Lymphadenitis caused by infection with the bacterium Tropheryma whipplei.

The incidence of Whipple disease is low (1). Only 1,000 cases were reported by 1987 and less than 0.1% in autopsy studies (1,2,3). It occurs throughout the world, however, the majority of reported cases are in white men with a mean age of 50 years (1,2). The typical rDNA sequence has been also detected in persons without clinical or histologic evidence of the disease, which may indicate that the agent is ubiquitous, inducing lesions only in hosts with a particular susceptibility (3,4).

T. whipplei, a rod-shaped, silver-stained bacillus, presently classified with the actinomycetes, was demonstrated in 1991 (5) to be the agent of the disease described in 1907 by George Whipple as intestinal lipodystrophy (6). Earlier efforts to culture this organism failed, and the bacterium was finally identified only through a molecular genetic approach. Thus, its unique 16S ribosomal DNA gene sequence was amplified directly by the polymerase chain reaction (PCR) from the involved tissues of patients with Whipple disease (7). Recently, T. whipplei isolated from the aortic valve of a patient with endocarditis was cultured and successfully passaged in a human fibroblast cell line (8). The same authors developed an immunofluorescence serologic test. Subsequently, more strains of T. whipplei were isolated from blood, synovium, lymph nodes, and stool (9). The bacterium is present in the general environment. PCR studies have detected it in human stool and sewage plant effluent (10,11). An association with Giardia lamblia has been reported and it may be acquired by fecal-oral transmission (9,10,11,12).

The unique cell wall structure of the bacillus T. whipplei attracts macrophages that engulf and degrade it; as a result, inclusions that stain with periodic acid–Schiff (PAS) can be seen in prepared tissues (13). Macrophages containing the diastase-resistant, PAS-positive inclusions infiltrate the lamina propria of the gastrointestinal tract, but may also involve the mesentery, lymph nodes, joints, testis, heart, central nervous system (CNS), and nearly every other organ system (7,14,15,16,17). The bacterium does not form hyphae in human tissues; however, like other actinomycetes, it is gram-positive and PAS-positive (4,7). Whether the infection is acquired primarily or exclusively through the gastrointestinal tract is not clear (4). The patients appear to have predisposing factors, particularly deficient immune functions such as decreased interleukin 12, CD 11b, and interferon levels (3).

Whipple disease is an uncommon, chronic, relapsing, multisystem illness. The largest study published includes 29 patients seen at the Mayo Clinic during a 30-year period (18). The main symptoms are fever, diarrhea, and weight loss. The major syndrome is that of malabsorption, expressed by significant weight loss in 90% of patients. The usual radiographic pattern is one of prominent and edematous jejunal folds, consistent with malabsorption and extensive paraaortic and mesenteric lymphadenopathy. Arthritis, endocarditis, and uveitis may also occur, as well as CNS involvement expressed by headache, diplopia, ataxia, and dementia sometimes with permanent sequelae (3,15,16,17). On physical examination, the most frequent abnormalities are lymphadenopathies involving predominantly the axillary and cervical lymph nodes (19,20). Cases of Whipple disease with peripheral lymphadenopathy as primary presentation were reported (18,19,20). Hepatomegaly and generalized hyperpigmentation may also be present (2,14). Before the introduction of antibiotic treatment, the disease usually ended in death. A variety of antibiotics, singly or in combination, are now used, but even with proper treatment, relapses may occur. Treatment for at least a year is recommended, including antibiotics that readily cross the blood–brain barrier to prevent CNS complications (3,12). Recently, a case of chronic wasting illness accompanied by massive abdominal lymphadenopathy was reported in a veteran of the Persian Gulf war. A lymph node biopsy indicated a diagnosis of Whipple disease; however, the epidemiologic significance of this isolated case is unclear (21). Equally interesting is a case report of a 55-year-old woman with arthralgia, weight loss, and lymphadenopathies. T. whippleii bacilli were identified in the duodenum and in mesenteric and axillary lymph nodes. At the same time, a κ-restricted monoclonal B-cell population was detected in the lymph nodes, peripheral blood, and bone marrow, raising the possibility of a B-cell lymphoma with a Helicobacter pylori-type pathogenesis induced by the T. whippleii infection (22).