A new piece added to the puzzle describing the natural history of Whipple disease. A, Interhuman transmission likely takes place through fecaloral contamination. However, infection might also possibly follow exposure to human saliva and/or aerosols or be associated with yet unknown environmental or zoonotic risks. B, Primary infection might be asymptomatic but may also present as a febrile illness associated with cough and sleep disorders, as demonstrated by Fenollar et al. in this issue [17]. This additional piece added to the Whipple puzzle also supports previous reports that suggest a role of T. whipplei as an agent of pneumonia [18, 19]. Nevertheless, primary infection might also present as a common gastroenteritis [15] and some yet unknown additional syndromes. C, Only a limited number of patients will later develop focal or multifocal clinical manifestation of late-onset Whipple disease. Immunogenetic factors are likely important in this rare pathological evolution [23]. Please note that the list of manifestations provided here is not exhaustive. Focal manifestations such as prodromal arthritis may precede classic multifocal Whipple disease for years. D and E, Most infected patients would either became asymptomatic carriers or completely recover from T. whipplei primary infection. Whether asymptomatic carriers are at risk to later develop clinical manifestations of focal or multifocal late-onset Whipple disease is yet unknown.