Clostridial Difficile and Leukocytosis

Introduction

• Clostridioides difficile (formerly referred to as Clostridium difficile) is a spore-forming, toxin-producing anaerobic bacteria that may colonize or infect the colon, typically after the normal gut flora has been disrupted (frequently in association with antibiotic therapy).¹
• C. difficile was identified as the major agent of antibiotic-associated colitis in 1978, accounting for 15% to 25% of cases.²
• C. difficile is a leading cause of healthcare-associated infections worldwide.³
• Between 2001 and 2012, there was an increase in the annual C. difficile infection (CDI) incidence of 43%.⁴
• Surveillance data from 2011 estimated the number of CDI in the United States to be 453,000 annually, with nearly 14,000 deaths directly attributable to the infection.⁵
• CDI can cause a spectrum of manifestations ranging from an asymptomatic carriage to fulminant disease with toxic megacolon.
• Initial presentation can be fulminant and rapidly fatal, and assessment of severity is key to management.
• CDI is associated with a “particularly high leukocyte count”.⁶
• CDI-associated leukocytosis is used to inform:
  • Severity of disease
  • Treatment:
    • Admission to hospital
    • Antibiotics, especially duration
    • Surgical consultation
  • Prognosis

Pathophysiology

• Toxin A, which is largely responsible for fluid accumulation in rodent loop assays, initiates an inflammatory response in the colon that is thought to be responsible for the peripheral leukocytosis as well as other common features such as fever and cramps.⁷

Diagnosis

• Diagnosis of CDI is based on a combination of clinical and laboratory findings:⁸
  • Suspect diagnosis Symptoms usually include diarrhea (defined as ≥ 3 unformed stools in a 24-hour period) except in severe cases with ileus.
  • Confirm diagnosis by positive stool testing for C. difficile, or colonoscopic or biopsy findings consistent with pseudomembranous colitis.

Risk factors for severe disease:

• Risk factors for severe disease include:⁹
  • Older age (> 65 years old)
  • Use of antimotility agents
  • Underlying comorbidities
  • Acute or chronic kidney injury
  • Altered mental status
  • Fever
  • Hypotension
  • Severe abdominal pain or distention
  • ≥ 10 episodes of diarrhea daily
  • Leukocytosis
  • Hypoalbuminemia
  • Ascites
  • Ileus
  • Presence of pseudomembranes
• Risk scoring system (RSS) for daily clinical practice:¹⁰
  • Score included:
    • Age greater than 70 years – 2 points
    • White blood cell counts equal to or greater than > 20,000/μL or equal to or less than 2000/μL – 1 point
    • Cardiorespiratory failure – 7 points
    • Diffuse abdominal tenderness on physical examination – 6 points.
  • A value of 6 points was determined to be the threshold for reliably dividing low-risk (< 6) from high-risk (≥ 6) patients. Only patients with cardiorespiratory failure or diffuse abdominal tenderness were high risk.
• Sailhamer et al, 2009:
  • 4796 inpatients diagnosed with C. difficile colitis.
  • In 199 patients (4.1%) with fulminant CDI, the in-hospital mortality rate was 34.7%.
  • Independent predictors of mortality included:
    • Age of 70 years or older
    • Severe leukocytosis or leukopenia (white blood cell count, ≥35 000/μL or <4000/μL) or bandemia (neutrophil bands, ≥10%)
    • Cardiorespiratory failure (intubation or vasopressors
• 2009 European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance document for Clostridium difficile infection (CDI):¹¹
  • Clinical pictures compatible with CDI:
    • Diarrhea
    • Ileus :
    • Toxic megacolon :
  • Signs of severe colitis:
    • Fever (core body temperature > 38.5C)
    • Rigors
    • Hemodynamic instability including signs of septic shock
    • Signs of peritonitis
    • Signs of ileus
    • Marked leukocytosis (leukocyte count > 15 · 10⁹/L)
    • Marked left shift (band neutrophils > 20% of leukocytes)
    • Rise in serum creatinine (>50% above the baseline)
    • Elevated serum lactate
    • Pseudomembranous colitis (endoscopy)
    • Distension of large intestine (imaging)
    • Colonic wall thickening including low-attenuation mural thickening (imaging)
    • Pericolonic fat stranding (imaging)
    • Ascites not explained by other causes (imaging)
• Wilcox et al, 2012:
  • 1105 patients with CDI
  • Leukocytosis (risk ratio [RR], 2.29; 95% confidence interval [CI], 1.63-3.21) and renal failure (RR, 2.52; 95% CI, 1.82-3.50) were associated with treatment failure.
  • Fever, although associated with treatment failure (RR, 2.45; 95% CI, 1.07-5.61), was rare.
  • Renal failure was the only significant predictor of recurrence (RR, 1.45; 95% CI, 1.05-2.02).
  • Different timing of measurements of leukocyte count and serum creatinine level around the CDI diagnosis led to a different severity classification in many cases.
  • Conclusion: both leukocytosis and renal failure are useful predictors, although timing of measurement is important.
• NICE definitions of severity of CDI:
  • Mild infection: not associated with an increased white cell count (WCC). Typically associated with fewer than 3 episodes of loose stools (defined as loose enough to take the shape of the container used to sample them) per day.
  • Moderate infection: associated with an increased WCC (but less than 15 × 10⁹ per litre). Typically associated with 3 to 5 loose stools per day.
  • Severe infection: associated with a WCC greater than 15 × 10⁹ per litre, or an acutely increased serum creatinine concentration (greater than 50% increase above baseline), or a temperature higher than 38.5 degrees Celsius, or evidence of severe colitis (abdominal or radiological signs). The number of stools may be a less reliable indicator of severity. Life-threatening infection: symptoms and signs include hypotension, partial or complete ileus, toxic megacolon or CT evidence of severe disease.
• UpToDate:
  • Proposed criteria for disease severity (based on expert opinion) include:
    • Nonfulminant disease:
      • Nonsevere CDI – White blood cell count ≤15,000 cells/microL and serum creatinine <1.5 mg/dL:
      • Severe CDI – White blood cell count >15,000 cells/microL and/or serum creatinine ≥1.5 mg/dL:
    • Fulminant colitis (previously referred to as severe, complicated CDI) – Hypotension or shock, ileus, or megacolon:
• ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections:

Cohorts

• Bulusu et al, 2000:
  • 70 hospitalized patients who presented with diarrhea of variable severity and who underwent stool examination for enteric pathogens, including C. difficile
  • Leukocytosis was common in C. difficile-positive patients, compared to in C. difficile-negative patients (mean 15,800/mm3 vs 7700/mm3, p < 0.01).
  • Review of the 35 C. difficile-positive patients revealed three patterns:
    • Pattern A: sudden WBC increase coinciding with the onset of symptoms suggestive of C. difficile.
    • Pattern B: unexplained leukocytosis preceding the appearance of C. difficile-related diarrhea and serving as a harbinger of the infection
    • Pattern C: worsening of pre-existing leukocytosis as a surrogate marker of C. difficile infection. Treatment with metronidazole led to amelioration of symptoms and normalization of the leukocyte count in all cases.
  • Conclusions: Infection with C. difficile should be considered in the differential diagnosis of sudden onset of leukocytosis in hospitalized patients previously or concurrently treated with antibiotics. Doing so may obviate the need for expensive and time-consuming tests for other etiologies.
• Wanahita et al, 2003
  • 60 patients with unexplained leukocytosis (white blood cell count > or =15,000/mm3).
  • Thirty-five (58%) of the patients with unexplained leukocytosis had C. difficile toxin in at least one fecal specimen as compared with 3 (12%) of the controls (P <0.001).
  • Symptoms of colitis were often mild or absent at the time the white blood cell count was first elevated or, if present, had not been recognized by the attending physicians.
  • Leukocytosis resolved promptly in most patients who were treated with metronidazole. In the 25 patients (42%) who had a negative test for C. difficile toxin, leukocytosis also tended to resolve during empiric therapy with metronidazole; some of these patients may have had C. difficile infection.
  • Conclusion: The majority of patients in our hospital who had unexplained leukocytosis had C. difficile infection. Unexplained leukocytosis in hospitalized patients should prompt a search for symptoms and signs consistent with C. difficile infection and a study to detect C. difficile. Empiric therapy with metronidazole may be effective in the appropriate epidemiologic setting.
• Marinella et al, 2004:
  • Retrospective case series analysis of patients with a positive fecal assay for C difficile toxin and a peak leukocyte count greater than 35 x 10⁹/L.
  • Twenty cases that met these criteria were compared with 65 randomly selected control patients (patients with a positive C difficile toxin and a peak leukocyte count less than 35 x 10⁹/L.
  • The mean peak leukocyte count was:
    • 52 +/- 18.2 x 10⁹/L in the case group
    • 14.9 +/- 6.5 x 10⁹/L in the control group
  • Patients with a leukemoid reaction had:
    • Lower temperature,
    • Lower serum albumin level
    • Higher hematocrit value
  • Multivariable logistic regression showed respiratory tract infection and lower temperature to be independent predictors of a leukemoid reaction.
  • There were 10 deaths (50%) in the leukemoid reaction group and 5 deaths (7.7%) in the control group. All seven patients with a peak leukocyte count greater than 50 x 10⁹/L died, compared with eight deaths (10.3%) among the remaining 78 patients whose peak leukocyte count was less than 50 x 10⁹/L.
• Portich and Faulhaber, 2021:
  • Retrospective cohort study between January 2016 and July 2018 > 18 years with a total leukocyte count>50 cells×10⁹/L.
  • Only 2 patients had C. difficile.
• Teja et al, 2021:
  • Clostridioides difficile (formerly Clostridium difficile) infection was present in 15.0% (95% CI, 12.1–18.3%) of patients with extreme leukocytosis and diarrhea and that mortality for those with CDI, diarrhea, and extreme leukocytosis was 33.8%.
  • Conclusions: These data support consideration of empiric treatment for CDI in unstable critically ill patients with extreme leukocytosis and diarrhea, along with treatment of other possible sources of sepsis as appropriate. Empiric treatment for CDI can usually be discontinued promptly, along with narrowing of other broad-spectrum antimicrobial coverage, if a sensitive C. difficile test is negative.

Treatment

• UpToDate:
  • Nonfulminant disease:
    • Nonsevere CDI:
      • Most patients with mild CDI can be managed in the outpatient setting.
      • For patients with an initial episode of nonsevere CDI, appropriate treatment regimens include either oral fidaxomicin or oral vancomycin.
      • The duration of initial antibiotic therapy for treatment of nonsevere CDI is 10 days
    • Severe CDI:
      • Hospitalization should be considered in patients with severe CDI or in any patient who is frail, shows signs and symptoms of dehydration (eg, low blood pressure, orthostasis, poor urinary output), or who have poor social support and may not be able to call for help if symptoms worsen.
      • For patients with an initial episode of severe CDI, we suggest oral fidaxomicin over oral vancomycin
      • The standard duration of antibiotic therapy (with either vancomycin or fidaxomicin) for an initial CDI episode is 10 days; however, the duration of the antibiotic course should be individualized for patients with severe disease depending on response to therapy and clinical course.
  • Fulminant colitis (previously referred to as severe, complicated CDI):
    • All patients with fulminant CDI should be admitted immediately.
  • Early surgical consultation is warranted for patients with CDI who meet one or more of the following clinical indicators that have been associated with poor prognosis:
    • Hypotension
    • Fever ≥38.5°C
    • Ileus or significant abdominal distention
    • Peritonitis or significant abdominal tenderness
    • Altered mental status
    • White blood cell count ≥20,000 cells/microL
    • Serum lactate levels >2.2 mmol/L
    • Admission to intensive care unit
    • End organ failure (eg, requiring mechanical ventilation, renal failure)
    • Failure to improve after three to five days of maximal medical therapy