Prediagnostic immunosuppressive therapy and clinical outcomes in whipple's disease: a multicenter cohort study

Whipple's disease is a rare systemic infection caused by Tropheryma whipplei that may mimic gastrointestinal and inflammatory disorders, potentially leading to immunosuppressive therapy before recognition of the underlying infection. We evaluated the association between prediagnostic immunosuppressive therapy and short-term clinical outcomes using the TriNetX Global Collaborative Network. Adults with Whipple's disease diagnosed between 2014 and 2025 were stratified by immunosuppressive exposure during the preceding year and matched 1:1 using propensity scores. The primary outcome was 90-day mortality. Among 903 patients, 353 (39.1%) received immunosuppressive therapy before diagnosis. After matching, 288 patients remained in each cohort. Prediagnostic immunosuppression was associated with higher 30-day mortality (9.0% vs 3.8%; OR 2.50, 95% CI 1.22-5.16), intensive care unit admission (17.0% vs 8.7%; OR 2.16, 95% CI 1.29-3.60), and 90-day mortality (10.8% vs 4.5%; OR 2.55, 95% CI 1.31-4.98). Gastrointestinal, constitutional, and inflammatory manifestations were more frequently documented before diagnosis among patients receiving immunosuppression. These findings suggest that prediagnostic immunosuppressive therapy is associated with greater early clinical severity in Whipple's disease and support consideration of this infection before escalating immunosuppression in patients with otherwise unexplained inflammatory and gastrointestinal syndromes.