What is the cause of persistent diarrhea with stool white blood cells (WBCs) positive, but bacteral pathogen panel negative and C. difficile (Clostridium difficile) toxin testing negative?

From the Guidelines

For persistent diarrhea with positive stool white blood cells but negative bacterial pathogen panel and C. difficile testing, I recommend a trial of empiric antibiotic therapy with ciprofloxacin 500mg twice daily for 5-7 days or metronidazole 500mg three times daily for 7-10 days, as suggested by the most recent guidelines 1. This presentation suggests inflammatory diarrhea despite negative specific pathogen testing, which could be due to pathogens not included in standard panels or those requiring special culture techniques. Before starting antibiotics, consider additional stool tests including ova and parasites examination, particularly for Giardia and Entamoeba histolytica, as well as testing for other organisms such as Cryptosporidium, Cyclospora, and Cystoisospora, especially in immunocompromised patients 1. Also, consider inflammatory bowel disease as a potential cause, especially if symptoms persist beyond 2-4 weeks, and evaluate for other possible causes of chronic diarrhea, such as small bowel bacterial overgrowth, bile acid malabsorption, and disaccharidase deficiency 1. Maintain hydration with electrolyte solutions and consider loperamide 2mg after each loose stool (maximum 8mg/day) for symptom control, but avoid anti-motility agents if you suspect invasive bacterial infection with fever or bloody diarrhea. If symptoms don't improve with empiric therapy, further evaluation with colonoscopy may be necessary to rule out inflammatory bowel disease or microscopic colitis. The presence of white blood cells in stool indicates inflammation in the intestinal mucosa, which can be caused by infectious or non-infectious inflammatory conditions. Some key points to consider in the diagnosis and management of persistent diarrhea include:

• Testing for bacterial pathogens, including Salmonella, Shigella, Campylobacter, Yersinia, and STEC, as well as C. difficile toxin 1
• Considering a broader set of bacterial, viral, and parasitic agents in the context of a possible outbreak of diarrheal illness or in immunocompromised patients 1
• Evaluating for other possible causes of chronic diarrhea, such as small bowel bacterial overgrowth, bile acid malabsorption, and disaccharidase deficiency 1
• Maintaining hydration and considering symptom control with loperamide or other anti-diarrheal agents, while avoiding anti-motility agents in certain situations.

From the Research

Possible Causes of Persistent Diarrhea

• The presence of stool white blood cells (WBCs) positive, but bacterial pathogen panel negative and C. difficile (Clostridium difficile) toxin testing negative may indicate a non-bacterial cause of diarrhea 2, 3.
• Some studies suggest that C. difficile infection can be present even with a negative toxin test, especially if the test is not sensitive enough 4.
• However, the absence of C. difficile toxin in the stool does not rule out the possibility of other infectious or non-infectious causes of diarrhea 5, 6.

Diagnostic Considerations

• The diagnosis of C. difficile infection is typically based on the combination of clinical symptoms and a positive stool test for C. difficile toxins or endoscopic or histological findings of pseudomembranous colitis 2.
• The enzyme immunoassay (EIA) for toxin A, toxin B, or both is a commonly used test, but it may have limited sensitivity and specificity 4.
• Other diagnostic tests, such as the cell culture cytotoxin assay, may be more sensitive and specific, but are not always available 4.

Treatment Considerations

• The treatment of C. difficile infection typically involves cessation of the provoking antibiotic treatment, secondary prevention by infection control strategies, and treatment with metronidazole or vancomycin 2, 3.
• However, if the C. difficile toxin testing is negative, other causes of diarrhea should be considered and treated accordingly 5, 6.