Whipples Disease Lancet 2003

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Infection with Tropheryma whipplei is a good example ofthe contributions of modern molecular-based techniquesto pathogenetic, diagnostic, and therapeutic ideas inclinical medicine. The organism has been cultivated andcharacterised by molecular-genetic techniques. Clinicalmanifestation of T whipplei infection seems to occur in thepresence of low activity of T-helper cells of type 1 (Th1).These findings, together with other results, have led to animproved pathophysiological understanding of the diseaseand to new perspectives in treatment strategies.

BacteriologyThe cause of Whipples disease remained obscure foryears. In his initial description, Whipple reported thatsilver-stained rod-shaped microorganisms were visible inthe vacuole of macrophages, but he did not link thisobservation with a possible causative agent.1 Laterstaining procedures with periodic-acid-Schiff (PAS)showed abnormal material.2,3 In 1960 and 1961,observations of bacteria-like bodies were made bytransmission electron microscopy, and a bacterial causewas strongly suspected.46

The nature of this bacterium was difficult to establish.It has an atypical morphology for a gram-positive or agram-negative bacterium.7,8 Many of the observedbacteria in Whipples disease are apparently degraded in

macrophages, and intact bacteria can be seenextracellularly.712 The Whipples bacillus does not stainwell with gram stain in tissues and is gram-negative in cellculture.10,13,14 The PAS-positive material seen inmacrophages and culture is thought to correspond withcapsular mucopolysaccharides.5,10 In an effort to stain this

Lancet 2003; 361: 23946

Division of Gastroenterology, Stiftung Deutsche Klinik fr

Diagnostik, Wiesbaden, Germany (T Marth MD); and Unit des

Rickettsies, CNRS UMR 6020, IFR 48, Facult de Medicine,

Marseille, France (Prof D Raoult MD)

Correspondence to: Dr Thomas Marth, Division of Gastroenterology,

Stiftung Deutsche Klinik fr Diagnostik, Aukammallee 33,

65191 Wiesbaden, Germany

(e-mail: [email protected])

bacterium, antibodies to shigella and streptococcus Bwere tested; they cross-reacted with the bacteria, allowingpreliminary immunohistochemical testing.1518

Several attempts at culture were made but not pursuedor reproduced. The Whipples bacillus was tentativelygrown in peripheral-blood mononuclear cells deactivatedby interleukin 4.19 T whipplei was propagated in humanfibroblast cells in 1999 in minimum essential mediumwith 10% calf serum.20 The first strain has been widelydistributed and is now deposited in two official bacterialcollections.14 The bacterium grows slowly (estimated

doubling time 17 days initially), and has not been grownin axenic (cell-free) media. The site of multiplication iscontroversial; some researchers believe that the bacteriummultiplies in the digestive lumen and is taken up byphagocytosis and slowly degraded in macrophages.7,8 Invitro, the bacteria grow within peripheral-bloodmononuclear cells19 and are released from infected cells.Within HeLa cells, T whipplei multiplies actively in anacidic vacuole at pH 5.21 This high acidity impairs theactivity of antibiotic compounds22,23 and could well be thereason for the ineffectiveness of many antibiotic regimens.

The first attempt to classify the Whipples diseasebacterium was by Wilson and colleagues in 1991.24 Theinvestigators sequenced, by universal genomicamplification and PCR, a portion of the 16S rRNA of the

presumed bacterium from a duodenal-biopsy sample of apatient with Whipples disease. The sequence wasconfirmed later, and the name Tropheryma whippeliiwas

Whipples disease

Thomas Marth, Didier Raoult

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THE LANCET Vol 361 January 18, 2003 www.thelancet.com 239

Whipples disease, or intestinal lipodystrophy, is a systemic infectious disorder affecting mostly middle-aged whitemen. Patients present with weight loss, arthralgia, diarrhoea, and abdominal pain. The disease is commonly diagnosedby small-bowel biopsy; the appearance of the sample is characterised by inclusions in the lamina propria staining withperiodic-acid-Schiff, which represent the causative bacteria. Tropheryma whipplei has been classified as anactinomycete and has been propagated in vitro, which allows the possibility of improving diagnostic strategies, forexample through antibody-based detection of the bacillus on duodenal tissue or in circulating monocytes. Cell-mediated immunity in active and inactive Whipples disease has subtle defects that might predispose some individualsto symptomatic infection with this bacillus, which probably occurs ubiquitously. Although most patients respond wellto empirical antibiotic treatment, some with relapsing disease have a poor outlook. The recent findings and concerted

research might allow development of new strategies for diagnosis, treatment, and monitoring of patients withWhipples disease.

Search strategy and selection criteria

We undertook a computer-aided search of PubMed, which

identified 1216 publications on Whipples disease (1140 on

Whipple disease). In addition, mostly overlapping, we found

1139 references on intestinal lipodystrophy (111 on

Intestinale Lipodystrophie) and six on Morbus Whipple. We had

in-depth discussions with participants at the nine partner

institutes in the European project on Whipples disease.

Finally, we took into account several doctoral theses, several

general and specialist book chapters, proceedings, and one

monograph to supplement our awareness of the publishedwork.


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suggested (Greek trophe nourishment and eryma barrier,and from Whipple).25 Since culture became available thename was corrected and the organism was officiallynamed Tropheryma whipplei.14 It belongs to the high-G+Cphylum of gram-positive bacteria (figure 1). T whippleiisgrouped with bacteria mainly found in the environment

including cellulomonadacae, but also human-associatedbacteria such as Rothia dentocariosa.25,29 T whippleimeasures about 0220 m in size.5,7,9

Bacteria of the T whipplei species have some geneticheterogeneity, as shown by sequencing of the 16S23SrDNA interspacer29,30 and the 23S rDNA.31 The genomicvariants are associated with the place of residence of thepatients and might be geographically distributed.32

T whippleihas a single circular chromosome and smallgenome size (925 kb); its genome has been sequencedand deposited in Genbank (unpublished). There is noclear link between genotype and symptom pattern;however, the issue of subspecies pathogenic specificityremains unresolved. Some strains could be non-pathogenic, some cause typical Whipples disease, and

others cause atypical clinical forms such as infectiousendocarditis.12,32,33

The habitat of T whippleiis unknown. Detection of thebacterium by PCR in sewage water in Germany34 and inhuman faeces12,35 led to speculation that it exists in theenvironment and contaminates people through drinkingwater. However, the possibility that human beings are thereservoir cannot be excluded. PCR-based studies havealso shown that T whippleican be amplified from saliva,gastric fluid, and duodenal-biopsy samples of peoplewithout Whipples disease.3638 The frequency of samplespositive for T whipplei by PCR in people who areasymptomatic depends on the geographical origin of theindividual;12 this feature could explain why otherresearchers did not find such results in other geographicalregions.39 The reliability of PCR tests in people withoutWhipples disease is also controversial.

Epidemiology and pathogenesisWhipples disease is rare, and no valid estimate of theincidence is available. The disorder has been describedmost frequently in white people and in mid-Europe (of696 cases, 55% were reported from Europe and 38% fromNorth America).40 Only a few cases have been reported inHispanic, black, Indian, or Asian populations. Many of

the published cases come from rural regions, and farmersare frequently among the documented occupations.40,41

The disease sometimes occurs in local clusters.4244

Specific environmental factors or habits have not yet beenassociated with the disorder.

Despite the presumed ubiquitous presence ofT whipplei,34 Whipples disease occurs mainly in middle-aged individuals (mean age at diagnosis about 50 years)and in about eight times more men than women,40,4547

which supports the effect of genetic factors in the cause. Astudy by von Herbay and colleagues48 and data from thetherapy study SIMW (Study on the Initial Therapy ofMorbus Whipple, within the European project onWhipples disease) suggested that the disease is moreprevalent in women, but this finding is not confirmed by

larger epidemiological series. Several familial cases(brother pairs, father and daughter) have beenreported,4951 but most of the analysed cases do not suggestfamilial components. A genetic susceptibility is suggestedby the finding that about 26% of patients (three to fourtimes more than expected) are positive for HLA B27;40,52

however, this characteristic is not found in all populations(for example, Italy53 and Argentina54). The disease canhave a chronic relapsing course, and the organism canpersist in affected tissues for a long time, even withextended antibiotic therapy. Collectively, theseobservations suggest that a host factor, putatively of animmunological nature, has a role in the occurence of thedisease.

Figure 2 shows the defective immune responses seen in

patients infected with T whipplei. The presumedimmunological defect is likely to be subtle and quitespecific for T whipplei, since patients are not generallyprediposed to infection with other organisms. Only a fewcase reports have pointed to the possibility that Whipplesdisease also occurs in a setting of immunodeficiency55 orimmunosuppression56,57 or concomitantly with otherinfections (eg, in individuals with AIDS,58 nocardiasis, orlambliasis59,60).

Results of several immunohistological studies7,61 haveshown that despite the influx of macrophages, intestinaltissue has little lymphocytic infiltration and few plasmacells in Whipples disease. Although this lack couldreflect a secondary loss of lymphocytes caused byintestinal lymphangiectasia, some investigators have

identified more profound phenotypical and functionalchanges in immunity. Populations of T cells in thelamina propria and the circulation in active Whipplesdisease are characterised by a low CD4/CD8 T-cellratio, a shift towards mature T-cell subpopulations (eg,high expression of CD45RO, low CD45RA expression),and increased cell-activation markers.62,63 Reducedproliferative responses of peripheral T cells are found,for example, in response to phytohaemagglutinin,concanavalin A, and antibodies to CD2.52,64 In somecases, as yet unidentified inhibitory serum factors havebeen identified, which downregulate T-cell-mediatedresponses.63,64 These changes, and the impaired delayed-type hypersensitivity reaction to recall antigens, arepresent not only in patients who are acutely ill but alsoin those with long-standing remission.60,61,63,64 Themucosa contains low numbers of IgA-positive B cells but

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240 THE LANCET Vol 361 January 18, 2003 www.thelancet.com

Mycobacterium lactis D21343

Mycobacterium liquefaciens X77444Agromyces ramosus X77447

Curtobacterium citreum X77436

Tropheryma whipplei AF251035

Cellulomonas hominis X82598

Cellulosimicrobium cellulans AB023355

Brevibacterium linens AJ315491

Kocuria rosea Y11330

Arthrobacter globiformis X80736

Micrococcus luteus AJ409096Arcanobacterium pyogenes X79225

Corynebacterium renale X84249Pseudonocardia thermophila AJ252830

Mycobacterium leprae X55587

Mycobacterium chelonae AJ419969

Nocardia asteroides Z82231

Rhodococcus equi X80614

Bacillus subtilis AF447803

Clostridium perfringens AB075767

002

Figure 1: Phylogenic position of T whippleibased on 16S rRNAsequencingThe complete nucleotide sequences of the 16S rRNA gene of all testedspecies were aligned by use of CLUSTAL W.26 Phylogenetic relationsamong these bacteria were inferred by use of PHYLIP software (version3.4).27 The distance matrices generated by DNADIST were determinedunder the assumptions of Kimura and were used to infer dendrograms bythe neighbour-joining method.28 Scale bars represent the percentage ofnucleotide differences.


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increased numbers of surface-IgM-positive B cells.65

Secretory IgA concentrations measured in intestinalaspirates and humoral immune responses to infectiousagents in the periphery are normal.17,66 In addition, serumconcentrations of total IgG are normal in most cases,whereas IgM concentrations are low and those of IgAhigh in acute stages of the disease.43,6668 We have recordedlow concentrations of the IgG2 subclass in severalpatients with Whipples disease, which is produced inresponse to infection with encapsulated bacteria and is

regulated by cell-mediated immune responses andinterferon .69

Studies on macrophages in Whipples disease aresparse. Macrophages from infected patients showdecreased intracellular degradation70 and a decrease inphagocytosis.71 Patients with either active or inactiveWhipples disease have lower than normal numbers ofcirculating cells expressing CD11b. This molecule servesas a facilitator of microbial phagocytosis, has a role inantigen processing, and mediates intracellular killing ofingested bacteria that is induced by interferon .63

Furthermore, at least during active disease, intestinalmacrophages do not express CD11b.72 Thus, a reductionin CD11b expression could indicate a decrease in theability to cope with intracellular infection. Results of our

studies69,73 on 20 patients show that the impaired functionof antigen-presenting cells in Whipples disease is relatedto low production of interleukin 12 in macrophages; thiscytokine has important functions in regulation of cell-mediated immune responses. Low serum concentrationsof interleukin 12p40 have also been recorded(unpublished data). By contrast, functional Th2responses increase and Th1 responses decrease inperipheral and mucosal T cells73 lending support to theobservation that T whipplei replicates in macrophagesdeactivated by interleukins 4 and 10.19 As a furtherindication of the pathogenetic relevance of the impairedcellular immune responses, in one patient who hadWhipples disease refractory to antibiotic regimens andlow concentrations of interferon , treatment withantimicrobials and supplemental recombinant interferongamma led to clearance of the infection.74

Thus, the persistent subtle defect ofcellular immunity seems to involveactivation and interaction of macro-phages and T cells. These processescould result in disturbed phagocytosisand intracellular degradation ofT whipplei and allow invasion of the

bacillus from the gastrointestinalmucosa to peripheral organs. Futurestudies with more patients are needed toclarify the exact nature of these defectsand possible genetic components.

Clinical features and diagnosisWhipples disease has traditionally beenregarded as a gastrointestinal disease,but in most cases, the disease beginsinsidiously with arthropathy. In onelarge series,63,75 arthropathy was the firstsymptom in 63% of patients, precedingthe diagnosis of Whipples disease by amean of 8 years. Arthropathy, in many

cases associated with HLA-B27positivity, consists of chronic, migra-tory, non-destructive, and seronegativejoint disease, mainly in the peripheraljoints.40,43 The sacroiliac region is

affected in up to a third of patients,76 and radiologicalchanges are found in around a fifth.77 The arthropathy iscommonly accompanied by myalgias.40,47,75 Since newdiagnostic methods enable detection of T whipplei insynovial fluid,78 which can occur as effusion besides othermicroscopic signs of synovitis, patients with such diseasemight be diagnosed earlier in future.

Weight loss and diarrhoea are the other major symptomsby the time of diagnosis. Weight loss is found almostinvariably. In one large series,43 two-thirds of patients had

clinically relevant weight loss (up to 20% of the previousweight) more than 4 years before diagnosis. Gastro-intestinal symptoms, which generally begin later andultimately lead to diagnosis, consist of episodic and waterydiarrhoea or steatorrhoea, in many cases accompanied bycolicky abdominal pain and, in 2030% of patients, byoccult blood in the stool.40,46,47 These symptoms andconcomitant anorexia lead to the full picture of amalabsorption syndrome with severe weight loss,weakness, general cachexia, and the associated secondarysigns and symptoms.

On endoscopy, the lesions of Whipples disease arecommonly described as pale yellow shaggy mucosaalternating with an erythematous, erosive, or mildly friablemucosa in the postbulbar region of the duodenum or in the

jejunum; alternatively, whitish-yellow plaques can be seenin a patchy distribution.79,80 Therefore, biopsy samplesshould be taken from both the proximal and distalduodenum or the jejunum. Endoscopy also plays animportant part in follow-up. The duodenal mucosarecovers during the first weeks to months of antibiotictreatment, whereas the PAS-positive material in themacrophages can persist for several years; an increase inPAS-positive material after a previous resolution can bethe first indicator of a relapse.79,80 A subtype classificationof PAS-positive cells indicative of florid or chronicWhipples disease lesions has been suggested, which mightbe helpful for the clinician in some patients.81

We emphasise that clinical presentation can vary to agreat extent owing to differential organ involvement, andsome patients present without gastrointestinalmanifestations.75,82 Systemic symptoms in about half of

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Reduced intracellular

degradation

ofT whipplei

Growth of T whipplei

in IL 4/IL 10 deactivated

monocytes

In vitro production of monocyte-secreted IL 12

and reduced expression of IL 12 in lamina propria

Functional effects:

cutaneous reactivity to recall antigens

Benefit effect of additive therapy with

recombinant IFN in antibiotic refractory patients

Serum: unidentified inhibitory factors

T-cell proliferative response

CD4/CD8 ratio

Expression of CD11b

Expression of mature T cells

Expression of naive T cells

Th1 responses: IL 2 , IFN

Th2 responses: IL 4

Macro-

phage

Tropheryma

whipplei IFN

IL 12

T cell

Figure 2: Defective immune responses in T whippleiinfectionIL=interleukin. IFN=interferon.


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patients consist of intermittent, mostly low-grade fever andnight sweats. Common features are also peripheral andabdominal lymphadenopathy; the mesenteric lymph-adenopathy is identified frequently on radiographs butcould also be present as an abdominal mass. Skin hyper-pigmentation, particularly affecting light-exposed areas andsuggesting Addisons disease (which has not been observedin patients with Whipples disease), has been recorded in upto a third of patients in a large series.41,44 No major organ isexcluded from infection by T whipplei, and chronic non-productive cough or chest pain indicative of lunginvolvement or pleuritis, polyserositis, ascites, hypotension,

and oedema are among other signs and symptomsfrequently noted (table 1). Hepatomegaly or splenomegalycan be present in some patients with this disorder. Lessfrequent involvement has been reported for thegenitourinary and endocrine systems.40,4547,56

Cardiac involvement is common and has been reportedto be an important clinical sign. It might present as cardiacmurmurs, insufficiency of the aortic or mitral valvenecessitating replacement, or with the clinical picture ofblood-culture-negative endocarditis; many of these casesare diagnosed by histological analysis of the cardiacvalves.8388 In many of these patients, endocarditis isisolated; no other evidence of clinical Whipples disease isobserved and duodenal biopsy is negative.85,87

A CNS manifestation can first become apparent as a

memory disorder, personality change, or dementia in manypatients. Other more common clinical signs areophthalmoplegia, nystagmus, and myoclonia. These arefrequently noted in combination with a disturbed sleeppattern, ataxia, seizure, or symptoms of cerebralcompression (due to hydrocephalus). Various cranial-nervesymptoms, such as hearing loss and blurred vision, havebeen reported.40,45,89,90 In some patients, a specificoculomasticatory myorhythmia or myoclonus withophthalmoplegia has been described.91,92 Such CNSsymptoms have a frequency of up to 15% and can occur inrare instances with little or no gastrointestinalinvolvement.40,92

Radiographic assessment including routine radiographicexamination, barium enema, CT, and MRI, oftenundertaken because of gastrointestinal symptoms, canreveal abdominal lymphomas, a thickening of the mucosal

folds, hepatosplenomegaly, ascites, or other specific organinvolvement. MRI is useful in diagnosis of CNSmanifestations.93 Laboratory tests can show evidence ofmalabsorption and protein-losing enteropathy, such as lowserum concentrations of carotene, vitamin deficiency(B12, D, K, and folic acid), and low albumin andcholesterol concentrations; additionally, stool fat excretion

might be raised, and D-xylose absorption low.40,46,56

Manypatients with Whipples disease have, for unknown reasons,pronounced eosinophilia87 and abnormalities of serumimmunoglobulins as mentioned in the pathogenesissection.43,61,64 Other non-specific laboratory abnormalitiesinclude a high erythrocyte sedimentation rate, increasedconcentrations of acute-phase proteins such as C-reactiveprotein, lymphocytopenia, thrombocytosis, and hypo-chromic anaemia.

Histopathological and laboratory diagnosisThe first diagnostic method is the histological appearance.When the disease is suspected, duodenal-biopsy specimensshould be obtained. Depending on the clinicalmanifestations, other samples should be tested, such as

cerebrospinal fluid (CSF), cardiac-valve tissue, lymphnodes, and synovial tissue.46,94 The infiltration of the bowelwall is associated with a widening and flattening of the villiand with dilated lacteals containing yellow lipid deposits,the result of blockade of the villous lymphatics (thereforeWhipple suggested the name intestinal lipodystrophy).1,7,11,13

Histological analysis reveals granular foamy macrophagesstained purple with PAS (figure 3); in addition, diastase-resistant and silver-positive inclusions representing more orless intact remnants of ingested bacteria might bevisible.5,10,13 Duodenal samples from patients with Whipplesdisease are infiltrated by macrophages; the proportion ofmacrophages among duodenal cells in these samples canrange from under 5% (in the normal host) to 50% (ourobservation). However, PAS staining is not completely

specific; patients with infection caused by Mycobacteriumavium-intracellulare, Rhodococcus equi, Bacillus cereus,corynebacterium, histoplasma, or fungi also have PAS-positive macrophages (only partly ruled out by a Ziehl-Neelsen stain for acid-resistant microorganisms).40,9597

Samples from patients with melanosis coli and histocytosis,and colon samples from patients with Crohns disease, canalso be confused in rare instances with Whipplesdisease.40,98 Involvement of lymphatic tissues, thegastrointestinal tract, and rarely other organs can beaccompanied by non-caseating, epithelioid-cell (sarcoid-

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Approximate frequency

Major clinical features

Weight loss 90%

Arthropathy 85%

Diarrhoea 75%

Abdominal pain 60%

Frequent signs and symptoms

Fever 45%

Lymphadenopathy 45%

Hyperpigmentation 35%

Hypotension 35%

Peripheral oedema 30%

Cardiac murmurs 30%

Occult bleeding 25%

Myalgia 25%

Abdominal mass 20%

CNS/eye involvement* 15%

Chronic cough 15%

Splenomegaly 15%

Hepatomegaly 10%

Ascites 10%

Other signs and symptoms Rare

*Dementia, ophthalmoplegia, myoclonus, ataxia, nystagmus, visual loss,uveitis, retinitis. eg, pleuritis, pleural effusion, endocarditis, muscle wasting,glossitis, peripheral neuropathy.

Table 1: Signs and symptoms in Whipples disease

Figure 3: Histopathology of Whipples disease(A) Control patient biopsy sample (negative). (B) Whipples disease jejunal

biopsy sample. 1=stained by PAS (macrophages are stained in red inpatients with Whipples disease). 2=stained by immunohistochemistrywith a polyclonal antibody to T whipplei(courtesy of H Lepidi).


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like) granulomas.99 Bacteria can also be reliably visualisedby electron microscopy,7,9 but this approach is lessconvenient. Since Whipples disease is systemic, PAS-positive macrophages and electron-microscopicallydetectable bacilli have been shown in many cell types and inalmost all organs.9,13

Immunohistochemistry is of diagnostic help.100102 Non-

specific cross-reactions have prompted very low cross-reactions (with shigella and Streptococcus agalactiae) andshould be very useful (figure 3). We have shown thatimmunohistochemistry can detect T whippleiin circulatingmonocytes of patients with active Whipples disease.101

Culture is currently undertaken only for researchpurposes in highly specialised laboratories. It may notbecome a method of diagnosis until culture conditions areimproved. T whipplei grows slowly in human fibroblasts(MRC 5 and HEL cells),14 Hela cells, and humanperipheral-blood monocytes.19 The major difficulty is thatprimoculture takes a very long time. Our first successfulculture showed a cytopathic effect in cells after 2 months.Antibiotic treatment of patients precludes isolation of thebacterium (unpublished data). Culture from contaminated

samples necessitates use of an antibiotic cocktail in theculture medium.100

PCR gene amplification is a promising technique.However, discrepancies occur, depending on the teaminvolved and the samples tested. Positive PCR results werereported with testing of gastric fluid, small-bowel samples,and saliva from patients without disease.3638 These resultswere not confirmed by other teams.39,102 We reportedquantitative detection of T whippleiRpoB sequence by real-time PCR and showed that we can identify a cut-off on thebasis of the number of DNA copies to avoid false-positiveresults.103 We detected 102 to 105 copies in digestive samplesin infected patients and none in 150 controls. QuantitativePCR could also help in the future, as suggested by regularPCR,103 to follow up treated patients. Several gene

sequences are available94 based on 16S rRNA (such asinterspacer), 23S rRNA, or RpoB.104 We recommendbefore definitive diagnosis, when atypical cases arereported, use of at least two PCR tests based on primersobtained from two different genes to avoid false-positiveresults caused by contamination. Samples useable for PCRare duodenal-biopsy tissue, synovial fluid, lymph nodes,cardiac valve, vitreous humour, and CSF. The usefulness ofsaliva and faeces for diagnosis remains unclear.35,36 Blood isnot reproducibly a good sample for this purpose.105,106 DNAextraction is a crucial step in the procedure, and severalprotocols have been proposed, which could be used onparaffin-embedded tissues.91,107,108 There is a risk ofcontamination with PCR, which is higher with semi-nestedor nested methods. Results have to be interpreted with

caution and according to the clinical situation.Serology gave promising preliminary results,20 but after

subcultures there is an antigenic shift of the bacterium, andcrude antigen lacks specificity after a few subcultures invitro (unpublished data). Biological monitoring of treatedpatients with Whipples disease has not been established. Atpresent, there is no clear link between any of the tests usedfor diagnostic purposes and the achievement of remission inpatients. PCR on repeated samples is inefficient forprediction of outcome.108 PAS staining generally is notsufficiently predictive in our experience, because PAS-positive material clears slowly during treatment. Theclinician always has to interpret the histopathological andlaboratory findings in view of the clinical presentation of thepatientie, treatment should not be started for a positivePCR test without clinical correlation. In cases of doubt, aspecialist should be contacted.

Treatment and prognosisUntreated Whipples disease can be fatal. However, inmany patients with the disease, antibiotic therapy leads torapid improvement in clinical status and to lastingremission.11,40,109111 Diarrhoea and fever can resolve asquickly as within 1 week of the start of therapy, andarthropathy and other symptoms improve in many casesafter a few weeks. Clinical improvement is generallyaccompanied by a normalisation of laboratory findings andgradual reconstitution of the villous architecture of thesmall intestine. Immunological abnormalities, such asincreased IgA or shifts in T-cell subpopulations, resolve

within a few months in most patients, but the subtle defectin cell-mediated immunity persists, as mentionedearlier.40,46

In the past, various antibiotic regimens were used on anempirical basis. Many patients were treated up to the 1980swith a 2-week course of intravenous penicillin plusstreptomycin followed by oral tetracycline.110 Tetracyclinetreatment seems to be associated with a high frequency ofrelapse (table 2), so trimethoprim-sulfamethoxazole(160/800 mg orally twice daily) given for at least a year isnow recommended (panel).46,111 In addition, tetracyclinedoes not cross the bloodbrain barrier to a relevant extent,and many patients with Whipples disease have a positivePCR for T whipplei in the CSF or a CNS manifes-tation.111113 In the case of sulphonamide intolerance,

second-line regimens including minocycline, tetracycline,or oral penicillin have been applied, and other antibioticssuch as fluoroquinolones and cephalosporins have be usedon an individual basis. Oral treatment should be preceded,especially in patients who are severely ill, by a 2-weekcourse of parenteral therapy, which can consist, on thebasis of available clinical data, of ceftriaxone (2 g per dayintravenously) or treatment with another antibiotic thatreadily penetrates the blood-brain barrier.53,111,114 In patientswho are severely ill, replacement therapy is indicatedsimilar to other malabsorption syndromes.

No prospective studies are available on the choice orduration of antibiotic treatment. Culture of T whippleiand

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Currently recommended treatment

2 weeks parenteral therapyCeftriaxone (or penicillin plus streptomycin)

Long-term therapy (1 year)Trimethoprim-sulfamethoxazole (or tetracycline or minocycline)

Individual therapeutic approaches on experimental basisPrimary CNS manifestation, relapse with CNS manifestation, antibiotic

refractory (two or more relapses), antibiotic-resistant course.

Contact: Prof T Marth, Division of Gastroenterology, Stiftung Deutsche

Klinik fr Diagnostik, Aukammallee 33, 65191 Wiesbaden, Germany

(tel +49 611 577 628; fax + 49 611 577 460; email

[email protected]) or Prof G E Feurle, Innere Medizin I,

DRK Krankenhaus, D 56566 Neuwied (tel +49 2631 981401)

Note: no prospective therapy trial is available for empirical treatment

strategies. Doctors should consider including newly diagnosed and refractory

patients into the prospective treatment trial SIMW. Contact the European

project on Whipples disease (QLGI-CT-2002-01049).(www.whipplesdisease.info or [email protected]).

Number of patients treated Relapses

Initial treatment*

Tetracycline 115 322%

Penicillin plus streptomycin 34 118%

Trimethoprim-sulfamethoxazole 23 43%

Other antibiotics 29 276%

Total 201 250%

*From references 97,112.

Table 2: Frequency of relapse in Whipples disease


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development of susceptibility tests should enable definitionof more adequate treatment regimens for Whipples disease;prospective trials will be required to allow therapy on thebasis of clinical evidence. Thus, we strongly encourage earlycontact with specialised centres for every newly diagnosedand refractory patient. The inclusion of patients into thefirst prospective antibiotic trial in Whipples disease

(SIMW) is recommended (panel). The study isinvestigating use of either ceftriaxone or meropenemintravenously for 2 weeks followed by oral trimethoprim-sulfamethoxazole for 1 year to prevent CNS manifestations,and the possibility of treating patients refractory toconventional drugs with supportive interferon gamma. Afollow-up European trial within the European project onWhipples disease (a consortium of nine institutes,www.whipplesdisease.info) based on data from suscepti-bility testing will, besides studies on the pathogenesis anddiagnosis of the disorder, compare long-term therapy withnew substances with trimethoprim-sulfamethoxazole(panel).

If the patients have a good clinical response, they cansimply be followed up with duodenal biopsies 6 months and

12 months after diagnosis.79 Antibiotic treatment cangenerally then be stopped if no PAS-positive material isidentified. In the rare cases in which bacterial materialpersists, a more closely followed therapy must becontinued, and an alternative antibiotic regimen should beconsidered. Cerebral manifestations of Whipples diseaseoccur more frequently in a relapse and have a badprognosis.111 Follow-up of these patients includes analysis ofthe liquor fluid every 6 months until bacterial material isundetectable.112

The rate of clinical relapses seems to be lower but stillsignificant after treatment with trimethoprim-sulfametho-xazole than with tetracycline therapy.112 Some patients havean antibiotic-refractory disease course and others have aprimary or recurrent CNS manifestation for which

beneficial treatment still needs to be defined. The newfindings in the pathogenesis of Whipples disease ondeficient cellular immunity might lead to developments inthe therapeutic approach.

Future perspectivesThe reservoir of T whipplei should be identified beyonddoubt. At present, environment waste is suspected to becontaminated, and the atypical geographical distributioncan be explained by unknown environmental factors. Thetrue prevalence of the infection by T whipplei may differfrom that of recognised Whipples disease. Benign formsand atypical manifestations without PAS-positive foamymacrophages could exist. The complete clinical range,including infectious endocarditis, might differ from what we

know now.The genome has already been completely sequenced, and

the final annotation is on its way (unpublished data). Itshould provide information about the physiology of thebacterium and many DNA sequences to be used fordiagnostic purposes. Such methods could allow control forall atypical results of amplification by a second or third PCRor consensus PCR procedures, increasing the predictivevalue of the result and could also clarify whetherasymptomatic carriers exist.

Antibiotic-susceptibility testing could be helpful,because empirical treatment regimens have beendisappointing and many relapses occur. The alkalinisationby lysosomotropic agents of the macrophage vacuole inwhich T whipplei resides could be crucial as in chronicinfection with C burnetii; this procedure also restores thebactericidal effect of doxycycline.115

Immunohistochemistry of circulating monocytes, orembedded tissues, could facilitate retrospective diagnosticas well as non-invasive procedures. New PCR techniqueswith higher sensitivity and specificity might be useful totest samples such as faeces and serum. Follow-up ofpatients with Whipples disease could be based on newtests such as quantitative PCR and immunohisto-

chemistry, which remain to be assessed for this purpose.Other diagnostic methods, such as serology, should bedeveloped. Specific epitopes of the bacterium can beidentified by monoclonal antibodies,116 and recombinantproteins selected and used as serological reagents.

Finally, identification of the risk factors of the disease,exposure, and host predisposition (ie, immunogenetichost factors that have a role in the clinical manifestation)should help in prevention. The many unansweredquestions and the rarity of the disorder necessitatecooperative studies to elucidate improved strategies fordiagnosis and treatment of Whipples disease.

Conflict of interest statementD Raoult has patented the culture process, the serology, and the RpoB

sequence of T whippeias a diagnostic procedure. T Marth has no conflict

of interest to declare.

Role of the funding sourceThis work was supported by the Programme Hospitalier de Recherche

Clinique, 2001 numero UF1658 (French Ministry of Health). The

sponsor of the study had no role in study design, data collection, data

analysis, data interpretation, or in the writing of the report.

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