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Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e318168ff5f
Case Reports

Whipple Disease: Ocular and Neurological Complications in a Patient With Previous Lymphoma

Checkley, Anna M. MBChB, BA, MRCP*; Egan, Cathy FRANZCO; Finlayson, Caroline MBBS, FRCPath*; Maibach, Romana C. PhD; Griffin, George E. BSc, PhD, FRCP, F MedSci*

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*St George's Hospital, London; †Moorfields Eye Hospital, London; and ‡Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland.

There was no financial support for the study. There are no conflicts of interest for any of the authors.

Address correspondence and reprint requests to Anna M. Checkley, MBChB, BA, MRCP, St George's Hospital, Blackshaw Rd, London SW17 0QT, UK. E-mail:

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Abstract: We describe a case of Whipple disease in a patient with a previous history of lymphoma. Lymph node excision biopsy showed periodic acid-Schiff with diastase-positive granulomata, positive on polymerase chain reaction for Tropheryma whippelii. The patient subsequently developed neurological and ocular complications. This case is unusual because the infection progressed to central nervous system and ocular disease while the patient remained on treatment, and central nervous system disease occurred despite normal cerebrospinal fluid and a negative polymerase chain reaction for T. whippelii. The clinical management is discussed, as well as the association of Whipple disease with lymphoma.

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A 47-year old Caucasian male presented with a 9-month history of fevers, night sweats, weight loss, and painful feet and knees. He had been diagnosed with a stage 1A diffuse large B-cell lymphoma at the age of 28 years, which was treated with local excision and radiotherapy after a staging laparotomy including splenectomy. There was no subsequent evidence of recurrence of disease. He was also a type 2 diabetic patient, taking oral hypoglycemic therapy. Examination revealed a small axillary lymph node and tender metatarsophalangeal joints. Investigations confirmed the presence of a systemic inflammatory response, with an erythrocyte sedimentation rate of 63 mm/h and a C-reactive protein of 46 mg/L. Full blood count, urea and electrolytes, and liver function tests were normal. A Heaf test was grade 1. Urine and blood cultures were sterile, and serology for toxoplasmosis, Ebstein Barr virus, cytomegalovirus, Bartonella henselae, B. quintana, and Histoplasma capsulatum were negative. An autoimmune screen was negative, and an immunoglobulin profile demonstrated a polyclonal immunoglobulin G response. A computed tomographic scan of the abdomen and pelvis showed small paraaortic lymph nodes, which were biopsied atlaparotomy and submitted for histological examination. Well-formed granulomata were seen, containing periodic acid-Schiff with diastase-positive and Grocott-positive flocculant material. Gram and Ziehl-Nielsen stains were negative, and there was no evidence of lymphoma. Whipple disease was suspected, and the sample was sent for polymerase chain reaction (PCR) for Tropheryma whippelii.1 The result was positive.

The patient was commenced on oral trimethoprim-sulfamethoxazole 160/800 mg o.d. Within 3 days, his symptoms had dramatically improved, and he remained well until 1 month later when he developed partial motor seizures with secondary generalization. He was commenced on carbamazepine, and a magnetic resonance imaging brain scan and electroencephalogram were performed, both of which were normal. Cerebrospinal fluid (CSF) was normal: white cell count <3/mL, protein 0.24 g/L glucose, 4 mmol/L (plasma 6 mmol/L) culture, cytology, and PCR for T. whippelii negative. Six months after commencing trimethoprim-sulfamethoxazole, while still receiving this agent, the patient suddenly developed blurred vision in the right eye. Visual acuity was 6/9 on the right (normal on the left), and fundoscopy showed macular edema with a multifocal chorioretinitis (Fig. 1). Fundus fluorescein angiography showed macular edema and multiple lesions at the level of the choroid (Fig. 2).

Figure 1
Figure 1
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Figure 2
Figure 2
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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.

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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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14. Mariette X. Lymphomas complicating Sjogren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells. Ann Rheum Dis. 2001;60:1007-1010.

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16. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993;342:575-577.

17. Morgner A, Bayerdorffer E, Neubauer A, et al. Gastric MALT lymphoma and its relationship to Helicobacter pylori infection: management and pathogenesis of the disease. Microsc Res Tech. 2000;48:349-356.

18. Marth T, Roux M, von Herbay A, et al. Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease. Clin Immunol Immunopathol. 1994;72:217-226.

19. Dobbins WO III. HLA antigens in Whipple's disease. Arthritis Rheum. 1987;30:102-105.

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