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Whipple's disease

Michael D Apstein, MD
Thomas Schneider, MD, PhD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Allyson Bloom, MD


In 1907, George H. Whipple described a 36-year-old clinician with "gradual loss of weight and strength, stools consisting chiefly of neutral fat and fatty acids, indefinite abdominal signs, and a peculiar multiple arthritis" [1]. The patient died of this progressive illness; Whipple called it intestinal lipodystrophy since he observed accumulation of "large masses of neutral fats and fatty acids in the lymph spaces." It was renamed Whipple's disease in 1949 upon description of the sine qua non of this disorder, accumulation of macrophages in the lamina propria with intensely periodic acid-Schiff (PAS)-positive intracellular material [2]. An infectious etiology was suspected as early as Whipple's initial report; however, successful treatment with antibiotics was not reported until 1952 [3].

Scientific understanding of the histology, immunology, and treatment of Whipple's disease has improved since the initial description, and the etiologic agent was identified in 1991. The cause is now known to be Tropheryma whipplei (from the Greek "trophe," nourishment, and "eryma," barrier, in reference to the nutrient malabsorption characteristic of the disease), a discovery made upon application of a new technique for identifying microbes based upon the DNA sequence encoding their 16S ribosomal RNA. T. whipplei is closely related to many other soil-borne Actinomycetes [4,5].

This topic discusses the clinical manifestations, diagnosis, and treatment of Whipple’s disease. Discussion of the approach to chronic diarrhea and the evaluation of polyarticular pain in adults is found elsewhere. (See "Approach to the adult with chronic diarrhea in resource-rich settings" and "Evaluation of the adult with polyarticular pain".)


Whipple’s disease is caused by T. whipplei, a gram-positive bacillus related to Actinomycetes. Whipple suspected an infectious agent in 1907 when he noted the numerous "rod-shaped organisms" within the submucosa and macrophages of the index patient. Careful light and electron microscopy by numerous investigators between 1960 and 1992 subsequently identified a gram-positive, non-acid-fast, PAS-positive bacillus with a characteristic trilamellar plasma membrane surrounded by a cell wall.

Application of polymerase chain reaction (PCR) allowed identification of a unique bacterial 16S ribosomal RNA in the intestinal and lymphatic tissue of 5 patients with Whipple's disease that was absent in 10 control patients [5]. Culture of the organism is extremely difficult. This had not been achieved until a 1997 report in which T. whipplei was propagated in cell culture; deactivation of peripheral blood monocytes with interleukin-4 was required for intracellular growth to occur [6]. Unfortunately, this culture technique could not be reproduced [7].


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Literature review current through: Sep 2016. | This topic last updated: Mar 18, 2016.
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  1. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bull Johns Hopkins Hosp 1907; 18:382.
  2. BLACK-SCHAFFER B. The tinctoral demonstration of a glycoprotein in Whipple's disease. Proc Soc Exp Biol Med 1949; 72:225.
  3. PAULLEY JW. A case of Whipple's disease (intestinal lipodystrophy). Gastroenterology 1952; 22:128.
  4. Wilson KH, Blitchington R, Frothingham R, Wilson JA. Phylogeny of the Whipple's-disease-associated bacterium. Lancet 1991; 338:474.
  5. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med 1992; 327:293.
  6. Schoedon G, Goldenberger D, Forrer R, et al. Deactivation of macrophages with interleukin-4 is the key to the isolation of Tropheryma whippelii. J Infect Dis 1997; 176:672.
  7. Swartz MN. Whipple's disease--past, present, and future. N Engl J Med 2000; 342:648.
  8. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple's disease. N Engl J Med 2000; 342:620.
  9. Raoult D, La Scola B, Lecocq P, et al. Culture and immunological detection of Tropheryma whippelii from the duodenum of a patient with Whipple disease. JAMA 2001; 285:1039.
  10. Maiwald M, von Herbay A, Fredricks DN, et al. Cultivation of Tropheryma whipplei from cerebrospinal fluid. J Infect Dis 2003; 188:801.
  11. Raoult D, Fenollar F, Birg ML. Culture of T. whipplei from the stool of a patient with Whipple's disease. N Engl J Med 2006; 355:1503.
  12. Renesto P, Crapoulet N, Ogata H, et al. Genome-based design of a cell-free culture medium for Tropheryma whipplei. Lancet 2003; 362:447.
  13. Fenollar F, Trani M, Davoust B, et al. Prevalence of asymptomatic Tropheryma whipplei carriage among humans and nonhuman primates. J Infect Dis 2008; 197:880.
  14. Schöniger-Hekele M, Petermann D, Weber B, Müller C. Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers. Appl Environ Microbiol 2007; 73:2033.
  15. Ehrbar HU, Bauerfeind P, Dutly F, et al. PCR-positive tests for Tropheryma whippelii in patients without Whipple's disease. Lancet 1999; 353:2214.
  16. Street S, Donoghue HD, Neild GH. Tropheryma whippelii DNA in saliva of healthy people. Lancet 1999; 354:1178.
  17. Zinkernagel AS, Gmür R, Fenner L, et al. Marginal and subgingival plaque--a natural habitat of Tropheryma whipplei? Infection 2003; 31:86.
  18. Maibach RC, Dutly F, Altwegg M. Detection of Tropheryma whipplei DNA in feces by PCR using a target capture method. J Clin Microbiol 2002; 40:2466.
  19. Dutly F, Altwegg M. Whipple's disease and "Tropheryma whippelii". Clin Microbiol Rev 2001; 14:561.
  20. Amsler L, Bauernfeind P, Nigg C, et al. Prevalence of Tropheryma whipplei DNA in patients with various gastrointestinal diseases and in healthy controls. Infection 2003; 31:81.
  21. Fenollar F, Puéchal X, Raoult D. Whipple's disease. N Engl J Med 2007; 356:55.
  22. Dobbins WO III. Whipple's Disease, Charles C Thomas, Springfield 1987.
  23. Bai JC, Mota AH, Mauriño E, et al. Class I and class II HLA antigens in a homogeneous Argentinian population with Whipple's disease: lack of association with HLA-B 27. Am J Gastroenterol 1991; 86:992.
  24. Olivieri I, Brandi G, Padula A, et al. Lack of association with spondyloarthritis and HLA-B27 in Italian patients with Whipple's disease. J Rheumatol 2001; 28:1294.
  25. Martinetti M, Biagi F, Badulli C, et al. The HLA alleles DRB1*13 and DQB1*06 are associated to Whipple's disease. Gastroenterology 2009; 136:2289.
  26. Bentley SD, Maiwald M, Murphy LD, et al. Sequencing and analysis of the genome of the Whipple's disease bacterium Tropheryma whipplei. Lancet 2003; 361:637.
  27. Li W, Fenollar F, Rolain JM, et al. Genotyping reveals a wide heterogeneity of Tropheryma whipplei. Microbiology 2008; 154:521.
  28. 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.
  29. Ectors N, Geboes K, De Vos R, et al. Whipple's disease: a histological, immunocytochemical and electronmicroscopic study of the immune response in the small intestinal mucosa. Histopathology 1992; 21:1.
  30. Marth T, Neurath M, Cuccherini BA, Strober W. Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease. Gastroenterology 1997; 113:442.
  31. Marth T, Kleen N, Stallmach A, et al. Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease. Gastroenterology 2002; 123:1468.
  32. Schneider T, Stallmach A, von Herbay A, et al. Treatment of refractory Whipple disease with interferon-gamma. Ann Intern Med 1998; 129:875.
  33. Ectors NL, Geboes KJ, De Vos RM, et al. Whipple's disease: a histological, immunocytochemical, and electron microscopic study of the small intestinal epithelium. J Pathol 1994; 172:73.
  34. Bai JC, Sen L, Diez R, et al. Impaired monocyte function in patients successfully treated for Whipple's disease. Acta Gastroenterol Latinoam 1996; 26:85.
  35. Moos V, Schmidt C, Geelhaar A, et al. Impaired immune functions of monocytes and macrophages in Whipple's disease. Gastroenterology 2010; 138:210.
  36. Maiwald M, von Herbay A, Persing DH, et al. Tropheryma whippelii DNA is rare in the intestinal mucosa of patients without other evidence of Whipple disease. Ann Intern Med 2001; 134:115.
  37. Schinnerling K, Moos V, Geelhaar A, et al. Regulatory T cells in patients with Whipple's disease. J Immunol 2011; 187:4061.
  38. Schinnerling K, Geelhaar-Karsch A, Allers K, et al. Role of dendritic cells in the pathogenesis of Whipple's disease. Infect Immun 2015; 83:482.
  39. Desnues B, Lepidi H, Raoult D, Mege JL. Whipple disease: intestinal infiltrating cells exhibit a transcriptional pattern of M2/alternatively activated macrophages. J Infect Dis 2005; 192:1642.
  40. Desnues B, Ihrig M, Raoult D, Mege JL. Whipple's disease: a macrophage disease. Clin Vaccine Immunol 2006; 13:170.
  41. Desnues B, Raoult D, Mege JL. IL-16 is critical for Tropheryma whipplei replication in Whipple's disease. J Immunol 2005; 175:4575.
  42. Moos V, Kunkel D, Marth T, et al. Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in patients with Whipple's disease. J Immunol 2006; 177:2015.
  43. Durand DV, Lecomte C, Cathébras P, et al. Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Société Nationale Française de Médecine Interne. Medicine (Baltimore) 1997; 76:170.
  44. Marth T. Systematic review: Whipple's disease (Tropheryma whipplei infection) and its unmasking by tumour necrosis factor inhibitors. Aliment Pharmacol Ther 2015; 41:709.
  45. Raoult D, Fenollar F, Rolain JM, et al. Tropheryma whipplei in children with gastroenteritis. Emerg Infect Dis 2010; 16:776.
  46. Fenollar F, Mediannikov O, Socolovschi C, et al. Tropheryma whipplei bacteremia during fever in rural West Africa. Clin Infect Dis 2010; 51:515.
  47. Bassene H, Mediannikov O, Socolovschi C, et al. Tropheryma whipplei as a Cause of Epidemic Fever, Senegal, 2010-2012. Emerg Infect Dis 2016; 22:1229.
  48. Ramharter M, Harrison N, Bühler T, et al. Prevalence and risk factor assessment of Tropheryma whipplei in a rural community in Gabon: a community-based cross-sectional study. Clin Microbiol Infect 2014; 20:1189.
  49. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic Tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine (Baltimore) 2010; 89:337.
  50. Schneider T, Moos V, Loddenkemper C, et al. Whipple's disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 2008; 8:179.
  51. Moos V, Schneider T. Changing paradigms in Whipple's disease and infection with Tropheryma whipplei. Eur J Clin Microbiol Infect Dis 2011; 30:1151.
  52. Günther U, Moos V, Offenmüller G, et al. Gastrointestinal diagnosis of classical Whipple disease: clinical, endoscopic, and histopathologic features in 191 patients. Medicine (Baltimore) 2015; 94:e714.
  53. Alzahrani AS, Al Sheef M. Severe primary hyperparathyroidism masked by asymptomatic celiac disease. Endocr Pract 2008; 14:347.
  54. Mori K, Ando I, Kukita A. Generalized hyperpigmentation of the skin due to vitamin B12 deficiency. J Dermatol 2001; 28:282.
  55. Riemer H, Hainz R, Stain C, et al. Severe pulmonary hypertension reversed by antibiotics in a patient with Whipple's disease. Thorax 1997; 52:1014.
  56. Urbanski G, Rivereau P, Artru L, et al. Whipple disease revealed by lung involvement: a case report and literature review. Chest 2012; 141:1595.
  57. Damaraju D, Steiner T, Wade J, et al. CLINICAL PROBLEM-SOLVING. A Surprising Cause of Chronic Cough. N Engl J Med 2015; 373:561.
  58. Rickman LS, Freeman WR, Green WR, et al. Brief report: uveitis caused by Tropheryma whippelii (Whipple's bacillus). N Engl J Med 1995; 332:363.
  59. Razonable RR, Pulido JS, Deziel PJ, et al. Chorioretinitis and vitreitis due to Tropheryma whipplei after transplantation: case report and review. Transpl Infect Dis 2008; 10:413.
  60. Cremniter J, Bauer T, Lortat-Jacob A, et al. Prosthetic hip infection caused by Tropheryma whipplei. J Clin Microbiol 2008; 46:1556.
  61. Vital Durand D, Gérard A, Rousset H. [Neurological manifestations of Whipple disease]. Rev Neurol (Paris) 2002; 158:988.
  62. Louis ED, Lynch T, Kaufmann P, et al. Diagnostic guidelines in central nervous system Whipple's disease. Ann Neurol 1996; 40:561.
  63. Matthews BR, Jones LK, Saad DA, et al. Cerebellar ataxia and central nervous system whipple disease. Arch Neurol 2005; 62:618.
  64. Gerard A, Sarrot-Reynauld F, Liozon E, et al. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine (Baltimore) 2002; 81:443.
  65. Panegyres PK, Edis R, Beaman M, Fallon M. Primary Whipple's disease of the brain: characterization of the clinical syndrome and molecular diagnosis. QJM 2006; 99:609.
  66. Elkins C, Shuman TA, Pirolo JS. Cardiac Whipple's disease without digestive symptoms. Ann Thorac Surg 1999; 67:250.
  67. Gubler JG, Kuster M, Dutly F, et al. Whipple endocarditis without overt gastrointestinal disease: report of four cases. Ann Intern Med 1999; 131:112.
  68. Fenollar F, Lepidi H, Raoult D. Whipple's endocarditis: review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis. Clin Infect Dis 2001; 33:1309.
  69. Lepidi H, Fenollar F, Dumler JS, et al. Cardiac valves in patients with Whipple endocarditis: microbiological, molecular, quantitative histologic, and immunohistochemical studies of 5 patients. J Infect Dis 2004; 190:935.
  70. Geissdörfer W, Moos V, Moter A, et al. High frequency of Tropheryma whipplei in culture-negative endocarditis. J Clin Microbiol 2012; 50:216.
  71. Marín M, Muñoz P, Sánchez M, et al. Tropheryma whipplei infective endocarditis as the only manifestation of Whipple's disease. J Clin Microbiol 2007; 45:2078.
  72. Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Microbiol Rev 2001; 14:177.
  73. Dobbins WO 3rd. The diagnosis of Whipple's disease. N Engl J Med 1995; 332:390.
  74. Ramzan NN, Loftus E Jr, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med 1997; 126:520.
  75. Wendler D, Mendoza E, Schleiffer T, et al. Tropheryma whippelii endocarditis confirmed by polymerase chain reaction. Eur Heart J 1995; 16:424.
  76. Cohen L, Berthet K, Dauga C, et al. Polymerase chain reaction of cerebrospinal fluid to diagnose Whipple's disease. Lancet 1996; 347:329.
  77. O'Duffy JD, Griffing WL, Li CY, et al. Whipple's arthritis: direct detection of Tropheryma whippelii in synovial fluid and tissue. Arthritis Rheum 1999; 42:812.
  78. Lowsky R, Archer GL, Fyles G, et al. Brief report: diagnosis of Whipple's disease by molecular analysis of peripheral blood. N Engl J Med 1994; 331:1343.
  79. Pron B, Poyart C, Abachin E, et al. Diagnosis and follow-up of Whipple's disease by amplification of the 16S rRNA gene of Tropheryma whippelii. Eur J Clin Microbiol Infect Dis 1999; 18:62.
  80. Fenollar F, Amphoux B, Raoult D. A paradoxical Tropheryma whipplei western blot differentiates patients with whipple disease from asymptomatic carriers. Clin Infect Dis 2009; 49:717.
  81. 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.
  82. Masselot F, Boulos A, Maurin M, et al. Molecular evaluation of antibiotic susceptibility: Tropheryma whipplei paradigm. Antimicrob Agents Chemother 2003; 47:1658.
  83. Boulos A, Rolain JM, Raoult D. Antibiotic susceptibility of Tropheryma whipplei in MRC5 cells. Antimicrob Agents Chemother 2004; 48:747.
  84. Boulos A, Rolain JM, Mallet MN, Raoult D. Molecular evaluation of antibiotic susceptibility of Tropheryma whipplei in axenic medium. J Antimicrob Chemother 2005; 55:178.
  85. Feurle GE, Junga NS, Marth T. Efficacy of ceftriaxone or meropenem as initial therapies in Whipple's disease. Gastroenterology 2010; 138:478.
  86. Schnider PJ, Reisinger EC, Berger T, et al. Treatment guidelines in central nervous system Whipple's disease. Ann Neurol 1997; 41:561.
  87. Feurle GE, Moos V, Bläker H, et al. Intravenous ceftriaxone, followed by 12 or three months of oral treatment with trimethoprim-sulfamethoxazole in Whipple's disease. J Infect 2013; 66:263.
  88. Lagier JC, Fenollar F, Lepidi H, et al. Treatment of classic Whipple's disease: from in vitro results to clinical outcome. J Antimicrob Chemother 2014; 69:219.
  89. Keinath RD, Merrell DE, Vlietstra R, Dobbins WO 3rd. Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients. Gastroenterology 1985; 88:1867.
  90. Feurle GE, Marth T. An evaluation of antimicrobial treatment for Whipple's Disease. Tetracycline versus trimethoprim-sulfamethoxazole. Dig Dis Sci 1994; 39:1642.
  91. Cooper GS, Blades EW, Remler BF, et al. Central nervous system Whipple's disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime. Gastroenterology 1994; 106:782.
  92. Feurle GE. Whipple's disease. Orphanet Encyclopedia 2004. http://www.orpha.net/data/patho/GB/uk-WhipplesDisease.pdf (Accessed on January 10, 2013).
  93. Feurle GE, Moos V, Schinnerling K, et al. The immune reconstitution inflammatory syndrome in whipple disease: a cohort study. Ann Intern Med 2010; 153:710.
  94. Fleming JL, Wiesner RH, Shorter RG. Whipple's disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988; 63:539.