years. This increasing incidence and severity is thought to be at least partially due to frequent antibiotic use and the emergence of a hypervirulent C. difficile strain.

The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings.

The purpose of this study was to evaluate risk factors, protective factors, and outcomes associated with Clostridium difficile-associated disease (CDAD) in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. A case-control study was performed with 37 CDAD cases and 67 controls. In the multivariable logistic regression analysis, receipt of a third or fourth generation cephalosporin was associated with increased risk of CDAD (OR = 4.6, 95% CI 1.6-13.1). Receipt of growth factors was associated with decreased risk of CDAD (OR=0.1, 95% CI 0.02-0.3). Cases were more likely to develop a blood stream infection after CDAD than were controls at any point before discharge (p < 0.001). CDAD cases were more likely than controls to develop new onset graft-vs.-host disease (GVHD) (p < 0.001), new onset severe GVHD (p < 0.001), or new onset gut GVHD (p = 0.007) after CDAD/discharge. Severe CDAD was a risk factor for death at 180 d in multivariable Cox proportional hazards regression (HR=2.6, 95% CI 1.1-6.2). CDAD is a significant cause of morbidity and mortality in allogeneic HSCT patients, but modifiable risk factors exist. Further study is needed to determine the best methods of decreasing patients' risk of CDAD.

Clostridium difficile-associated disease in allogeneic hematopoietic stem-cell transplant recipients: risk associations, protective associations, and outcomes.

The purpose of this study was to develop and test a Clostridium difficile-associated disease (CDAD) grading system based on presenting symptoms in allogeneic stem cell transplant recipients. Patients with severe CDAD had significantly shorter median survival times and more adverse outcomes than patients with mild or moderate CDAD.

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Severity of Clostridium difficile-associated disease (CDAD) in allogeneic stem cell transplant recipients : Evaluation of a CDAD severity grading system

disease (CDAD) in allogeneic stem cell transplant recipients: evaluation of a CDAD severity grading system. Infect Control Hosp Epidemiol 2007; 28:208-211. 6. Grundfest-Broniatowski S, Quader M, Alexander F, Walsh RM, et al. Clostridium difficile colitis in the critically ill. Dis Colon Rectum 1996; 39:619-623. 7. Lipsett, PA, Samantaray, DK, Tam, ML, et al. Pseudomembranous colitis: a surgical disease. Surgery 1994; 116:491-496. 8. Medich DS, Lee KK, Simmons RL, Grubbs PE, et al. Laparotomy for fulminant pseudomembranous colitis. Arch Surg 1992; 127:847-852. 9. Koss K, Clark MA, Sanders DS, Morton D, Keighley MR, Goh J. The outcome of surgery in fulminant Clostridium difficile colitis. Colorectal Dis 2006; 8:149-154. 10. Lamontagne F, Labbe AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg 2007; 245: 267-272.

Robert Gatti

Papers

Clostridium difficile-associated disease in allogeneic hematopoietic stem-cell transplant recipients: risk associations, protective associations, and outcomes.

Severity of Clostridium difficile-associated disease (CDAD) in allogeneic stem cell transplant recipients : Evaluation of a CDAD severity grading system

Reply to Jaber et al.