Whipple’s Disease: A Diagnostic Challenge in Patients With Chronic Diarrhea

, is an uncommon multisystem condition. It is frequently underdiagnosed because of its nonspecific and variable symptoms. Early recognition is important, as delays in diagnosis can result in multisystem involvement and potentially serious outcomes. A 74-year-old man experienced chronic diarrhea, weight loss, and fatigue over three months. Initial investigations, including imaging and endoscopy, did not reveal any abnormalities. As symptoms persisted, a repeat endoscopy was performed after one month, showing multiple whitish elevated plaques in the duodenum. Histology identified periodic acid-Schiff and CD68-positive foamy macrophages with negative Ziehl-Neelsen staining, confirming Whipple's disease. The patient was treated with ceftriaxone for two weeks, followed by a year of doxycycline and hydroxychloroquine, leading to rapid clinical remission. Due to ongoing histological changes, antibiotic therapy was continued for another year with trimethoprim-sulfamethoxazole and an additional six months of doxycycline. The patient remains asymptomatic on follow-up. Whipple's disease has clinical features that overlap with other chronic gastrointestinal and rheumatologic disorders, often leading to diagnostic challenges. This case demonstrates the importance of maintaining a high index of suspicion and performing repeat endoscopic evaluation if symptoms continue despite unremarkable initial findings. Timely administration of suitable antibiotic therapy is associated with favorable clinical outcomes, even in cases with prolonged or atypical presentations.