Changing paradigms in Whipple’s disease and infection with Tropheryma whipplei



More than a century after its first description through G.H. Whipple, the understanding of the chronic multisystemic infection called Whipple’s disease is still limited. However, within recent years the knowledge about diagnosis and treatment, the pathogenesis, and the biology of the agent itself have been improved by molecular biological and immunological methods. Despite the ubiquitous presence of the causative bacterium Tropheryma whipplei, Whipple’s disease is very rare, and immunogenetic host factors rather than the genotype of the agent influence the course of infection. Since the clinical features of classical Whipple’s disease are non-specific and the spectrum of isolated organ-specific manifestations might be underestimated, diagnosis often still is a challenge. Moreover, besides classical Whipple’s disease, there are newly recognized infections with T. whipplei, which do not fit in the concept of classical Whipple’s disease, for example, acute self-limiting infection and isolated T. whipplei endocarditis. Antibiotic therapy is usually successful. However, several problems are still unresolved, of which the most important are the following: which antibiotic should be used; how long treatment should be continued; how the immunoreconstitution inflammatory syndrome, which may occur after initiation of treatment, should be managed; and which is the best treatment of severe neurological manifestations.



This work was supported by EU Contract No. QLG1-CT-2002-01049 and the Deutsche Forschungs Gemeinschaft KFO 104 and SFB 633.


  1. 1.
    Whipple GH (1907) A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bull Johns Hopkins Hosp 18:382–393Google Scholar
  2. 2.
    Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D (2008) Whipple’s disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 8(3):179–190PubMedCrossRefGoogle Scholar
  3. 3.
    Lagier JC, Lepidi H, Raoult D, Fenollar F (2010) Systemic Tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine (Baltimore) 89(5):337–345CrossRefGoogle Scholar
  4. 4.
    Raoult D, Fenollar F, Rolain JM et al (2010) Tropheryma whipplei in children with gastroenteritis. Emerg Infect Dis 16(5):776–782PubMedGoogle Scholar
  5. 5.
    Fenollar F, Trani M, Davoust B et al (2008) Prevalence of asymptomatic Tropheryma whipplei carriage among humans and nonhuman primates. J Infect Dis 197(6):880–887PubMedCrossRefGoogle Scholar
  6. 6.
    Schoniger-Hekele M, Petermann D, Weber B, Muller C (2007) Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers. Appl Environ Microbiol 73(6):2033–2035PubMedCrossRefGoogle Scholar
  7. 7.
    Marth T, Kleen N, Stallmach A et al (2002) Dysregulated peripheral and mucosal Th1/Th2 response in Whipple’s disease. Gastroenterology 123(5):1468–1477PubMedCrossRefGoogle Scholar
  8. 8.
    Moos V, Kunkel D, Marth T et al (2006) Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in patients with Whipple’s disease. J Immunol 177(3):2015–2022PubMedGoogle Scholar
  9. 9.
    Moos V, Schmidt C, Geelhaar A et al (2010) Impaired immune functions of monocytes and macrophages in Whipple’s disease. Gastroenterology 138(1):210–220PubMedCrossRefGoogle Scholar
  10. 10.
    Geelhaar A, Moos V, Schinnerling K et al (2010) Specific and nonspecific B-cell function in the small intestines of patients with Whipple’s disease. Infect Immun 78(11):4589–4592PubMedCrossRefGoogle Scholar
  11. 11.
    Feurle GE, Junga NS, Marth T (2010) Efficacy of ceftriaxone or meropenem as initial therapies in Whipple’s disease. Gastroenterology 138(2):478–486PubMedCrossRefGoogle Scholar
  12. 12.
    Fenollar F, Rolain JM, Alric L et al. (2009) Resistance to trimethoprim/sulfamethoxazole and Tropheryma whipplei. Int J Antimicrob Agents 34(3):255–259Google Scholar
  13. 13.
    Feurle GE, Marth T (1994) An evaluation of antimicrobial treatment for Whipple’s disease. Tetracycline versus trimethoprim-sulfamethoxazole. Dig Dis Sci 39(8):1642–1648PubMedCrossRefGoogle Scholar
  14. 14.
    Panegyres PK (2008) Diagnosis and management of Whipple’s disease of the brain. Pract Neurol 8(5):311–317PubMedCrossRefGoogle Scholar
  15. 15.
    Feurle GE, Moos V, Geelhaar A et al (2010) Immune reconstitution inflammatory syndrome in Whipple disease - an observational cohort study. Ann Intern Med 153:710–717PubMedGoogle Scholar
  16. 16.
    Paulley JW (1952) A case of Whipple’s disease (intestinal lipodystrophy). Gastroenterology 22(1):128–133PubMedGoogle Scholar
  17. 17.
    Cohen AS, Schimmel EM, Holt PR, Isselbacher KJ (1960) Ultrastructural abnormalities in Whipple’s disease. Proc Soc Exp Biol Med 105:411–414PubMedGoogle Scholar
  18. 18.
    Relman DA, Schmidt TM, MacDermott RP, Falkow S (1992) Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 327(5):293–301PubMedCrossRefGoogle Scholar
  19. 19.
    Schoedon G, Goldenberger D, Forrer R et al (1997) Deactivation of macrophages with interleukin-4 is the key to the isolation of Tropheryma whippelii. J Infect Dis 176(3):672–677PubMedCrossRefGoogle Scholar
  20. 20.
    Raoult D, Birg ML, La Scola B et al (2000) Cultivation of the bacillus of Whipple’s disease. N Engl J Med 342(9):620–625PubMedCrossRefGoogle Scholar
  21. 21.
    La Scola B, Fenollar F, Fournier PE, Altwegg M, Mallet MN, Raoult D (2001) Description of Tropheryma whipplei gen. nov., sp. nov., the Whipple’s disease bacillus. Int J Syst Evol Microbiol 51(Pt 4):1471–1479PubMedGoogle Scholar
  22. 22.
    Dobbins WI (1987) Whipple’s disease. Charles C. Thomas, SpringfieldGoogle Scholar
  23. 23.
    Martinetti M, Biagi F, Badulli C et al. (2009) The HLA alleles DRB1*13 and DQB1*06 are associated to Whipple’s disease. Gastroenterology 136(7):2289–2294Google Scholar
  24. 24.
    Boulos A, Rolain JM, Mallet MN, Raoult D (2005) Molecular evaluation of antibiotic susceptibility of Tropheryma whipplei in axenic medium. J Antimicrob Chemother 55(2):178–181PubMedCrossRefGoogle Scholar
  25. 25.
    Li W, Fenollar F, Rolain JM et al (2008) Genotyping reveals a wide heterogeneity of Tropheryma whipplei. Microbiology 154(Pt 2):521–527PubMedCrossRefGoogle Scholar
  26. 26.
    Bentley SD, Maiwald M, Murphy LD et al (2003) Sequencing and analysis of the genome of the Whipple’s disease bacterium Tropheryma whipplei. Lancet 361(9358):637–644PubMedCrossRefGoogle Scholar
  27. 27.
    Raoult D, Ogata H, Audic S et al (2003) Tropheryma whipplei Twist: a human pathogenic Actinobacteria with a reduced genome. Genome Res 13(8):1800–1809PubMedGoogle Scholar
  28. 28.
    Kowalczewska M, Villard C, Lafitte D, Fenollar F, Raoult D (2009) Global proteomic pattern of Tropheryma whipplei: a Whipple’s disease bacterium. Proteomics 9(6):1593–1616PubMedCrossRefGoogle Scholar
  29. 29.
    Crapoulet N, Barbry P, Raoult D, Renesto P (2006) Global transcriptome analysis of Tropheryma whipplei in response to temperature stresses. J Bacteriol 188(14):5228–5239PubMedCrossRefGoogle Scholar
  30. 30.
    Bonhomme CJ, Renesto P, Desnues B et al (2009) Tropheryma whipplei glycosylation in the pathophysiologic profile of Whipple’s disease. J Infect Dis 199(7):1043–1052PubMedCrossRefGoogle Scholar
  31. 31.
    Raoult D, Fenollar F, Birg ML (2006) Culture of T. whipplei from the stool of a patient with Whipple’s disease. N Engl J Med 355(14):1503–1505PubMedCrossRefGoogle Scholar
  32. 32.
    Rolain JM, Fenollar F, Raoult D (2007) False positive PCR detection of Tropheryma whipplei in the saliva of healthy people. BMC Microbiol 7:48PubMedCrossRefGoogle Scholar
  33. 33.
    Bousbia S, Papazian L, Auffray JP et al (2010) Tropheryma whipplei in patients with pneumonia. Emerg Infect Dis 16(2):258–263PubMedGoogle Scholar
  34. 34.
    Fenollar F, Mediannikov O, Socolovschi C et al (2010) Tropheryma whipplei bacteremia during fever in rural West Africa. Clin Infect Dis 51(5):515–521PubMedCrossRefGoogle Scholar
  35. 35.
    Fenollar F, Trape JF, Bassene H, Sokhna C, Raoult D (2009) Tropheryma whipplei in fecal samples from children, Senegal. Emerg Infect Dis 15(6):922–924PubMedCrossRefGoogle Scholar
  36. 36.
    Escher R, Roth S, Droz S, Egli K, Altwegg M, Tauber MG (2010) Endocarditis due to Tropheryma whipplei: rapid detection, limited genetic diversity, and long-term clinical outcome in a local experience. Clin Microbiol Infect 16(8):1213–1222PubMedCrossRefGoogle Scholar
  37. 37.
    Fenollar F, Lepidi H, Raoult D (2001) Whipple’s endocarditis: review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis. Clin Infect Dis 33(8):1309–1316PubMedCrossRefGoogle Scholar
  38. 38.
    Mallmann C, Siemoneit S, Schmiedel D et al (2010) Fluorescence in situ hybridization to improve the diagnosis of endocarditis: a pilot study. Clin Microbiol Infect 16(6):767–773PubMedCrossRefGoogle Scholar
  39. 39.
    Geissdorfer W, Wittmann I, Rollinghoff M, Schoerner C, Bogdan C (2001) Detection of a new 16 S-23 S rRNA spacer sequence variant (type 7) of Tropheryma whippelii in a patient with prosthetic aortic valve endocarditis. Eur J Clin Microbiol Infect Dis 20(10):762–763PubMedCrossRefGoogle Scholar
  40. 40.
    Mahnel R, Kalt A, Ring S, Stallmach A, Strober W, Marth T (2005) Immunosuppressive therapy in Whipple’s disease patients is associated with the appearance of gastrointestinal manifestations. Am J Gastroenterol 100(5):1167–1173PubMedCrossRefGoogle Scholar
  41. 41.
    Durand DV, Lecomte C, Cathebras P, Rousset H, Godeau P (1997) Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Societe Nationale Francaise de Medecine Interne. Med Baltim 76(3):170–184CrossRefGoogle Scholar
  42. 42.
    Gerard A, Sarrot-Reynauld F, Liozon E et al (2002) Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Med Baltim 81(6):443–457CrossRefGoogle Scholar
  43. 43.
    Pruss H, Katchanov J, Zschenderlein R, Loddenkemper C, Schneider T, Moos V (2007) A patient with cerebral Whipple disease with gastric involvement but no gastrointestinal symptoms: a consequence of local protective immunity? J Neurol Neurosurg Psychiatry 78(8):896–898PubMedCrossRefGoogle Scholar
  44. 44.
    von Herbay A, Maiwald M, Ditton HJ, Otto HF (1996) Histology of intestinal Whipple’s disease revisited. A study of 48 patients. Virchows Arch 429(6):335–343CrossRefGoogle Scholar
  45. 45.
    von Herbay A, Ditton HJ, Maiwald M (1996) Diagnostic application of a polymerase chain reaction assay for the Whipple’s disease bacterium to intestinal biopsies. Gastroenterology 110(6):1735–1743CrossRefGoogle Scholar
  46. 46.
    Fenollar F, Laouira S, Lepidi H, Rolain JM, Raoult D (2008) Value of Tropheryma whipplei quantitative polymerase chain reaction assay for the diagnosis of Whipple disease: usefulness of saliva and stool specimens for first-line screening. Clin Infect Dis 47(5):659–667PubMedCrossRefGoogle Scholar
  47. 47.
    Bakkali N, Fenollar F, Biswas S, Rolain JM, Raoult D (2008) Acquired resistance to trimethoprim-sulfamethoxazole during Whipple disease and expression of the causative target gene. J Infect Dis 198(1):101–108PubMedCrossRefGoogle Scholar
  48. 48.
    Baisden BL, Lepidi H, Raoult D, Argani P, Yardley JH, Dumler JS (2002) Diagnosis of Whipple disease by immunohistochemical analysis: a sensitive and specific method for the detection of Tropheryma whipplei (the Whipple bacillus) in paraffin-embedded tissue. Am J Clin Pathol 118(5):742–748PubMedCrossRefGoogle Scholar
  49. 49.
    Kowalczewska M, Fenollar F, Lafitte D, Raoult D (2006) Identification of candidate antigen in Whipple’s disease using a serological proteomic approach. Proteomics 6(11):3294–3305PubMedCrossRefGoogle Scholar
  50. 50.
    Bonhomme CJ, Renesto P, Nandi S, Lynn AM, Raoult D (2008) Serological microarray for a paradoxical diagnostic of Whipple’s disease. Eur J Clin Microbiol Infect Dis 27(10):959–968PubMedCrossRefGoogle Scholar
  51. 51.
    Fenollar F, Amphoux B, Raoult D (2009) A paradoxical Tropheryma whipplei western blot differentiates patients with Whipple disease from asymptomatic carriers. Clin Infect Dis 49(5):717–723PubMedCrossRefGoogle Scholar
  52. 52.
    Keinath RD, Merrell DE, Vlietstra R, Dobbins WO 3rd (1985) Antibiotic treatment and relapse in Whipple’s disease. Long-term follow-up of 88 patients. Gastroenterology 88(6):1867–1873PubMedGoogle Scholar
  53. 53.
    Lagier JC, Fenollar F, Lepidi H, Raoult D (2010) Failure and relapse after treatment with trimethoprim/sulfamethoxazole in classic Whipple’s disease. J Antimicrob Chemother 65(9):2005–2012PubMedCrossRefGoogle Scholar
  54. 54.
    Cannon WR (2003) Whipple’s disease, genomics, and drug therapy. Lancet 361(9372):1916PubMedCrossRefGoogle Scholar
  55. 55.
    Schneider T, Stallmach A, von Herbay A, Marth T, Strober W, Zeitz M (1998) Treatment of refractory Whipple disease with interferon-gamma. Ann Intern Med 129(11):875–877PubMedGoogle Scholar
  56. 56.
    Lagier JC, Fenollar F, Lepidi H, Liozon E, Raoult D (2010) Successful treatment of immune reconstitution inflammatory syndrome in Whipple’s disease using thalidomide. J Infect 60(1):79–82PubMedCrossRefGoogle Scholar
  57. 57.
    Pauletti C, Pujia F, Accorinti M et al (2010) An atypical case of neuro-Whipple: Clinical presentation, magnetic resonance spectroscopy and follow-up. J Neurol Sci 297(1–2):97–100PubMedCrossRefGoogle Scholar
  58. 58.
    Panegyres PK, Edis R, Beaman M, Fallon M (2006) Primary Whipple’s disease of the brain: characterization of the clinical syndrome and molecular diagnosis. QJM 99(9):609–623PubMedCrossRefGoogle Scholar
  59. 59.
    Thwaites GE, Nguyen DB, Nguyen HD et al (2004) Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 351(17):1741–1751PubMedCrossRefGoogle Scholar
  60. 60.
    Raoult D, Lepidi H, Harle JR (2001) Tropheryma whipplei circulating in blood monocytes. N Engl J Med 345(7):548PubMedCrossRefGoogle Scholar
  61. 61.
    Kalt A, Schneider T, Ring S et al (2006) Decreased levels of interleukin-12p40 in the serum of patients with Whipple’s disease. Int J Colorectal Dis 21(2):114–120PubMedCrossRefGoogle Scholar
  62. 62.
    Al Moussawi K, Ghigo E, Kalinke U, Alexopoulou L, Mege JL, Desnues B (2010) Type I interferon induction is detrimental during infection with the Whipple’s disease bacterium, Tropheryma whipplei. PLoS Pathog 6(1):e1000722PubMedCrossRefGoogle Scholar
  63. 63.
    Desnues B, Raoult D, Mege JL (2005) IL-16 is critical for Tropheryma whipplei replication in Whipple’s disease. J Immunol 175(7):4575–4582PubMedGoogle Scholar
  64. 64.
    Ghigo E, Barry AO, Pretat L et al (2010) IL-16 promotes T. whipplei replication by inhibiting phagosome conversion and modulating macrophage activation. PLoS ONE 5(10):e13561PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Medical Department ICharité - University Medicine Berlin, Campus Benjamin FranklinBerlinGermany

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