Whipple's diseaseK90.8; M14.8

Author:Prof. Dr. med. Peter Altmeyer

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Last updated on: 21.06.2022

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Synonym(s)

intestinal lipodysthrophy; T whipplei infection; Whipple's disease; Whipple`s Disease

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HistoryThis section has been translated automatically.

George Hoyt Wipple 1907

DefinitionThis section has been translated automatically.

Rare, chronic recurrent, systemic infection caused by the bacterium Tropheryma whipplei, clinically characterized by diarrhea/steatorrhea, abdominal pain, malabsorption syndrome, severe weight loss and other extraintestinal symptoms (Feurle EG et al. (2015). Although the bacterium is often detectable, very few people develop Whipple's disease (El-Abassi R et al. 2017). In a larger Italian population (n=1240) the average colonisation rate with Tropheryma whipplei was 6.9% (Italians: 4.9%/migrants:9.3%). The younger volunteers showed a higher colonization rate with Tropheryma whipplei than the older ones (12.7 vs 5.9%). The prevalence in children < 10 years was 17.3 vs. 7.3% in older children (Beltrame A et aal. 2019).

PathogenThis section has been translated automatically.

Tropheryma whipplei (rod-shaped bacterium), species of actinobacteria, order actinomycetes. The pathogens persist both intra- and extracellularly. No transmission from person to person. The path of infection is unclear.

Occurrence/EpidemiologyThis section has been translated automatically.

Worldwide occurrence; more common in rural areas. Rare in Germany: about 20-50 cases/year. m:f= 3:1 (Feurle GE et al. 2010)

EtiopathogenesisThis section has been translated automatically.

The pathogen Tropheryma whipplei is widely distributed in the environment, e.g. in sewage. Asymptomatic colonization of the intestinal lumen is present in about 2% to 4% of the population. Tropheryma whipplei causes systemic disease in genetically predisposed individuals. Rarer are localized forms of T. whipplei infection, e.g., at heart valves or in the CNS.

Association with HLA B7 antigen in 25-30% of cases. Familial clustering and clustering have been described.

  • A defect in cellular defense (T-lymphocyte and monocyte-macrophage function) seems to be the main cause in the pathogenesis, but the complete pathogenesis is not yet well understood.
  • Phagocytosis of the pathogens by macrophages occurs in the upper small intestine; the macrophages cause lymphatic congestion. This often results in a blockage of nutrient absorption in the small intestine with malabsorption syndrome.

ManifestationThis section has been translated automatically.

Mainly white men between 30 and 60 years of age. M. Whipple patients are on average 55 years old at diagnosis. In a rheumatological clientele the annual Wipple incidence was 3.6/100000 inhabitants ((Feurle GE et al. 2010, Herbette M et al. 2018).

Clinical featuresThis section has been translated automatically.

The main focus is on intestinal symptoms, which often reach their maximum expression only after many years. Typically, diarrhea, weight loss, abdominal pain, malabsorption syndrome are seen; less frequently, non-viral hepatitis or jaundice. On small bowel endoscopy, the lymphatic congestion is manifested by mucosal swelling with whitish mottling (snow flurries).

General symptoms are nonspecific: fever, night sweats, joint complaints (often long before gastrointestinal symptoms), myalgias. Lymphadenopathy.

Integument: purpura (30% of cases); icterus if liver is involved. Occasionally intensely pruritic or burning erythema; also blisters, vesicles, wheals, papules, pustules. The picture may resemble dermatitis herpetiformis.

Furthermore, Whipple's patients are conspicuous by diffuse hyperpigmentation of skin and mucous membranes of unexplained etiology. Remarkably, Tropheryma-whipplei is also encountered in apparently unaffected skin in cases of full-blown Wipple symptoms, so it is assumed that the skin serves as a reservoir for this Gram-positive bacterium (Angelakis E et al.2010). Specific skin lesions, however, are rare and externalize as septal panniculitis with PAS-positive macrophages in which Tropheryma whipplei antigen was detectable (Canal L et al. 2014). Furthermore, eosinophilic vasculitis and dermatomyositis have been reported as manifestations of Wipple disease (Al-Hamoudi W et al.2007, Helliwell TR et al. 2000) and erythema nodosum in the context of an immunological reconstitution syndrome.

Heart: Symptomatology similar to heart failure and angina pectoris. Endocardium, myocardium, pericardium, valves, coronary arteries may be affected.

Bone changes, arthralgias (leading symptom!).

Neurology/psychiatry (about 10% of cases): Headache, impaired concentration, cranial nerve deficits, epilepsies, depression, dementia, headache, parkinsonism, apathy, tinnitus, ophthalmoplegia, dysarthria.

Lung: cough, dyspnea, pleurisy, pleural effusion.

LaboratoryThis section has been translated automatically.

Iron deficiency anemia.

Leukocytosis.

ESR and CRP elevation.

Protein deficiency (albumin).

Vitamin B12 and folic acid deficiency.

Calcium, potassium and phosphate deficiency.

Anemia, albumin↓, ferritin↓; IgM and IgA ↓;

HistologyThis section has been translated automatically.

Intestine: Swollen intestinal villi, atrophic epithelium, wide lymphatic vessels, in the mucosa storage cells with lipid droplets and stainable bacteria in the cytoplasm. PAS staining of the intestinal preparation shows PAS-positive SPC cells (siccle particles containing cells).

Liver: granulomatous hepatitis.

DiagnosisThis section has been translated automatically.

If M. Whipple is suspected, the first diagnostic measure should be an esophagogastroduodenoscopy (ÖGD) with collection of duodenal biopsies. Important: PAS-staining of the biopsy, if necessary additional PCR for antigen detection. The detection of macrophages containing large amounts of PAS-positive particles is still considered the diagnostic standard of M. Whipple, which should always be used primarily (Von Herbay A et al. 2001; Von Herbay A et al. 1996). In addition: Ziehl-Neelsen staining to exclude mycobacteriosis.

In many cases of Whipple's disease no macroscopic abnormalities of the duodenal mucosa are visible in gastroscopy, but whitish yellowish mucosal changes in the duodenal mucosa and a recognizable flattening of the villi in zoom endoscopy or mosaic patterns in chromoendoscopy may be an indication of Whipple's disease (Lagier JC et al. 2010). Erythematous and/or erosive changes in the duodenum are not typical. In any clinical suspicion several biopsies should be taken at different sites, because infiltration by macrophages may be spotty and because histological examination may be positive even if gastrointestinal symptoms are absent. In contrast to diagnostics from the gastrointestinal tract and the lung, T. whipplei PCR is unambiguous and irreplaceable for diagnostics in body fluids (CSF, synovial fluid, pleural effusion, ascites, etc.) in patients who have not been pretreated with antibiotics.

Associated diseases: Occasionally associations with lymphomas, amyloidosis, candidasepsis and (more frequently) with Gardia lamblia infection have been reported.

Differential diagnosisThis section has been translated automatically.

Rheumatic diseases; Lyme disease; M. Reiter; sarcoidosis; tumour diseases; neuropsychiatric diseases.

Complication(s)This section has been translated automatically.

Strong tendency to relapse (starting from the brain).

Internal therapyThis section has been translated automatically.

An antibiotic therapy with ceftriaxone/cotrimoxazole should be administered to M. Whipple:

Subsequently: Cotrimoxazole 960 mg 2 x 1 daily per os over 1 year

Alternatively: Doxycycline 100 mg 2 x daily per os + Hydroxychloroquine 200 mg 3 x daily per os over 1 year. Afterwards mostly Doxycyclin for life. In case of CNS infestation additionally: 960 mg Cotrimoxazol 5 x daily until CSF PCR negative, then 2 x daily per os

T. whipple endocarditis occurring in the context of M. Whipple can heal under the recommended therapy even without heart valve resection, as long as the valve is not too severely damaged, but there are no prospective data on this (Feurle EG et al. (2015).

Drug intolerance: In case of intolerance to ceftriaxone, meropenem should be administered and in case of intolerance to cotrimoxazole, doxycycline.

Side effects:

  • Jarisch-Herxheimer reaction: rare, highly febrile complication. Fever occurs immediately after the first administration of antibiotics and persists for up to 48 hours (see also under syphilis). Apart from antipyretic measures there is no indication for therapy.
  • Inflammatory immune reconstitution syndrome (IRIS): after the start of antibiosis: fever, polyarthritis, orbitopathy, perforation of the small intestine, erythema nodosum, pleuritis. In a cohort of 142 patients with Whipple's disease, IRIS occurred complicatively in 10% of patients. IRIS can occur years after the initial antibiotic therapy and can be lethal (Feurle GE et al. 2010). Therapeutically, early and temporary use of glucocorticoids is important.

Progression/forecastThis section has been translated automatically.

Untreated cases are progressive and in most cases fatal.

After antibiotic therapy, clinical improvement occurs very quickly, fever and joint pain disappear within a few days. The intestinal symptoms subside within 1-4 weeks.

A potential side effect of the therapy can be animmune reconstitution inflammatory syndrome (IRIS).

After therapy, relapses are quite common and can occur even years later. If a relapse is suspected, a new small bowel biopsy should be performed.

AftercareThis section has been translated automatically.

Clinical, laboratory chemical, imaging and endoscopic controls for 10 years.

LiteratureThis section has been translated automatically.

  1. Al-Hamoudi W et al.(2007) Eosinophilic vasculitis: a rare presentation of Whipple's disease.Can J Gastroenterol 21:189-191.
  2. Angelakis E et al.(2010) Tropheryma whipplei in the skin of patients with classic Whipple's disease.J Infect 61:266-269.
  3. Beltrame A et al. (2019) Tropheryma whipplei intestinal colonization in Italian and migrant population: a retrospective observational study. Future Microbiol 14:283-292. https://www.ncbi.nlm.nih.gov/pubmed/30855186
  4. Canal L et al (2014) Specific cutaneous involvement in Whipple disease.At J Dermatopathol 36:344-346.
  5. Desnues B et al. (2006) Whipple's disease: a macrophage disease. Clin Vaccine Immunol 13: 170-178.
  6. El-Abassi R et al. (2017) Whipple's disease.J Neurol Sci 377:197-206. https://www.ncbi.nlm.nih.gov/pubmed/28477696
  7. Fenollar F et al (2001) Whipple's endocarditis: review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis. Clin Infect Dis 33:1309-1316
  8. Feurle EG et al (2015) S2k Guideline Gastrointestinal Infections and Whipple's Disease. Z Gastroenterol 53:418-459
  9. Feurle GE et al (2010) The immune reconstitution inflammatory syndrome in whipple disease: a cohort study. Annals of internal medicine 153:710-717
  10. Feurle GE et al (2010) Efficacy of ceftriaxone or meropenem as initial therapies in Whipple's disease. Gastroenterology 138:478-486.
  11. Helliwell TR et al (2000) Dermatomyositis and Whipple's disease. Neuromuscular disord 10:46-51.
  12. Herbette M et al (2018) Usefulness of polymerase chain reaction for diagnosing Whipple's disease in rheumatology. PLoS One 13:e0200645.
  13. Hujoel IA et al.(2019) Tropheryma whipplei infection (Whipple Disease) in the USA. Dig Dis Sci 64:213-223.
  14. Lagier JC et al (2010) Systemic Tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine 89:337-345
  15. Marin M et al (2007) Tropheryma whipplei Infective Endocarditis as the Only Manifestation of Whipple's Disease. J Clin Microbiol 45: 2078
  16. Marth T et al (2003) Whipple's disease. Lancet 361: 239
  17. Marth T et al (2016) Tropheryma whipplei infection and Whipple's disease. Lancet Infect Dis 16:e13-22.
  18. Marth T (2016) Whipple's disease. Acta Clin Belg 71:373-378.
  19. Ojeda E et al (2010) Whipple's disease in Spain: a clinical review of 91 patients diagnosed between 1947 and 2001 Rev Esp Enferm Dig 102:108-123.
  20. Panegyres PK et al (2006) Primary Whipple's disease of the brain: characterization of the clinical syndrome and molecular diagnosis. QJM 99: 609
  21. Schneider T et al (2008) Whipple's disease: new aspects of pathogenesis and treatment. The Lancet infectious diseases 8:179190
  22. From Herbay A (2001) Whipple's disease. Histological diagnosis after the discovery of Tropheryma whippelii. The pathologist 22:82-880
  23. Revised by Herbay A et al (1996) Histology of intestinal Whipple's disease. A study of 48 patients. Virchows Arch 429:335-343
  24. Whipple GH (1907): A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bulletin Johns Hopkins Hosp 18: 382-391.

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Last updated on: 21.06.2022