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Whipple's Disease Author: Professor Gerhard E. Feurle1 Creation Date: March 2001 Update: January 2002 December 2004 Scientific Editor: Professor Wolfgang Rösch 1 DRK-Krakenhaus Neuwied, Marktstraße: 104, 56504 Neuwied, Germany. [email protected] Abstract Keywords Disease and synonyms Definition Differential diagnosis Prevalence Clinical description Etiology Diagnostic methods Management including treatment Unresolved questions Clinical trials Research project Website References Abstract Whipple’s disease (WD) is a chronic infectious disorder in which almost all organ systems can be invaded by the rod-shaped bacterium – Tropheryma whipplei. Main symptoms are weight loss, polyarthritis, diarrhea/malabsorption, fever and sometimes a complex cerebral manifestation. As WD is frequently misdiagnosed, no reliable data on incidence and prevalence are available. Although WD is susceptible to antimicrobial treatment, no final data from controlled trials are available. Empirical treatment consists of an initial phase of intravenous antibiotics followed by 12 months of antibiotic maintenance therapy. In 1999, a randomised controlled trial on antibiotic treatment of WD has been initiated (SIMW). Patients with untreated Whipple’s disease are welcome in the trial: “Third Arm of SIMW”. Keywords Tropheryma whipplei, Whipple’s disease, Morbus Whipple. Disease and synonyms Whipple disease, Morbus Whipple Intestinal lipodystrophy (4) Intestinal lipophagic granulomatosis Secondary non-tropical sprue Definition Whipple’s Disease (WD) is a chronic infectious systemic disorder in which all organs can be invaded by the rod-shaped bacterium – Tropheryma whipplei. The main symptoms are weight loss, polyarthritis, diarrhea/malabsorption and sometimes manifestation. a complex Differential diagnosis Seronegative polyarthritis, malabsorption syndrome, endocarditis, cerebrovascular dementia, HIV infection. cerebral vasculitis, lymphoma, disease, Prevalence As WD is frequently misdiagnosed, no reliable data on incidence and prevalence are available. Feurle GE. Whipple's disease. Orphanet encyclopedia, December 2004. http://www.orpha.net/data/patho/GB/uk-WhipplesDisease.pdf 1 Clinical description Main symptoms of WD are weight loss, non– destructive polyarthritis, diarrhea/malabsorption, fever, lymphadenopathy, cardiac valvular disease, pleuritis and ocular inflammatory disease. Central nervous manifestations consist of the almost pathognomonic triad: dementia, ophthalmoplegia and myoclonus but also of meningoencephalitis with occlusion of the aqueductus and consecutive hydrocephalus, hypothalamic syndromes including disturbance of the sleep cycle, polydipsia and hyponatremia. Untreated WD is characterised by relentless progression and death either by wasting or by central nervous system involvement. Etiology Tropheryma whipplei (TW), the offending organism has been characterised as an actionomycete. It can be cultivated in human fibroblast cell lines and axenic media (1,2). The findings of Tropheryma whipplei in the environment (3) and in healthy persons (8,9), the rareness of the disorder, and the fact that patients affected by WD display an impaired Tcell function (10,11,12) suggest that a specific defect in cellular immunity may be a prerequisite for the infection with Tropheryma whipplei. Diagnostic methods Because of the protean manifestations of the disease, a high level of suspicion or chance observations are important for early diagnosis. The gold standard for diagnosis of WD is the histological demonstration of the free or phagocytosed rod-shaped bacteria with periodic–acid–SCHIFF (PAS) staining in the duodenal mucosa or other tissue. The diagnosis in extraintestinal tissue has to be supported by a positive PCR (polymerase chain reaction) for Tropheryma whipplei (5,6). Cytological demonstration of PAS-positive macrophages or a positive PCR for Tropheryma whipplei in the cerebrospinal fluid are diagnostic of cerebral Whipple disease (6,7). As the PCR techniques from different laboratories have not been validated, doubts have been raised concerning the comparability of the results from different laboratories. As asymptomatic carriers of TW in the gastrointestinal tract have been described, an isolated positive PCR for TW in gastrointestinal mucosa or contents is not sufficient for a definite diagnosis of WD. As PAS-positive macrophages may persist in the intestinal mucosa or frequently in the submucosa for months and perhaps years after successful treatment, the cytological macrophage subtype has to be determined (16). Management including treatment Treatment of WD is still empirical as the final results of SIMW are not yet available. Already 50 years ago, it was shown that WD can be cured by antibiotics (13). Antimicrobial treatment may eradicate Tropheryma whipplei from the gut, the joints, the heart and lymph nodes whereas central nervous system involvement can persist and can lead to a devastating course some years later (7). The present concept consists of an initial phase of intravenously administered antibiotics known to penetrate the blood-brain barrier followed by 12 months of maintenance treatment (14). As evidence-based data are not available, any patient with diagnosed WD should be admitted to controlled treatment trials (see below). Unresolved questions In vitro microbial susceptibility testing has been performed (17). However, the establishment and maintenance of an in vitro culture is not always possible. Resistance of TW against quinolone antibiotics seems to be a generalised phenomenon (17). Further, the defect in cellular immunity has not been clearly delineated and it remains an attractive but unproven hypothesis that an impaired T cell function is a prerequisite for the infection with Tropheryma whipplei. It can not be excluded that the T cell defect is the consequence of the infection. Lastly, the natural source of the actinomycete Tropheryma whipplei in the environment remains to be studied systematically. Clinical trials The recruitment of patients with WD to the SIMW trial (Study for the Initial treatment of Morbus Whipple), initiated 1999, has successfully been terminated in January 2004 after enrolling the predetermined number of 42 patients with untreated WD (15). Final results are not yet available. Follow-up will be complete in 2006. A successor trial based on preliminary results of SIMW with a maintenance treatment period shortened to three months has been established. Trial case report forms and the investigator brochure for the “Third Arm of SIMW” are available in German and English for physicians caring for patients with untreated WD. Patient consent forms are available also in French, Italian, and Flemish (tel. study center: 49 2631 98 1405). Patients with recurrent disease may be admitted to the Study of Recurrent Morbus Whipple (SRMW). Feurle GE. Whipple's disease. Orphanet encyclopedia, December 2004. http://www.orpha.net/data/patho/GB/uk-WhipplesDisease.pdf 2 Research project A multicenter research project on Whipple’s disease is supported by the European Commission (QLG1-CT-2002-01049): The randomised Study of the Initial treatment of Morbus Whipple (SIMW) is registered by ISRCTN45658456. Website www.whipplesdisease.info References 1. Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H, Roux V, Piette C, Vandenesch F, Vital-Durand D, Marrie TJ. Cultivation of the bacillus of Whipple’s disease. N Engl J Med 2000; 342: 620-5. 2. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992; 327: 293-301. 3. Maiwald M, Schumacher F, Ditton HJ, von Herbay A. Enviromental occurrence of the whipple disease bacterium (Tropheryma whippelii). Appl Environ Microbiol 1998; 64: 7602. 4. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Johns Hopkins Hosp Bull 1907; 18: 382-91. 5. Von Herbay A; Ditton HJ, Schumacher F, Maiwald M. Diagnostic application of a polymerase chain reaction assay for the Whipple’s disease bacterium to intestinal biopsies. Gastroenterology 1996; 110: 1735-43. 6. Von Herbay A, Ditton HJ, Schuhmacher F, Maiwald M. Whipple’s disease: Staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology 1997; 113: 434-41. 7. Feurle GE, Volk B, Waldherr R. Cerebral Whipple’s disease with negative jejunal histology. N Engl J Med 1979; 300: 907-8. 8. Ehrbar HU, Bauerfeind P, Dutly F, Koelz HR, Altwegg M. PCR-positive tests for Tropheryma whippelii in patients without Whipple’s disease. Lancet 1999; 353: 2214. 9. Street S, Donoghue HD, Neild G.H. Tropheryma whippelii DNA in saliva of healthy people. Lancet 1999; 354: 1178-9. 10. Feurle GE, Dörken B, Schöpf E, Lenhard V. HLA B27 and defects in the T-cell system in Whipple’s disease. Eur J Clin Invest. 1979; 9: 385-9. 11. Feurle GE, Volk B, Waldherr R. Cerebral Whipple’s disease with negative jejunal histology. N Engl J Med 1979; 300: 907-8. 12. Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T. Dysregulated peripheral and mucosal Th1/Th2 response in Whipple’s disease. Gastroenterology 2002; 123: 1468-77. 13. Paulley JW. A case of Whipple’s disease (intestinal lipodystrophy). Gastroenterology 1952; 22: 128-33. 14. Feurle GE, Marth T. An evaluation of antimicrobial treatment for Whipple’s disease. Tetracycline versus trimethoprimsulfamethoxazole. Dig Dis Sci 1994; 39: 1642-8. 15. Feurle GE, Maiwald M, Marth T, von Herbay A. Eine randomisierte Studie zur Initialtherapie des Morbus Whipple (MW). SIMW. 1998. Neuwied, Heidelberg, Homburg. 16. Von Herbay A, Maiwald M, Ditton HJ; Otto HF. Histology of intestinal Whipple’s disease revisited. Virchows Arch 1996; 429: 335-43. 17. Boulos A, Rolain JM, Raoult D. Antibiotic susceptibility of tropheryma whipplei in MRC5 cells. Antimicrobial agents and chemotherapy 2004; 48: 747-52. Feurle GE. Whipple's disease. Orphanet encyclopedia, December 2004. http://www.orpha.net/data/patho/GB/uk-WhipplesDisease.pdf 3