Treated Whipple Disease With Erythema Nodosum Leprosum–Like Lesions: Cutaneous PAS-Positive Macrophages Slowly Decrease With Time and Are Associated With Lymphangiectases

Pathologically, Whipple disease (WD) is characterized by the accumulation of myriad macrophages parasitized by Tropheryma whipplei (TW) bacilli denoted by periodic acid–Schiff (PAS) positivity. These PAS+ macrophages are typically found in the duodenum associated with lymphangiectasia. Recently, we reported the presence of PAS+ macrophages and free TW in erythema nodosum leprosum (ENL)–like lesions and normal skin in a patient with WD who suffered from the immune reconstitution inflammatory syndrome (IRIS). We extend that report by describing the clinical and pathologic findings over 5 years of follow-up. First, the IRIS gradually diminished and abated over 18-month time. Second, at no point did WD recur, and all duodenal and skin biopsies tested by polymerase chain reaction were negative for TW DNA. Third, PAS+ macrophages were identified in 26 of 27 skin biopsies (96%) and decreased along with free TW over time. Fourth, ENL-like lesions had significantly greater numbers of PAS+ macrophages than normal skin. Moreover, normal abdominal skin (region of ENL-like lesions) had greater PAS+ counts than arm skin (not a site of IRIS). Last, lymphangiectases, a histologic sign of lymphostasis, was found in all skin biopsies. Overall, these findings implicate bacillary burden as a factor in the immune tolerance to live TW in active WD and the initiation of ENL-like nodules against dead/nonreplicative TW in treated WD. In addition, poor lymphatic drainage is likely responsible for the gradual clearance of TW from the skin and the impaired delayed-type hypersensitivity reaction (absence of activated macrophages) against TW found in WD, presumptively due to reduced/absent immune cell trafficking necessary for lymphocyte–macrophage interactions and induction of adaptive immunity.