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Whipple’s disease

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Whipple’s disease is a rare multisystemic infectious disorder affecting predominantly middle-aged men. Clinical manifestations are very variable with a very long, insidious, prediagnostic course. Weight loss, chronic diarrhea, arthralgias, and low-grade fever are characteristic features in most patients. Although gastrointestinal compromise is very common, atypical clinical forms are being increasingly recognized. Although a bacterial cause was strongly suggested for many years, the infectious agent was elusive until recently. The bacillus that was classified as an actinomycete was named Tropheryma whipplei and has singular characteristics. It presents affinity for the periodic acid-Schiff stain, but it is negative for Ziehl-Neelsen staining and has a characteristic trilamellar cell wall. Its genetic material has been recently sequenced, and culture was finally performed on a human fibroblast cell line. Pathological specimens show macrophage infiltration with mostly intracellular invasion of live bacteria. Immunologic factors, such as a subtle defect of cellular immunity possibly specific for the Whipple’s bacterium, are believed to play a role in pathogenesis. The diagnosis requires the histologic assessment of diseased tissue, showing the characteristic infiltration, as a first approach, and confirmatory tests such as electron microscopy and/or polymerase chain reaction. Antibiotic treatment is mandatory and leads to a rapid clinical improvement and remission in most patients. Although the rationale for treatment is largely empiric, current recommendations include a 2-week parenteral therapy (third generation cephalosporin) followed by a long-term therapy with trimethoprim-sulphamethoxazole. This approach has been shown to reduce the number of relapses and was effective for prevention and/or treatment of the neurologic compromise.

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Epidemiology

Current epidemiologic information about WD is still very limited. In this context, Dobbins3 published an outstanding clinical and epidemiologic analysis based on the largest number of cases (n = 696) collected from his own observation, data from cases published in the English language literature (case reports and small series), and a series of nonpublished patients. The substantial information provided by the review clearly showed that the disease predominantly occurs in men (86% of cases),

Clinical manifestations

The clinical features of WD are protean, involving mainly the gatrointestinal tract, but also producing manifestations in other systems according to their pathological compromise.14 Although the clinical severity is usually associated with a multiorgan involvement, there is general consensus that more organs are involved than is suggested by clinical symptoms. Table 1 summarizes the most common symptoms and signs at the time of diagnosis of patients. There is a triad characteristic of WD:

Pathogenesis

A recently identified infectious agent causes WD. There is some evidence suggesting that a series of immunologic and nonimmunologic deficiencies detected in patients seem also to be necessary. Malabsorption is often present in patients with intestinal involement and has been associated with lymphatic obstruction from lacteal compression in lamina propria and lymph nodes, and with suspected epithelial dysfunction.

Host immunologic and nonimmunologic defects

WD disease is a systemic disorder in which the possibility of a defective immune response has been raised.52 There are still key questions. Do these abnormalities precede the infection, or are they a consequence of the nutritional compromise? Are these immunologic defects nonspecific alterations, or are they specifically directed against the T. whipplei? Contradictory immunologic findings have been reported. A genetic predisposition was formerly suggested on the basis of the high prevalence of

Clinical suspicion of Whipple’s disease

In general, the onset of WD is insidious, and it often takes several years until overt disease is present and a definitive diagnosis can be made. Very often, polyarthralgias and low-grade persistent fever are the main or only symptoms detected during the prediagnostic period.3, 8 On the other hand, a characteristic of the natural history of the disease before treatment is a chronic relapsing course in a high proportion of patients. Even though most patients have severe clinical compromise,

Treatment

The therapeutic goal in all patients with WD is to eradicate the infection and to avoid relapses. Until the 1950s, the disease was incurable, and most patients died of the disease.8 Paulley34 was the first to report the successful treatment of WD with the use of chloramphenicol and opened a new era in the understanding of the pathogenesis and treatment of the disease. Since then, a variety of antibiotics and different schedules were successfully used. Thus, patients have shown rapid improvement

Conclusions

WD is an extremely interesting infectious systemic disorder. The increased attention to this condition in recent years has led to a greater understanding and awareness of the disease by the medical community. Classic patients have predominantly gastrointestinal manifestations. Extraintestinal manifestations are protean, and when not associated with intestinal symptoms, the diagnosis might be difficult. The diagnosis of WD often requires endoscopic biopsy of the duodenal mucosa showing the

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