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Culture of Tropheryma whipplei, the agent of Whipple disease (WD), was achieved in our laboratory in 2000, allowing new perspectives for the diagnosis of this disease and for the description of other potential clinical manifestations caused by this microorganism. Since 2000, we have developed new tools in our center in Marseille, France, to optimize the diagnosis of T whipplei infections. Classic WD was characterized by positive periodic acid-Schiff performed on duodenal biopsy. In the absence of duodenal histologic involvement, localized infections were defined by specific positive T whipplei polymerase chain reaction (PCR) results obtained using samples of other tissues and body fluids. The physicians in charge of patients were asked to complete a questionnaire. A total of 215 diagnoses were performed or confirmed and, among these, 142 patients with sufficient clinical data were included.Herein, we report epidemiologic data, clinical manifestations, and diagnostic tools of T whipplei infections. In the 113 patients with classic WD, the main symptom was arthralgia (88/113, 78%), which explains the many cases misdiagnosed as inflammatory rheumatoid disease (56/113, 50%). Frequently immunosuppressive treatments, more recently including tumor necrosis factor inhibitor, had been previously prescribed (50%) and were often responsible for more rapid clinical progression (43%). Sometimes a short course of antibiotics improved the clinical status.Endocarditis was the second most frequent manifestation of T whipplei, with 16 cases. The clinical picture of this entity corresponds to cardiovascular involvement with acute heart failure (50%) occurring without fever (75%) or previous valvular disease (69%). Neurologic symptoms were the third major manifestation. Other localized infections such as adenopathy, uveitis, pulmonary involvement, or joint involvement were sporadic. Infection with T whipplei resulted in multifaceted conditions. Some localized infections due to this agent have recently been reported and may correspond to emerging entities. Patients with inflammatory rheumatoid disease must be systematically interviewed to determine the efficacy of previous immunosuppressive and antibiotic therapies.