Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review

Abstract

Background: Clostridium difficile infection (CDI) can lead to complications, recurrence, and death. Numerous studies have assessed risk factors for these unfavourable outcomes, but systematic reviews or meta-analyses published so far were limited in scope or in quality.

Methods: A systematic review was completed according to PRISMA guidelines. An electronic search in five databases was performed. Studies published until October 2013 were included if risk factors for at least one CDI outcome were assessed with multivariate analyses.

Results: 68 studies were included: 24 assessed risk factors for recurrence, 18 for complicated CDI, 8 for treatment failure, and 30 for mortality. Most studies accounted for mortality in the definition of complicated CDI. Important variables were inconsistently reported, such as previous episodes and use of antibiotics. Substantial heterogeneity and methodological limitations were noted, mainly in the sample size, the definition of the outcomes and periods of follow-up, precluding a meta-analysis. Older age, use of antibiotics after diagnosis, use of proton pump inhibitors, and strain type were the most frequent risk factors for recurrence. Older age, leucocytosis, renal failure and co-morbidities were frequent risk factors for complicated CDI. When considered alone, mortality was associated with age, co-morbidities, hypo-albuminemia, leucocytosis, acute renal failure, and infection with ribotype 027.

Conclusion: Laboratory parameters currently used in European and American guidelines to define patients at risk of a complicated CDI are adequate. Strategies for the management of CDI should be tailored according to the age of the patient, biological markers of severity, and underlying co-morbidities.

Figure 1. Flowchart of included and excluded publications.

Figure 2. Forest plots of associations of age, antibiotic use and PPIs with recurrence of CDI.

*Effect of age in deciles in interaction with previous dialysis/chemotherapy. *Non-CDI antimicrobial within 30-days of completing treatment for CDI.

Figure 3. Other risk factors for recurrence of CDI.

* History of recurrence vs. new CDI. ** Modified Horn’s index (3 pts). ∞ Lymphopenia at completion of CDI treatment: Absolute cell count <1.0×10⁹/L. ¥<2.22 ELISA units, adjusted on disease severity. † Elective admission vs. emergency if previous dialysis/chemotherapy (interaction). ◊ History of surgery within 1 month before CDI treatment. MRSA = previous methicillin-resistant Staphylococcus aureus (interaction). VRE = vancomycin-resistant enterococci.

Figure 4. Forest plots of reported associations with complicated CDI: age and co-morbidities or health status.

Figure 5. Forest plots of reported associations with complicated CDI: white blood cells count (WBC) and creatinine levels.

WBC units were converted to the international system unit (10⁹/L). Creatinine levels were converted to the conventional unit using the formula: Creatinine [mg/dL]  =  creatinine/88.4 [µmol/L].

Figure 6. Forest plots of reported associations with treatment failure. *PMC = pseudomembranous colitis.

Figure 7. Forest plots of associations of age and co-morbidities with mortality. (¥≤30-day mortality; § >30-day).

Figure 8. Forest plots of associations of blood tests with mortality.

(¥≤30-day mortality; § >30-day). *Increase in serum urea associated with 28-days and long-term mortality. †Original value: Sodium per 3 mmol/L higher <136; HR = 0.88 (0.83–0.93). **Leucocytosis: WBC≥35×10⁹/L or leucopenia: WBC<4×10⁹/L. ‡Original value: Albumin per 5 g/dL higher; HR = 0.74 (0.71–0.78).

Figure 9. Quality evaluation of included studies (n = 68) according to reported clinical data.