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Whipple disease is a systemic bacterial disease caused by Tropheryma whippelii. Described by Whipple in 1907, it is a chronic disease involving mainly the intestine, causing diarrhea, malabsorption, and weight loss. There are a number of extraintestinal symptoms and occasional patients may not have malabsorption. Cases include lymphadenopathies and polyarthritis, cardiovascular manifestations such as endocarditis, and neurologic or ophthalmologic manifestations such as uveitis.


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Tropheryma whippelii

J Bacteriol. 2000;182:3292-3297.
Int J Syst Bacteriol. 1999;49:1701-1706.

To date, 6 genotypes (numbered 1-6) of uncultured T whippelii have been reported based on sequence variation within the inter 16S-23S rDNA spacer (ITS) and 2 genotypes (named A and B) based on that of the 23S rRNA gene

Culture and Immunological Detection of Tropheryma whippelii From the Duodenum of a Patient With Whipple Disease

JAMA. 2001;285:1039-1043

A second strain of T whippelii has been isolated

Immunofluorescence staining performed on the vial examined on day 30 after inoculation resulted in the detection of numerous fluorescent bacteria. On confocal fluorescent microscopy of the second-passage shell vial, numerous fluorescent bacteria mostly aggregated within intracellular vacuoles were observed

Appearance was comparable to that of the Twist-Marseille T whippelii strain

The supernatant of positive vials, as well as of the remaining 2 vials, was inoculated onto confluent layers of HEL cells allowing the isolate to establish itself

This isolate was named the Slow-Marseille strain

Amplification and sequencing of the 16S rRNA gene of both the isolate and the biopsy specimen generated a 1484–base pair (bp) sequence, which was compared with DNA sequences accessible in public databases. The sequence was identical to 16S rRNA gene sequences of T whippelii (GenBank accession numbers X996361 and M874841)

The 472-bp sequence derived from the ITS of the isolate was identical to the ITS sequence of T whippelii (GenBank accession number X99636)

The 250-bp sequence derived from domain III of the 23S rDNA sequence from the isolate was identical to the sequence available in GenBank under the accession number AF 148136

Thus, the genotype of the T whippelii Slow-Marseille strain corresponded to molecular variant 1A



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N Engl J Med. 2000;342:620-625.

Human fibroblast cell line (HEL), in cultivating T. whippelii. They completed seven passages of an isolate obtained from the aortic valve of a patient with endocarditis due to Whipple's disease

Confirmation that the passaged isolates were T. whippelii was provided by the following findings:
PAS-positive bacilli (not acid-fast but gram-positive) were identified in an intracellular location in the cell-culture monolayer
Amplified sequences of the 16S rRNA gene of the isolate were identical to those of T. whippelii
Transmission electron microscopy of the isolate revealed the distinctive trilamellar appearance of Whipple's bacillus
Indirect immunofluorescence staining of the isolate in infected HEL cells with use of the patient's serum as the primary antibody were strongly positive
Polyclonal antibodies were produced in high titers in mice and used to detect the bacterium in the patient's excised heart valve


J Clin Microbiol. 2000;38:595-599.
Ann Intern Med. 1997;126:520-527.

Standard for diagnosing Whipple disease

PCR with 16S rDNA primers of T. whippelii has proved useful for monitoring the response to therapy. PCR results were positive in 36 of 38 specimens from patients with histologically confirmed or clinically suspected Whipple's disease

Good sensitivity despite false-negative results probably due to PCR inhibitors in the samples

Specificity of intestinal PCR for Whipple disease has been shown to vary with different investigators and PCR procedures

4.8% of patients without Whipple disease have a PCR-positive duodenal biopsy sample, 11.4% have PCR-positive gastric fluid,17 and 35% have PCR-positive saliva

  Discrepancy between the high prevalence of the bacterial genes in the population and the low prevalence of the disease could also be explained by pathogenic variations among strains

N Engl J Med 2000;342:620-5.

Immunofluorescence serologic test with which they examined serum from 9 patients with Whipple's disease and 40 control subjects

When a cutoff value of 1:100 was selected, IgG antibodies against the bacillus were detected in serum samples from all nine patients with Whipple's disease as well as in almost 75 percent of samples from the control subjects

The specificity of the presence of IgM antibodies was greater; using a cutoff value of 1:50

Results were positive for 7 of 9 patients with Whipple's disease as compared with 3 of 40 control subjects. Also, higher titers of IgM antibodies (greater than or equal to 1:400) were present in three of seven patients with classic Whipple's disease and in both patients with Whipple's disease endocarditis but in none of the control subjects


Whipple disease: a case report and review of the literature.

Muir-Padilla J, Myers JB.

Department of Pathology, Madigan Army Medical Center, Tacoma, Wash 98431, USA.
Arch Pathol Lab Med. 2005 Jul;129(7):933-6. Abstract quote  

Whipple disease is a chronic, relapsing, and multisystem disease. It presents a diagnostic challenge for both clinicians and pathologists. Recent advances in isolation and culture have identified the organism responsible for the disease to be a member of the order Actinomycetes designated Tropheryma whipplei.

Several immune system changes have been noted in patients with Whipple disease, but whether these are primary or secondary is as yet undetermined.

Long-term antibiotic therapy is required, and relapses are common, especially with central nervous system involvement.

Primary diagnosis of Whipple's disease in bone marrow.

Krober SM, Kaiserling E, Horny HP, Weber A.

Institute of Pathology, University of Tubingen, Tubingen, Germany.
Hum Pathol. 2004 Apr;35(4):522-5. Abstract quote  

Whipple's disease (WD) is a chronic systemic inflammatory disease of infectious origin caused by Tropheryma whipplei (TW). Abdominal pain and recurrent diarrhea are usually the main symptoms leading to the suspicion of a primary bowel disease. Systemic manifestations can mimic hematologic disorders. A 49-year-old man presented with fever, weight loss, long-standing arthralgia, and diarrhea. A duodenal biopsy was unremarkable.

Bone marrow histology provided no evidence of a malignant hematological disorder but revealed noncaseating granulomas. TW was detected in the bone marrow trephine by polymerase chain reaction. This is the first report to describe TW-associated granulomatous myelitis as the initially recognized organ manifestation of WD, proven at the molecular level.

This observation is relevant for the differential diagnosis of patients with systemic symptoms and granulomatous diseases affecting the bone marrow, emphasizing that WD should be considered in cases of unexplained granulomatous myelitis, even when small bowel biopsy specimens are negative.
Erythema nodosum-like lesions in treated Whipple's disease: signs of immune reconstitution inflammatory syndrome.

Department of Dermatohistology, Catholic Clinics, Duisburg, Germany.


J Am Acad Dermatol. 2009 Feb;60(2):277-88. Abstract quote

Treatment of systemic infections due to mycobacteria and HIV infection can lead to paradoxical worsening, the immune reconstitution inflammatory syndrome, in a minority of patients.

Herein we describe a patient with Whipple's disease, a chronic systemic inflammatory disease caused by Tropheryma whipplei, who developed cutaneous and later ocular disease after initiation of antibiotic therapy. A 42-year-old man with a 12-year history of arthralgias presented with deteriorating health, including weight loss, diarrhea, fever, and acral hyperkeratosis. Whipple's disease was suspected and subsequently confirmed by finding periodic acid-Schiff (PAS)-positive foamy macrophages and T whipplei DNA by polymerase chain reaction (PCR) assays in duodenal biopsy specimens. After 5 weeks of antibiotic treatment with ceftriaxone, erythema nodosum (EN)-like lesions developed on the legs and trunk. Notably, lesional and nonlesional skin harbored intracellular and extracellular degenerated bacteria that were associated with a neutrophilic and granulomatous inflammatory response in lesional skin. Continued antibiotic therapy was associated with recurring EN-like skin nodules, orbital swelling, and facial herpes simplex virus 1 infection. Corticosteroid therapy controlled the duration and severity of the EN-like nodules and orbital swelling.

Apart from cutaneous hyperpigmentation, skin disease in Whipple's disease is infrequent and can be categorized as disorders due to malnutrition from malabsorption or so-called reversal reactions consisting of reactive erythemas, and neutrophilic and granulomatous responses to T whipplei, the latter of which can represent an immune reconstitution inflammatory reaction after initiation of antibiotic therapy. Finally, based on the presence of T whipplei in normal skin, skin biopsy may serve as another site for diagnostic testing in patients suspected of having Whipple's disease.



Sections of small intestines reveal large, foamy macrophages within the lamina propria of small intestinal mucosa

Contained numerous intracytoplasmic granules that were positive on PAS staining and resistant to diastase and represent intact or partially degradated bacteria, phagolysosomes that contain bacilliform bodies at various states of degeneration

Giemsa, Brown-Hopps, GMS, and Warthin-Starry stains revealed no microorganisms

Detection of numerous PAS-positive macrophages is nonspecific, since they may also be seen in other gut or lymph node disorders such as histiocytosis, melanosis coli, and pneumatosis cystoides intestinalis

Mycobacterium avium complex infection of the intestine in patients with acquired immunodeficiency syndrome may be confused with Whipple disease, although mycobacteria are also Ziehl-Nielsen positive, allowing the differentiation of mycobacterial infection from Whipple disease

Sarcoidlike granulomas as an early manifestation of Whipple's disease

Gastroenterology. 1984;87:941-947.

Lymph nodes and other tissues may also present diagnostic problems, since the changes in routinely stained sections may mimic those of sarcoidosis, with well-formed granulomas and sometimes foreign-body giant cells surrounding fat globules


Electron microscopy (EM)

N Engl J Med. 1995;332:390-392.

Trilamellar membrane appearance


Whipple's disease: Immunospecific and quantitative immunohistochemical study of intestinal biopsy specimens.

Lepidi H, Fenollar F, Gerolami R, Mege JL, Bonzi MF, Chappuis M, Sahel J, Raoult D.


Hum Pathol. 2003 Jun;34(6):589-96. Abstract quote

Whipple's disease may be diagnosed by periodic acid-Schiff (PAS) staining, electron microscopy, or polymerase chain reaction of intestinal biopsy specimens.

The aim of this study was to evaluate the diagnostic value of immunohistochemistry and the quantification of infected cells in intestinal Whipple's disease. A total of 29 duodenal biopsy specimens from 15 patients with untreated and treated Whipple's disease were examined and compared with biopsy specimens from control patients with normal intestinal mucosa or various pathologic processes.

Percentages of staining surfaces with PAS stain and antibodies directed against CD68, a macrophage marker, or the Whipple bacillus, Tropheryma whipplei, were studied quantitatively using a computerized system of image analysis. Positive detection of T. whipplei was obtained using immunohistochemistry in all 15 patients with Whipple's disease. No bacteria were detected in any of the negative controls. The use of quantitative image analysis showed a massive intestinal macrophagic infiltration before (20.3%) and after (13.4%) antibiotic therapy completion as compared with controls (2.1%). The 2 detection methods for T. whipplei, PAS stain and immunohistochemistry, were quantitatively similar before therapy (19.9% versus 17.5%), but the immunodetection-based surface area was significantly lower than the PAS staining surface area after therapy (2.8% versus 7.9%).

Our findings indicate that immunohistochemistry is highly specific and sensitive and is applicable as a diagnostic method on intestinal tissue specimens to detect T. whipplei during active infection or in retrospective studies.

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

Blaire L. Baisden, MD,
Hubert Lepidi, MD, PhD,
Didier Raoult, MD, PhD,
Pedram Argani, MD,
John H. Yardley, MD,
and J. Stephen Dumler, MD

Am J Clin Pathol 2002;118:742-748 Abstract quote

Whipple disease is a rare infection characterized clinically by diarrhea, fever, weight loss, arthralgia, malabsorption, and other systemic manifestations. The etiologic agent, Tropheryma whipplei, has been cultured only rarely.

By using a polyclonal rabbit antibody produced against a cultured strain of T whipplei, tissue sections from 18 patients with Whipple disease were studied. Specimens from patients with histologic mimics and other infections served as control specimens. Immunostaining was identified in all 18 patients. Granular immunostaining was observed similar to that in periodic acid–Schiff (PAS) stains. In 2 patients, immunostaining was identified in specimens negative by H&E and PAS stains.

In 4 patients studied before and after antibiotic therapy, immunostaining was retained but diminished in intensity and quantity. Immunostaining was not identified in any control specimen.

Immunohistochemical analysis is a sensitive and specific method for the diagnosis of Whipple disease in paraffin-embedded tissue and may provide new opportunities to investigate the pathogenesis of the infection.


Treatment Some patients have responses to prolonged courses of antibiotics (12 months or longer), particularly a combination of penicillin and streptomycin, followed by trimethoprim-sulfamethoxazole

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

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Last Updated February 11, 2009

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