Whipple's disease K90.8; M14.8

George Hoyt Wipple 1907

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).

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

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.

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).

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.

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 ↓;

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.

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.

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

• Ceftriaxone 2 g daily for 14 days

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.

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.

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