The pathogenesis of T. whippelii infection is poorly understood; immune defects involving T cells and macrophages have been described [8-12]. Recently, reduced interleukin-12 and interferon- production in patients with Whipple disease has been detected [13]. These cytokines may be important in this context because of their ability to contain and clear intracellular bacteria [14, 15]. Therefore, we tested the usefulness of antibiotic therapy supplemented by interferon- in treating a patient with a 10-year history of antibiotic-resistant Whipple disease.

Case Report

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In 1985, Whipple disease was diagnosed by periodic acid-Schiff (PAS)-positive macrophages in the duodenal biopsy specimen of a 66-year-old patient. The patient had a 10-year history of diarrhea and weight loss and was continuously treated with antibiotics to eradicate the bacterium. However, the patient had seven relapses despite this therapy. Duodenal biopsy results remained positive on testing for T. whippelii-specific DNA, PAS staining, and electron microscopy. In 1995, although the patient had no neurologic symptoms, involvement of the central nervous system was documented by the presence of T. whippelii-specific DNA and PAS-positive cells in the cerebrospinal fluid (Table 1). At this time, both in vivo and in vitro evidence of deficient T-cell function was detected. Testing of cutaneous delayed hypersensitivity with seven recall antigens (Multitest Merieux, Institut Merieux GmbH, Leimen, Germany) yielded abnormal results; only two responses were observed, and the combined diameter was 8 mm (normal test results yield at least 3 responses with a combined score >10 mm in diameter). The patient had no serologic evidence of HIV or cytomegalovirus infection, and repeated stool tests were negative for pathogenic bacteria and parasites.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Patient before and after Treatment with Combination Therapy (Interferon- and Trimethoprim-Sulfamethoxazole)*

Because of central nervous system involvement and the refractory course of the disease, the patient was treated with ceftriaxone and chloramphenicol (Table 1) and trimethoprim-sulfamethoxazole supplemented with recombinant human interferon- (Polyferon, Rentschler, Laupheim, Germany) (100 µg subcutaneously three times per week). The patient's clinical state indicated severe Whipple disease: weight loss, diarrhea, and reduced serum ß-carotene level (one of the best markers for malabsorption in Whipple disease [1]). Three weeks after initiation of therapy with interferon-, the patient recovered from clinical symptoms (Figure 1). Six months later, T. whippelii-specific DNA and PAS-positive cells were no longer found in the cerebrospinal fluid. However, duodenal biopsy continued to show PAS-positive cells and T. whippelii-specific DNA (Table 1).

View larger version (29K): [in this window] [in a new window]   Figure 1. Effects of interferon- therapy. Black diamonds indicate body weight; black triangles indicate serum concentration of ß-carotene; white diamonds indicate CD4+ T-cell count in the peripheral blood; and white triangles indicate interferon- concentrations produced by peripheral blood mononuclear cells after stimulation with phytohemagglutinin isolated from the patient before, during, and after interferon- therapy.

To deal with persistent subclinical infection, the dose of interferon- was increased to 150 µg three times per week. Four months after initiation of high-dose interferon- therapy, cutaneous hypersensitivity testing showed normal responses to three antigens (with a score of 28 mm in diameter); electron microscopy of duodenal mucosa showed no intact bacteria in the remaining PAS-positive macrophages. For the first time, polymerase chain reaction analysis of duodenal biopsy was negative for T. whippelii-specific DNA. Combination therapy was discontinued after 16 months, and the patient remained symptom-free. When he was reevaluated in July 1997, a normal duodenal mucosa was seen during endoscopy, no cells containing sickleform particles were seen in the biopsy specimens, and results of polymerase chain reaction assay remained negative. In December 1997, the dose of trimethoprim-sulfamethoxazole was reduced to one application daily. In March 1998, the patient had no clinical symptoms.

Methods

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Details of the use of the polymerase chain reaction assay to detect T. whippelii-specific DNA have been described previously [16, 17]. T-cell subpopulations were analyzed by flow cytometry, and interferon- production was studied in cultures of phytohemagglutinin-stimulated mononuclear cells from peripheral blood after 48 hours by a commercially available enzyme-linked immunosorbent assay (Laboserv, Staufenberg, Germany). The peripheral CD4⁺ T-cell count was as low as 126 cells/µL before treatment (control [n = 5]: median, 1006 cells/µL [range, 620 to 1295 cells/µL]). Nine months after initiation of interferon- therapy, the CD4⁺ T-cell count was 616 cells/µL, and 1 year after stopping interferon- therapy, the CD4⁺ T-cell count increased to 1003 cells/µL (Figure 1). Interferon- production increased from 329 ng/L per 10⁵ cells (control [n = 5]: median, 1595 ng/L per 10⁵ cells [range, 817 to 2235 ng/L per 10⁵ cells]) to 1865 ng/L per 10⁵ cells at 9 months. In March 1998, interferon- production still exceeded pretreatment levels (Figure 1).

Role of Funding Source

The funding source had no role in gathering, analyzing, or interpreting the data or in deciding to submit the paper for publication.

Discussion

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Our findings provide evidence that immunomodulatory therapy with interferon- in addition to antibiotics is beneficial in treating patients infected with the intracellular pathogen T. whippelii. Our patient had chronic Whipple disease that involved the central nervous system and was refractory to therapy with several usually effective antibiotics, including those that cross the blood-brain barrier. Final eradication of the bacterium occurred after the patient received combination therapy and has lasted for 1 year after interferon- therapy was stopped. It is unlikely that the eradication resulted from initial ceftriaxone-chloramphenicol treatment because the patient did not have a clinical response until 3 weeks after initiation of interferon- therapy. In addition, clearance of infection required a course of high-dose interferon-.

The decision to include interferon- in this patient's therapy was influenced by studies that showed the important role of this cytokine in controlling intracellular infections under experimental conditions and its success in treating persistent intracellular infections [15]. In addition, immunologic studies have shown reduced production of interleukin-12 and interferon- in patients with Whipple disease [13]. Of interest, the patient's immunologic status improved during and after interferon- therapy. However, our study does not allow us to determine whether the immunoregulatory defect is a primary or secondary result of the infection. The addition of interferon- may be an option in the treatment of patients with refractory Whipple disease, but further studies are needed to clarify the clinical benefit of this therapy.