Predicting the Severity of Clostridium Difficile Infection (2011)

We know that vancomycin is superior to metronidazole for the treatment of 'severe' Clostridium difficile infection (CDI).1-3 Furthermore, new therapeutic options may offer advantages to the hitherto 2 main treatment choices for CDI; for example, fidaxomicin reduces the risk of recurrent CDI.4 A key challenge therefore is predicting who should receive which treatment options, especially as not all patients will benefit to the same extent from these, and because there are considerable differences in acquisition costs. Clostridium difficile infection severity has been variably defined, usually retrospectively and sometimes using poorly predictive risk factors (eg, age).1,2,5,6 Recent guidelines advocate using severity markers that are associated with worse outcome (leukocytosis ≥15 ×109/L; serum creatinine ≥1.5× increase above baseline, core body temperature ≥38.5°C, or evidence of colitis) to determine whether metronidazole or vancomycin should be used.7-9 Prospectively validated scoring systems are therefore required to optimize treatment outcomes. In the current issue, Toro et al10 present the results of an interesting prospective study that aimed to validate a 9-point Severity Score Index (SSI), measured at the time of CDI diagnosis. The SSI had previously been shown in a retrospective analysis to be significantly associated with mortality risk.11 The patient sample size (n = 54) was very modest, and only 4 subjects (all of whom died) were classified by the authors as having severe CDI (SSI = 7-9). Nevertheless, higher SSI scores were significantly associated with the need for intensive care unit care and risk of death. It is interesting to note that the Charlson Comorbidity Index score12 did not correlate with CDI severity, although a Charlson Comorbidity Index of 2 or greater was associated with mortality (P = 0.0001). Twenty (37%) of 54 subjects died within 90 days of CDI diagnosis, which implies that the population under study was reflective of typical hospitalized CDI cohorts; that is, subjects had significant comorbidities and/or severe infection and a high average age (∼77 years). There are some clear weaknesses to the study by Toro et al. A major omission is that insufficient details are given of specifically who received which CDI treatment options, and thus we cannot assess whether treatment was adequate (at least according to current guidelines). It therefore remains unclear whether inadequate treatment (eg, therapeutic agent, dose, duration, timing of onset) could have been responsible for some cases with poor outcome. Furthermore, the authors state that SSI criteria were recorded "if present 48 hours before or after a positive toxin A/B test result." Treatment decisions may of course be made before 48 hours have elapsed following a laboratory test result for CDI. Also, some of the criteria are not rigorously defined. For example, "altered mental status" was assessed by comparing the baseline and current patient's mental status by the primary care physician. Clear, objective criteria are needed to enhance reproducibility of severity scoring. One of the SSI criteria was need for intensive care unit care; this may effectively be a part-fulfilling prophecy when predicting severe CDI. The authors' attempt to justify why a measure of renal function was not used as a severity criterion (ie, difficulty in determining the cause of renal impairment) is not convincing, especially as this argument could be used in respect of many of the other SSI parameters. Toro et al found that decreased albumin (54%) and white cell count greater than 20 × 109/L (or <1.5 × 109/L or raised proportion of band forms) (46%) were the most commonly found SSI criteria; conversely, fever (18%) was uncommon, as has been shown previously,13 and thus may be relatively redundant in the SSI score. No single parameter is highly predictive of severe CDI, with the possible exception of very high blood leukocyte counts.14-16 Of 400 patients with leukocytosis of 15 × 109/L or greater, infection was documented in 207, and 16% of these had CDI.15 Excluding those with hematologic malignancy, a quarter of patients with leukocytosis 30 × 109/L or greater had CDI. Zar et al1 used a severity score based on age (>60 years), leukocytosis (>15 × 109/L), temperature (>38.3°C), albumin (<25 g/L), endoscopy findings, and admission to an intensive therapy. Patients with severe CDI were significantly less likely to respond to metronidazole versus vancomycin. Louie et al2 used number of stools, leukocytosis, and abdominal pain to define severe CDI in clinical trials of tolevamer. Clostridium difficile infection was scored as mild, moderate, or severe in 25%, 41%, and 34% of cases, respectively. Alternatively, a score based on fever (≥38.0°C), ileus, low systolic blood pressure (<100 mm Hg), leukocytosis (≥15 × 109/L), and CT scan findings was used to determine the likelihood of response to metronidazole.6 The mean score was significantly higher for nonresponders versus responders (P < 0.0001). Interestingly, Toro and colleagues did not use diarrhea frequency in their SSI score. Definitions of severe CDI based on diarrhea frequency are prone to interpretation difficulties; for example, in elderly individuals with fecal incontinence, in confused patients, or when (overflow) diarrhea occurs because of, or following treatment for, constipation. Furthermore, patients with life-threatening CDI and colonic dilatation or toxic megacolon may have ileus and no diarrhea. Indeed, ileus is associated with poor response to metronidazole.6 Others have found no clear correlation between diarrhea frequency and CDI severity,13 and this underscores why current guidelines do not rely on diarrheal frequency to determine disease severity.7-9 The study of Toro et al is a step forward as it shows that the SSI score has the potential to predict severe CDI. Corroborative data from other institutions, examining larger numbers of patients and taking into account possible treatment bias, are needed. Data from different settings are needed because the incidence of CDI severity criteria may vary according to the prevalence of specific C. difficile strains, in particular ribotype 027, which is associated with poor outcome.9,17 Similarly, as host factors can influence CDI severity, some cohorts may have worse outcomes. For example, endoscopy and cognitive impairment were independent predictors of severe CDI in predominantly elderly patients.18 Last but not least, sensitivity analyses should be performed to determine which of the measurement s available at the time of CDI diagnosis (or suspicion of infection) are most predictive of outcome and so crucially can be used to optimize therapeutic response. In the ideal world, the chosen criteria can be used to monitor treatment response and so indicate when adjunctive or switched therapy is required. An earlier study noted that 26 of 30 symptomatic CDI patients had a "prompt" reduction in leukocytosis following antibiotic treatment.16 We are entering an era of increasing therapeutic choice for CDI.4 We owe it to our patients to use the increasing CDI armamentarium wisely, and highly predictive scoring systems will be a valuable tool to achieve this.