bactitech
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http://en.wikipedia.org/wiki/Whipple's_disease
"Common clinical signs and symptoms of Whipple's disease include weight loss, diarrhea, joint pain or arthritis, fever, and adenopathy. Diagnosis is made by intestinal biopsy, which reveals presence of the organism as PAS-positive macrophage inclusions. Immunohistochemical staining for antibodies against T. whipplei has been used to detect the organism in a variety of tissues, and a confirmatory PCR-based assay is also available."
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Clinical Microbiology since 1974
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Whipple's Disease — Past, Present, and Future
Knowledge of Whipple's disease started with Whipple's report in 1907 of a medical missionary with an illness that had begun five years earlier with episodes of arthritis but that subsequently included weight loss, cough, fever, diarrhea, hypotension, abdominal swelling, increased skin pigmentation, and severe anemia.1 Findings at autopsy consisted of polyserositis, aortic-valve lesions, and prominent deposition of fat within intestinal mucosa and mesenteric lymph nodes, with marked infiltration by foamy macrophages. The pattern of fat deposition suggested that this disorder was an obscure disease of fat metabolism, and Whipple proposed the name "intestinal lipodystrophy."
Whipple's description represents the ideal single case report, one that clearly describes a new, distinctive clinical process and that provides the impetus for the elucidation of its varied clinical manifestations, etiology, and treatment. Indeed, the 20th century has seen the evolution of the knowledge of Whipple's disease. During the first 90 years a growing understanding of the disease's atypical manifestations, diagnostic criteria, and the concept of bacterial infection as either a cause or a complication led to successful therapy.2 In the past decade the bacterial species causing Whipple's disease has been pinpointed and a valuable means of making the diagnosis has been devised for cases in which specimens are unavailable for analysis or pathological analysis is unrevealing.
The ability to diagnose Whipple's disease was advanced by the observation of Black-Schaffer in 1949 that staining with periodic acid–Schiff (PAS) stain identified granules within macrophages that most likely represented degenerating bacterial forms.3 The finding of PAS-staining macrophages in the small bowel, as well as in other tissue and fluid (e.g., pericardium, endocardium, lymph nodes, synovia, lung, brain, and meninges) added to the accumulating clinical evidence of the systemic nature of this process.4 The presence of PAS-positive macrophages is not pathognomonic. In patients with AIDS and Mycobacterium avium complex infection, the intestinal lamina propria may be packed with PAS-positive macrophages, but the intracellular bacilli are acid-fast. In one case, a pulmonary infiltrate in a patient with AIDS also contained macrophages with PAS-positive granules, but these granules were gram-positive coccobacilli (Rhodococcus equi).5 Among the rarer manifestations of Whipple's disease are ocular involvement (uveitis, retinitis, and optic neuritis), generalized lymphadenopathy, fever of obscure origin, endocarditis, central nervous system involvement (dementia, central motor deficits, ophthalmoplegia, myoclonus, and hypothalamic signs),6,7 and a sarcoidosis-like syndrome involving the mediastinal nodes.
Evidence of an infectious cause of Whipple's disease was provided in 1961 by the electron-microscopical finding of bacillary bodies within membrane-bound vesicles in the cytoplasm of macrophages.8 In addition, some patients had responses to prolonged courses of antibiotics (12 months or longer), particularly a combination of penicillin and streptomycin, followed by trimethoprim–sulfamethoxazole. Then, in the early 1990s, Relman et al. used the polymerase chain reaction (PCR) to amplify a unique 1321-base sequence of a bacterial 16S ribosomal RNA (rRNA) gene that was obtained from tissues from 5 patients with Whipple's disease but could not be obtained from 10 patients with other conditions.9 This sequence was that of a previously uncharacterized organism (Tropheryma whippelii ), which on the basis of phylogenetic analysis, was a gram-positive actinomycete unrelated to any known genus. This molecular genetic approach has been used to diagnose Whipple's disease in patients with atypical symptoms. For example, the organism was identified by PCR in a vitreous sample from a patient with uveitis in whom repeated duodenal-biopsy specimens did not have PAS-positive macrophages.10 The genetic material of T. whippelii has also been found in a pleural effusion and in peripheral-blood mononuclear cells.7 In the case of two patients with febrile illnesses, cachexia, and prior splenectomy, blood films showed numerous gram-positive bacilli adherent to erythrocytes. These bacilli were shown to be T. whippelii by partial sequencing of the 16S rRNA gene. Both patients recovered after prolonged courses of antibiotics.11
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.12 Although there was no correlation between post-treatment histologic findings and the clinical outcome, PCR results did correlate with therapeutic results. Seven of 12 patients with positive results on PCR analysis of a small-bowel–biopsy specimen subsequently had clinical relapses or had no response to treatment, whereas none of the 5 patients with negative PCR results relapsed.
Attempts to grow the bacillus of Whipple's disease in the laboratory have been unsuccessful. Preliminary passage of T. whippelii obtained from two patients with "culture-negative" endocarditis associated with Whipple's disease was reported in human macrophages deactivated with a combination of interleukin-4 and interleukin-10.13 This result has not been duplicated by others. In this issue of the Journal, Raoult et al.14 report their success, using a 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, the 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, and the results of indirect immunofluorescence staining of the isolate in infected HEL cells with use of the patient's serum as the primary antibody were strongly positive. Furthermore, polyclonal antibodies were produced in high titers in mice and used to detect the bacterium in the patient's excised heart valve.
Using a monolayer infected with the bacillus of Whipple's disease, Raoult et al. developed an 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, Raoult et al. found that the 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 ( 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.
A caveat is warranted regarding the interpretation of the serologic data, because of the small number of serum samples from patients with Whipple's disease that were tested. Also, there may be additional positive results on the IgM assay when larger numbers of serum samples from control subjects with various other bacterial infections are tested. The high frequency of IgG antibodies against the Whipple's disease isolate suggests that this pathogen is ubiquitous, causing illness only occasionally, perhaps because of differences in virulence among the strains or in host factors or as a result of the patient's exposure to other immunologically cross-reacting microorganisms.
What does the future hold? If the isolate passaged in cell culture by Raoult et al. is T. whippelii, we should anticipate the successful cultivation of isolates from other patients with Whipple's disease. Although the authors were unable to grow their isolate in axenic culture using different mediums under a variety of conditions, further attempts are warranted. The calculated doubling time of about 18 days for T. whippelii in cell culture is daunting, however. The present serologic approach, even with the use of the IgM immunofluorescence assay, is not ready for general diagnostic use in view of the possibility of cross-reacting antibodies. Growth of the organism in cell-free medium would provide the means for the preparation of selective antigens to enhance the specificity of serologic reactions and to allow antimicrobial-susceptibility testing.
Solving these problems may enable us to answer other important questions about T. whippelii. Is it a saprobe or a commensal intestinal organism that only invades certain hosts? Are there differences in pathogenicity among the various strains? Is infection acquired primarily through the gastrointestinal tract? Can the two remaining conditions of Koch's postulates be fulfilled — that is, the development of Whipple's disease in an animal model infected with the isolate and the subsequent isolation of T. whippelii from the animal? What manifestations will the disease produce in the animal model?
In the future, the development of more specific serologic tests and ways to expedite the cultivation process as well as continued use of molecular methods may enable us to identify other human illnesses caused by this pathogen. For example, does T. whippelii have any role in malacoplakia, a rare chronic infection also characterized by foamy macrophages (but these contain basophilic Michaelis–Gutmann bodies), most commonly involving the kidney, but sometimes the lung or colon? Electron-microscopical study of tissue samples from patients with malacoplakia has shown phagolysosomes containing bacteria in various stages of disintegration. Although gram-negative bacilli (Escherichia coli and klebsiella) have been isolated from the majority of patients, no culturable bacteria have been found in about 20 percent.
More revelations about Whipple's disease and T. whippelii should be forthcoming, and the rate of progress should be accelerated by the availability of the newly developed culture method.
Morton N. Swartz, M.D.
Massachusetts General Hospital
Boston, MA 02114
References
Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bull Johns Hopkins Hosp 1907;18:382-91.
Dobbins WO III. Whipple's disease: an historical perspective. QJM 1985;56:523-531. [Free Full Text]
Black-Schaffer B. The tinctoral demonstration of a glycoprotein in Whipple's disease. Proc Soc Exp Biol Med 1949;72:225-227.
Fleming JL, Wiesner RH, Shorter RG. Whipple's disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988;63:539-551. [Medline]
Wang HH, Tollerud D, Danar D, Hanff P, Gottesdiener K, Rosen S. Another Whipple-like disease in AIDS? N Engl J Med 1988;314:1577-1578. [Medline]
Dobbins WO III. Whipple's disease. Springfield, Ill.: Charles C Thomas, 1987.
Durand DV, Lecomte C, Cathébras P, Rousset H, Godeau P, SNFMI Research Group on Whipple Disease. Whipple disease: clinical review of 52 cases. Medicine 1997;76:170-84.
Yardley JH, Hendrix TR. Combined electron and light microscopy in Whipple's disease: demonstration of "bacillary bodies" in the intestine. Bull Johns Hopkins Hosp 1961;109:80-98.
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. [Abstract]
Rickman LS, Freeman WR, Green WR, et al. Uveitis caused by Tropheryma whippelii (Whipple's bacillus). N Engl J Med 1995;332:363-366. [Free Full Text]
Lowsky R, Archer GL, Fyles G, et al. Diagnosis of Whipple's disease by molecular analysis of peripheral blood. N Engl J Med 1994;331:1343-1346. [Free Full Text]
Ramzan NN, Loftus E Jr, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med 1997;126:520-527. [Free Full Text]
Schoedon G, Goldenberger D, Forrer R, et al. Deactivation of macrophages with interleukin-4 is the key to the isolation of Tropheryma whippelii. J Infect Dis 1997;176:672-677. [Medline]
Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple's disease. N Engl J Med 2000;342:620-625.
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