Leukocytosis Is Not an Independent Predictor of Clostridium Difficile

Researchers reviewed data of 16,568 consecutive patients from 4 hospitals over 4 years to determine if leukocytosis correlated with a positive C difficile NAAT results.

Although leukocytosis is a prognostic marker in patients with Clostridium difficile (C difficile) infection, it is not an independent predictor of a positive nucleic acid amplification test (NAAT) result for hospitalized patients, according to study results published in Clinical Infectious Diseases.

In this retrospective, cross-sectional study, researchers reviewed data of 16,568 consecutive patients from 4 hospitals over 4 years to determine if leukocytosis correlated with a positive C difficile NAAT results. Leukocytosis was defined as an elevated white blood cell count (WBC) that was greater than 15 thousand/µL. All patients had WBC and NAAT testing on the same day.

The majority of patients were men with a median age of 60 years; 74% (n=12,290) were inpatients, 15% (n=2507) were outpatients, and 11% (n=1771) were in the emergency department (ED). A total of 1681 patients were diagnosed with C difficile and the remaining 14,887 tested negative for C difficile.

WBC was not predictive of C difficile status between patients in the NAAT-positive vs NAAT-negative groups. Furthermore, NAAT positivity rates were similar for patients with and without leukocytosis (11% vs 10%, respectively).

A receiver-operator characteristic curve analysis found no difference in WBC among NAAT-positive and NAAT-negative inpatients. However, WBC was statistically higher in NAAT-positive patients among outpatients and patients in the ED with limited predictive value (area under the curve, 0.59 and 0.56, respectively).

In a subgroup analysis stratified to the presence or absence of various C difficile-related clinical factors (diarrhea, abdominal pain, fever, positive bacterial culture, prior antibiotic exposure, and other diagnosis associated with leukocytosis), WBC was not predictive of a positive NAAT result in any hospitalized patients.

However, in a subset of outpatients and patients in the ED (n=1084), WBC predicted a positive NAAT result with a receiver-operator characteristic area under the curve of 0.63 (95% CI, 0.57%-0.69%) for the following 3 clinical features: diarrhea, negative or no bacterial culture, and absence of antibiotic exposure within 4 weeks. Within this subset, NAAT positivity rates were 16% in those with leukocytosis and 9% in those without leukocytosis.

Consistent with prior studies, hospitalized patients with a high WBC and positive NAAT result “had longer inpatient stays and higher likelihood of in-hospital death, despite a higher probability of being treated with metronidazole or vancomycin,” noted the study authors. At the same time, compared with inpatients with low WBC, inpatients with a high WBC and negative NAAT result had higher stool frequency (P <.001), a longer length of hospital stay (19 vs 10 days; P <.001), and higher mortality (relative ratio, 1.9; 95% CI, 1.7%-22%; P <.001).

Thus, regardless of C difficile status, patients with leukocytosis have adverse prognosis, the study authors stated.

Leukocytosis not only had low specificity, considering that leukemoid reaction was not specific to C difficile infection, it also had low sensitivity, since 46% of patients with a positive NAAT result had WBC within the normal range. “Leukocytosis is not an independent predictor of C difficile NAAT status, particularly among inpatients, and should not be used in isolation as a justification for C difficile testing,” concluded the study authors.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Bosch DE, Mathias PC, Krumm N, Bryan A, Fang FC, Greninger AL. Elevated white blood cell count does not predict Clostridium difficile nucleic acid testing results. Clin Infect Dis. Published online February 10, 2021. doi:10.1093/cid/ciab106