Download Whipple`s Disease

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