Intravenous ceftriaxone 2 g o.d. was substituted for the trimethoprim-sulfamethoxazole. A review after 6 months of ceftriaxone demonstrated complete resolution of the ocular changes (images not shown), and on the basis of this finding, the patient was converted back to oral trimethoprim-sulfamethoxazole 160/800 mg b.d. Six months later, he again presented with visual blurring and evidence of macular edema and chorioretinitis (images not shown), necessitating a further 5-month course of intravenous ceftriaxone. He remains on oral trimethoprim-sulfamethoxazole and has had no further clinical problems to this date. His C-reactive protein remains in the normal range. Lymph node samples from the lymphoma staging laparotomy performed 19 years previously were obtained and were also tested by PCR for the presence of T. whippelii DNA (Maibach, Switzerland). The result was negative.
Whipple disease is a very rare infection caused by the actinomycete T. whippelii.2 Classically, the infection presents with diarrhea, weight loss, abdominal pain, and symptoms of inflammatory response including fever and malaise. Thirty percent individuals present as our patient did, with arthralgias or arthritis, which may precede the development of gastrointestinal symptoms by several years.3 Relapse is common, occurring in 5% to 30% of patients despite prolonged antibiotic treatment and frequently affecting the central nervous system (CNS). In this case, although there was no direct evidence for T. whippelii infection in the CSF, the development of seizures and ocular lesions and the resolution of these lesions with intravenous ceftriaxone therapy are strongly suggestive of CNS involvement. PCR of the CSF has a low sensitivity in this context, one study suggesting a sensitivity of 71%, reducing to 27% in patients on treatment.4
At present, there is little evidence to guide the treatment of Whipple disease. Current recommendations are based on the observation in retrospective cohorts that treatment with tetracycline was associated with a higher rate of relapse, particularly cerebral, compared with cotrimoxazole.5,6 This has been attributed to tetracycline failing to cross the blood-brain barrier. Current recommendations are an initial 2 weeks of intravenous ceftriaxone, particularly if there is evidence of CNS involvement, followed by oral trimethoprim-sulfamethoxazole 160/800 mg b.d. for at least a year.7 The first randomized controlled trial addressing the issues of choice and duration of antibiotic therapy and the use of gamma interferon as an immunomodulatory agent is currently in progress.8
Our patient had a large cell non-Hodgkin lymphoma at the age of 28 years, 19 years before he was diagnosed with Whipple disease. An association has been reported between lymphoma and Whipple disease, lymphomagenesis possibly occurring as a result of chronic antigenic stimulation. Lymphomagenesis occurs as a result of a monoclonal B-cell population gradually accumulating genetic mutations with decreasing response to external regulation.9 A number of case reports describe possible steps along that pathway in patients with Whipple disease. In one case, a patient with Whipple disease and massive lymphadenopathy was shown to have a clonal population of B cells with a BCL2-mbr rearrangement, a recognized step in lymphomagenesis.10 The lymphadenopathy and the clonal B-cell population disappeared after treatment of the Whipple disease, suggesting that monoclonal B-cell proliferation may have been antigenically driven by T.whippelii. In a similar case of Whipple disease with massive lymphadenopathy, a κ-restricted B-cell clone was isolated from blood, bone marrow, and spleen without evidence of lymphoma.11 The lymphadenopathy regressed after antibiotic treatment of the Whipple disease, but the monoclonal population persisted. Last, 2 cases of lymphoma occurring after treatment of Whipple disease have been described.12,13 This situation can be compared with other oligoclonal or monoclonal "smouldering" conditions associated with autoimmune diseases, hepatitis C, and Helicobacter pylori infection, which are at risk of evolution to lymphoma.14,15 Interestingly, antibiotic treatment of H. pylori infection has been associated with regression of primary low-grade B-cell gastric mucosa-associated lymphoid tissue lymphoma.16,17
A wide range of immune deficiencies has been reported in the context of Whipple disease, in particular reduced CD4 to CD8 T-cell ratio, impaired phagocytosis capacity of macrophages, and decreased Il-12 secretion leading to decreased gamma interferon production from Th1 T cells.18 It is unclear to what extent these changes precede the development of Whipple disease and to what extent they are a consequence of infection with T. whippelii, and indeed, some changes have been reported to disappear after successful treatment.19
It is interesting to speculate on the factors that lead to this particular patient becoming infected with T. whippelii. Could he have been infected before the development of lymphoma, lymphomagenesis resulting from the chronic antigenic stimulation of infection? We were unable to demonstrate T. whippelii DNA on samples from the original staging laparotomy for lymphoma, but it should be noted that PCR for T. whippelii is less sensitive when performed on paraffin-embedded tissues compared with fresh tissue (R. Maibach, personal communication). It seems much more plausible, however, that he became infected more recently, perhaps related to an increased susceptibility to infection after the splenectomy and the development of type 2 diabetes.
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