Toxic Megacolon With a Positive Clostridioides difficile Antigen but Negative Toxin Assay

The diagnosis of <i>Clostridioides difficile</i> infection (CDI) relies on a combination of clinical presentation and laboratory testing. However, a critical diagnostic discordance occurs when laboratory results contradict a rapidly evolving clinical picture. This is a case of a 78-year-old man with four comorbidities who presented with watery diarrhea and a <i>C. difficile</i> screen-positive but toxin-negative stool sample. His main risk factors included advanced age and the prolonged use of a proton pump inhibitor. Despite his initial negative toxin assay, his condition progressively worsened over three days following his admission, with the development of toxic megacolon, diagnosed clinically and radiologically. This report synthesizes evidence on the limitations of toxin enzyme immunoassays in severe CDI, contextualizing a well-documented, but dangerously overlooked, phenomenon where test sensitivity fails in the sickest patients. This case highlights the imperative to treat the patient, not the lab result, when clinical and radiological evidence suggests fulminant disease.