Whipple Disease

Definition

Whipple disease is a rare chronic systemic infection that is caused by Tropheryma whipplei and is characterized by a wide range of symptoms including fever, diarrhea, malabsorption, weight loss, arthralgias, arthritis, central nervous system involvement, lymphadenopathy, and serositis. T. whipplei can also cause asymptomatic infection, acute transient infections, and isolated endocarditis or pneumonia.

Epidemiology

Classical Whipple disease occurs rarely. The incidence is less than 1 per million, and the prevalence is approximately 3 per million in Europe and 10 per million in the United States. In the United States, Whipple disease accounts for about 4 to 5 per million hospitalizations. It is even more rare in Asia and rather unknown in Africa. White middle-aged males appear to be more commonly affected. In a German cohort, for example, 77% of patients were men, and the mean age at diagnosis was 57 years. Humans are the only identified host for T. whipplei . Environmental reservoirs include water and sewage, and humans presumably are exposed through contaminated drinking water. T. whipplei has been identified in human saliva and feces.

Pathobiology

The pathobiology ranges from asymptomatic colonization of the oropharynx and gastrointestinal tracts to disseminated disease. T. whipplei has been identified in macrophages in the small intestine, polymorphonuclear leukocytes, mast cells, plasma cells, and endothelial and epithelial cells. It is likely that bacteria replicate in the digestive system, are phagocytized by macrophages, and then replicate in peripheral blood mononuclear cells and macrophages. Infection of the lamina propria of the small bowel leads to diarrhea, abdominal pain, bloating, malabsorption, and weight loss. Dissemination of the organism through the blood and lymphatic system leads to infection of the central nervous system, lymph nodes, heart valves, lungs, and other organs. Overall, about 2 to 4% of the population are asymptomatic carriers of T. whipplei , a percentage that dwarfs the low estimated prevalence of classical Whipple disease, thereby suggesting that an underlying genetic or immunologic predisposition is likely necessary for an individual to develop classical Whipple disease. Dysfunction of immune cells, including T cells, macrophages, plasma cells, and dendritic cells, is associated with the development of Whipple disease. Multifactorial predisposition towards the development of Whipple disease has been reportedly related to specific human leukocyte antigen (HLA) associations (e.g., DRB1∗13 and DQB1∗6, but not B27) or polymorphisms within certain cytokine genes. Patients with classic Whipple disease have reduced CD4 ⁺ T-cell responses against the organism, thereby leading to multisystem disease.

In classical Whipple disease, uncontrolled bacterial replication and mucosal destruction results in translocation of the bacteria from the gastrointestinal tract into the blood stream, with subsequent development of systemic infection. Pathology demonstrates edematous, thick, flattened, and widened villi of the duodenum and jejunum. On microscopy, yellow lipid deposits are visible, and foamy granular periodic acid–Schiff (PAS)–positive inclusions are seen in the lamina propria. PAS-positive macrophages and T. whipplei nucleic acid (on polymerase chain reaction [PCR] testing) can be detected in many organs, body fluids, and tissues including liver, spleen, lymph nodes, synovium, bone marrow, heart, lung, central nervous system (CNS), and cerebrospinal fluid. Other pathologic manifestations include organomegaly, polyserositis, and CNS demyelination.