Original Article
Cultivation of the Bacillus of Whipple's Disease
N Engl J Med 2000; 342:620-625March 2, 2000
- Abstract
Background
Whipple's disease is a systemic bacterial infection, but to date no isolate of the bacterium has been established in subculture, and no strain of this bacterium has been available for study.
Methods
Using specimens from the mitral valve of a patient with endocarditis due to Whipple's disease, we isolated and propagated a bacterium by inoculation in a human fibroblast cell line (HEL) with the use of a shell-vial assay. We tested serum samples from our patient, other patients with Whipple's disease, and control subjects for the presence of antibodies to this bacterium.
Results
The bacterium of Whipple's disease was grown successfully in HEL cells, and we established subcultures of the isolate. Indirect immunofluorescence assays showed that the patient's serum reacted specifically against the bacterium. Seven of 9 serum samples from patients with Whipple's disease had IgM antibody titers of 1:50 or more, as compared with 3 of 40 samples from the control subjects (P<0.001). Polyclonal antibodies against the bacterium were generated by inoculation of the microorganism into mice and were used to detect bacteria in the excised cardiac tissue from our patient on immunohistochemical analysis. The 16S ribosomal RNA gene of the cultured bacterium was identical to the sequence for Tropheryma whippelii identified previously in tissue samples from patients with Whipple's disease. The strain we have grown is available in the French National Collection.
Conclusions
We cultivated the bacterium of Whipple's disease, detected specific antibodies in tissue from the source patient, and generated specific antibodies in mice to be used in the immunodetection of the microorganism in tissues. The development of a serologic test for Whipple's disease may now be possible.
Media in This Article
Figure 3
Transmission Electron Micrograph Showing the Bacterium (Arrow) in Infected HEL Cells.Figure 1
Large, Coarse, Round Structures (Arrows) within HEL Cells in a Six-Week-Old Culture of the Whipple's Disease Bacterium.Article Activity
- Article
Whipple's disease is a systemic bacterial infection characterized by fever, weight loss, diarrhea, lymphadenopathy, and polyarthritis and, occasionally, by cardiac manifestations such as myocarditis, pericarditis, and endocarditis1,2 or by central nervous system involvement.3 George Whipple described the disease in 1907,4 and its bacterial origins were confirmed by electron microscopy in 1961.5 The diagnosis is usually established on microscopy by the identification in a duodenal-biopsy specimen of infiltration by large macrophages with bacteria positive for the periodic acid–Schiff (PAS) stain.6 In 1991 Wilson et al.7 used broad-range primers to amplify and sequence a portion of the 16S ribosomal RNA gene of the bacterium for Whipple's disease, allowing classification of the bacterium within the Actinomycetes clade. These findings have been confirmed and extended.8 Since then the polymerase chain reaction (PCR) has been reported to be a useful tool for the diagnosis of Whipple's disease.9,10
Culture of the bacillus has been an elusive goal for many generations of microbiologists.11 In 1997 the bacterium was isolated and grown in human macrophages inactivated with interleukin-4.12 However, that isolate could not be subcultured, and no isolate is currently available.13
We report the successful isolation and establishment of a strain of the bacterium for Whipple's disease obtained from the mitral valve of a patient with blood-culture–negative endocarditis, the generation of specific antibodies against the bacterium in mice, the detection of the bacterium in the patient's mitral valve by immunochemistry with these antibodies, and the detection of specific antibodies against the bacterium in the patient's serum.
Methods
The Index Patient
A 42-year-old man with mental retardation owing to encephalitis as a child was noted to have clubbing and a heart murmur in the autumn of 1997. Apparently, he had also had rheumatic fever as a child, although this could not be confirmed. An echocardiogram showed a thickened aortic valve with severe insufficiency and normal left ventricular function. During the winter, worsening congestive heart failure developed, and the patient was hospitalized twice with weight loss and pneumonia. By May 1998, he had lost 15 kg in weight and was admitted to the hospital with nausea and vomiting. There was no history of diarrhea, no evidence of organomegaly on abdominal examination, and no lymphadenopathy. He was transferred to a hospital in Halifax, Nova Scotia, Canada, in May 1998. An echocardiogram demonstrated a vegetation on the anterior leaflet of the mitral valve and a small vegetation on the chordae of the anterior leaflet. There was associated mitral insufficiency with a flail anterior leaflet, severe aortic regurgitation, vegetations visible on the leaflets, and a small abscess of the annulus next to the septum. During surgery no aortic-valve tissue could be identified on gross examination, but there were masses of vegetations in the location of the aortic valve that were completely excised and replaced with a homograft. The patient recovered uneventfully and was sent home 14 days later while taking antibiotics. At a follow-up visit nine months later the patient remained well.
The surgically resected tissues were fixed in formalin or frozen at –80°C. Slices of paraffin-embedded tissue samples were cut 5 μm thick and stained with hematoxylin and eosin. The PAS stain and other stains were used to detect bacteria.14
Primary Isolation by Cell Culture
Culture was performed by the centrifugation–shell-vial technique with a human fibroblast cell line (HEL) that is used in our laboratory to detect intracellular bacteria, as previously described.15,16 All cell lines and culture reagents are checked weekly for bacterial contamination. Frozen cardiac-valve tissue was placed in minimal essential medium and crushed, and the suspension was used to inoculate three shell vials (Table 1Table 1
Summary of the Isolation Procedure.). The inoculated vials were processed as previously described.15,16 The cultures were analyzed for bacteria by cytocentrifugation of 100 μl of the shell-vial supernatant followed by Gimenez staining17 on days 10, 20, and 30. On day 30, the shell-vial supernatant and inoculated cells were harvested, inoculated into 25-cm2 cell-culture flasks (flask 1) with 5 ml of medium, and incubated at 37°C in an atmosphere of 5 percent carbon dioxide. Every week for six weeks (until day 72), the cells were examined with an inverted microscope for cytopathic effects, and the incubation medium was replaced. Before the medium was replaced, 200 μl of the supernatant was obtained for cytocentrifugation and staining with Gimenez, Gram's acridine orange, Ziehl–Neelsen, and PAS stains.Propagation of the Isolate
The isolate was propagated in HEL cells grown under previously described conditions (Table 1).15,16 On day 75, 3 ml of supernatant from flask 1 was used to inoculate 10 shell vials, and 2 ml was used to inoculate a confluent monolayer of cells in a 25-cm2 cell-culture flask (flask A) with 5 ml of medium. One of the shell vials was used to study generation time. The cells were harvested with the remaining supernatant and resuspended in fresh medium in order to obtain 10 ml of cell suspension, which was divided into five 2-ml aliquots. The cells of one aliquot were lysed by four cycles of freezing and thawing in liquid nitrogen and hot water (55°C) and inoculated onto confluent monolayers of cells in a 25-cm2 cell-culture flask (flask C) with 5 ml of medium. Two aliquots were inoculated onto a confluent monolayer of cells in two 25-cm2 cell-culture flasks (flasks B and D) with 5 ml of medium. On day 85, the medium in all flasks and shell vials was replaced by fresh medium. The cells in flask D were harvested and inoculated into a cell-free 75-cm2 cell-culture flask (flask D2) with 15 ml of medium. Before the medium was replaced, 200 μl of each supernatant was obtained for cytocentrifugation and PAS staining. On days 95 and 105, the medium in all flasks and shell vials was again replaced. Small portions of the cell monolayers were scraped to obtain cell smears for PAS staining. The efficacy of propagation was evaluated by semiquantitative counts of these cell smears. Each smear was analyzed microscopically at a magnification of 1000 for PAS-positive bacilli. A score of 0 was assigned if no PAS-positive bacilli were found; a score of + indicated that bacilli were present but hard to find, a score of ++ indicated that bacilli were easily detected but were not present in all fields, and a score of +++ indicated that bacilli were present in all fields. All smears were evaluated in a blinded fashion by two investigators. To ensure continued production of the isolate, as soon as a flask was given a score of +++, the cells were harvested and inoculated into three 150-cm2 cell-free cell-culture flasks, with the volume adjusted to 35 ml by the addition of fresh medium. We also attempted to propagate the isolate by inoculating the cells onto monolayers of MRC 5 cells cultured in the same way as were HEL cells and in axenic medium (chocolate agar and Columbia sheep's-blood agars, BioMérieux, Marcy l'Etoile, France) and incubated at 32° and 37°C in the presence of 5 percent carbon dioxide and in microaerophilic and anaerobic conditions. We also incubated the isolates with cell-culture medium alone and with cell-culture medium containing a lysate of HEL cells at 32° and 37°C in the presence of 5 percent carbon dioxide.
Transmission Electron Microscopy
On day 105, about 1000 infected cells from a second-passage flask were prepared for examination with a transmission electron microscope (model 1220, Jeol, Croissy sur Seine, France) as described previously.18
Immunofluorescence Staining
On day 105 the monolayer from one shell vial was examined by direct immunofluorescence as previously described,16,19 with the use of the patient's serum as the primary antibody. Coverslips were examined with a laser scanning confocal fluorescence microscope (model DMIRBE, Leica, Wetzlar, Germany) equipped with an oil-immersion lens (100×). To evaluate our serologic methods, we also analyzed nine serum samples from patients with proved Whipple's disease. The serum sample from our patient, one from a patient with endocarditis due to Whipple's disease as proved by PCR testing,20 and seven from patients with histologically proved Whipple's disease (in two of whom Tropheryma whippelii DNA was detected in duodenal tissue by PCR assay)1 were tested. The group of seven patients were considered to have classic Whipple's disease, to distinguish them from the two patients with endocarditis due to Whipple's disease. Forty-one serum samples were used as negative controls: 11 were obtained from patients with autoimmune diseases, 10 were obtained from patients with endocarditis due to Coxiella burnetii (5 patients) and to Bartonella quintana and B. henselae (5 patients), and 20 were obtained from healthy blood donors.
We devised a procedure that uses eight-well Lab-Tek chamber slides (Nunc, Naperville, Ill.) and allows 12 slides to be prepared at a time. The supernatant was removed from a 150-cm2 cell-culture flask containing approximately 10,000 HEL cells and in which infection was present in all fields (+++) by semiquantitative count. Four milliliters of 0.25 percent trypsin (GIBCO, Grand Island, N.Y.) was added to the cell monolayer, and the culture was incubated at 37°C for about 10 minutes until the cells became separated from the bottom of the flask. The cells were then resuspended in 35 ml of fresh medium, and 350 μl of suspension was added to each well of the Lab-Tek chamber slides. The slides were incubated for 12 hours at 37°C in the presence of 5 percent carbon dioxide so that the cells could adhere to the glass slide. The serum samples were diluted in phosphate-buffered saline (1:25, 1:50, and 1:100) that contained 3 percent nonfat dry milk, and the titers of IgG and IgM were determined. For patients with IgM titers of 1:25, the serum samples were diluted from 1:50 to 1:400. To remove IgG, rheumatoid factor adsorbant (RF-absorbant, Behringwerke, Marburg, Germany) was added before the determination of IgM, according to the manufacturer's instructions. The culture medium was removed, the cells were fixed with methanol, and then the wells were washed twice with phosphate-buffered saline. Next, 100-μl samples of each serum dilution were added to the wells, and the chamber slides were incubated in a moist chamber at 37°C for 30 minutes. The slides were washed three times with phosphate-buffered saline and then incubated for 30 minutes at 37°C with 100 μl of goat antihuman IgG (Fluoline G, BioMérieux) or IgM (Fluoline M, BioMérieux) at a dilution of 1:300 in phosphate-buffered saline. The slides were washed three times with phosphate-buffered saline, the plastic upper structures mounted on the slides were removed, and the slides were mounted in phosphate-buffered glycerol medium (pH 8) and examined at a magnification of 400 with an epifluorescence microscope (Zeiss, Thornwood, N.Y.).
Production and Characterization of Mouse Polyclonal Antibodies
Immunocompetent BALB/c mice that were six to eight weeks of age were inoculated subcutaneously with 0.5 ml of a solution containing 106 of the bacteria obtained from the supernatant of infected cells mixed with 0.5 ml of Freund's complete adjuvant. The mice were inoculated on days 0, 10, 20, and 30. On day 40, the mice were killed and the antibody titers were measured by microimmunofluorescence testing. Before further use, the serum samples were diluted 1:50 and adsorbed on HEL cells to remove nonspecific anti-cell antibodies.
Amplification and Sequencing of the 16s Ribosomal RNA Gene
Bacterial DNA was extracted from 500 μl of supernatant from a cell-culture flask by Qiagen columns (QIAmp tissue kit, Qiagen, Hilden, Germany) according to the manufacturer's instructions. PCR amplification with the broad-range 16S ribosomal RNA gene primers fD1 and rP2 and sequencing and purification of PCR products were performed as previously described.21
Statistical Analysis
We used Fisher's exact test for all statistical analyses. All P values are one-sided.
Results
Gross pathological examination of the excised aortic valve revealed that the cusps were thickened, distorted, and fibrotic, with a large friable vegetation. Histologically, the aortic valve had organizing superficial platelet–fibrin thrombi on the cusps with focal calcific deposits and necrotic cellular debris. These vegetations were associated with extensive fibrosis and with acute and chronic inflammation. The granulation tissue beneath the surface of the cusp included a chronic inflammatory infiltrate with numerous foamy macrophages. PAS-positive bacilli were identified in coarse masses of rod-shaped bodies within the foamy macrophages, the hallmark of Whipple's disease.22,23 However, no microorganisms were detected on staining with Giemsa, Brown and Hopps, Gomori–Grocott, or Warthin–Starry stains. The chronology of isolation of the bacterium for Whipple's disease is summarized in Table 1. A cytopathic effect and microorganisms were not detected until day 65 after inoculation. Using an inverted microscope, we identified small, coarse, dark inclusions and large, coarse, round structures within cells on day 72 (Figure 1Figure 1
Large, Coarse, Round Structures (Arrows) within HEL Cells in a Six-Week-Old Culture of the Whipple's Disease Bacterium.). Gimenez staining of the supernatant after centrifugation revealed several slender pink bacilli. The majority were intracellular, and the intracellular bacilli were shorter than those outside the cells. However, most of these bacilli were poorly stained or not stained by the Gimenez stain and appeared pale blue. Numerous bacilli were also revealed by Gram's staining. Most were gram-positive, but several were only partially purple or gram-negative. On Ziehl–Neelsen staining, these bacilli were not acid-fast. More bacilli were PAS-positive than were positive for the Gimenez or Gram's stains. The cells were filled with coarse, PAS-positive conglomerates and short, slender, PAS-positive rods.Amplification and sequencing of the 16S ribosomal RNA gene of the isolate produced a segment of 1450 bp. We compared the sequence with DNA-sequence data bases (Blast, version 2.0, National Center for Biotechnology and Information, Bethesda, Md.) and found that it was 99.9 percent homologous to the 16S ribosomal RNA sequence of T. whippelii (European Molecular Biology Laboratory accession number, X99636).
All subculture procedures used for the propagation of the isolate were effective, since in all cases, the isolate was recovered after 30 days of subculture. However, the most effective procedures were inoculation of supernatant onto fresh cell monolayers, as was done in the case of flask A, or the duplication of infected cells, as was done in the case of flask D2. In those cases, the cultures were evaluated semiquantitatively after 30 days of subculture, and bacilli were easily detected, but not in all fields. The results of attempts to subculture the bacilli on MRC 5 cells were similar. All attempts at subculture on axenic medium were unsuccessful. At each stage of the propagation procedure, 500-μl samples of the cultures were tested by PCR and the bacterium of Whipple's disease was confirmed to be present in the culture.
Immunofluorescence staining demonstrated that staining with PAS and other stains underevaluated the extent of cell infection. Immunofluorescence examination of shell-vial coverslips after 30 days of subculture showed that all cells contained large amounts of the isolated antigen. The intracellular location of the bacilli was confirmed by confocal microscopy (Figure 2AFigure 2
Whipple's Disease Bacterium.). Several bacteria were seen that resembled the short, slender rods observed on PAS staining. Nevertheless, most immunopositive material was found in larger inclusions, where individual bacteria were not seen. No immunopositive material was detected within the nuclei. Large numbers of bacteria were found by acridine orange staining of the cell-culture supernatant (Figure 2B). Transmission electron microscopy confirmed that the PAS-positive inclusions and immunopositive material corresponded to intact and degenerating bacteria. Dividing cells were observed. The cell wall included a structure whose presence was consistent with previous descriptions of the bacterium of Whipple's disease.24 The plasma membrane was surrounded by a thin, homogeneous wall, which was itself surrounded by a plasma-membrane–like structure, giving a trilamellar appearance (Figure 3Figure 3Transmission Electron Micrograph Showing the Bacterium (Arrow) in Infected HEL Cells.).IgG antibodies against the bacillus were detected in most serum samples, including those from the control subjects. Cutoff values were selected after the results were known. When a cutoff value of 1:100 was selected, samples from all nine patients with confirmed Whipple's disease (endocarditis or classic) were positive, as compared with samples from 29 of 40 controls (P=0.08) (Table 2Table 2
Results of Indirect Immunofluorescence Assay of Serum Samples from Patients with Whipple's Disease and Control Subjects.). The presence of IgM antibodies was more specific to patients with Whipple's disease. When a cutoff value of 1:50 was selected, 7 of 9 patients with Whipple's disease had positive results, as compared with 3 of 40 control subjects (P<0.001). Both patients with Whipple's disease endocarditis had a positive IgM antibody titer, as compared with none of the 10 control subjects with endocarditis from other causes (P=0.015). Five of 7 patients with classic Whipple's disease had a positive IgM antibody titer, as compared with 2 of 10 control subjects with autoimmune diseases (P=0.052). The IgM antibody titer was 1:400 or more in three of seven patients with classic Whipple's disease and in both patients with Whipple's disease endocarditis, but in none of the patients without Whipple's disease. The serologic results for one control subject with autoimmune disease who had antineutrophil cytoplasmic autoantibodies were uninterpretable because of the presence of diffuse immunofluorescence.Antibodies were produced in mice at high titers (1:1000) and were successfully used to detect the bacteria in the patient's excised tissue by immunochemistry.
Discussion
Although Whipple's disease was identified nearly a century ago, the causative agent of this bacterial infection has not been successfully established in vitro. Even though no type strain of the bacterium is available, it is usually referred to by its provisional name, T. whippelii. 8,25 The molecular identification of this bacterium in biopsy specimens or peripheral-blood samples is the basis for the diagnosis.9 However, this technique remains to be validated, and the diagnosis of Whipple's disease requires a biopsy specimen for either microscopical study or PCR analysis. Therefore, a serologic test could be highly useful, since the diagnosis could be made on the basis of a single blood sample. This is particularly important in patients with life-threatening complications such as endocarditis.
Unlike previous investigators who completed only two passages of the bacterium cultures of human macrophages,12 we used a human fibroblast cell line with no specific culture conditions. We completed seven passages of our isolate and believe that the culture is now definitely established. By day 285 we had 120 heavily infected 150-cm2 cell-culture flasks. The strain has been deposited in the French National Collection at the Pasteur Institute in Paris and is available. Since it requires 210 days to obtain 25 well-infected 150-cm2 cell-culture flasks from a 1-cm2 shell vial, the generation time (or doubling time) of the bacterium is about 18 days, which is similar to that for Mycobacterium leprae in animal models (12 days).26 Patience has been a key to culturing new pathogens, as in the case of bartonella species,27 which can take as long as 45 days to isolate, and Helicobacter pylori, for which a prolonged incubation is also necessary.28 One other difficulty is the staining of bacteria in cells. PAS is useful but fails to detect all bacteria, unlike immunofluorescence of the tested strain. Acridine orange was the most useful stain. However, mouse-specific antibodies may be very useful for this purpose.
The successful isolation of intracellular bacteria is partly based on two critical points. First, the ratio of bacteria to cells should be as high as possible. Second, centrifugation, which was shown to enhance the adhesion of other intracellular bacteria to the cells,29 probably favored isolation of the bacillus.
We used our serologic method in different groups of patients. IgG antibodies were detected more frequently in patients with Whipple's disease, but they were present at a titer of 1:100 or more in 29 of 40 control subjects and therefore are not suitable for diagnostic purposes. We do not know whether this high level of IgG results from previous contact with the bacterium or from a cross-reaction with other bacteria. However, the fact that all patients with Whipple's disease had antibodies to the isolated bacterium provides support for the idea that it has a causative role in the disease.
The presence of IgM antibodies at a titer of at least 1:50 was significantly associated with Whipple's disease overall and with Whipple's disease endocarditis. For the comparison with patients with classic Whipple's disease, we chose patients with autoimmune disease as the control group, a controversial choice, because these patients frequently have false positive serologic reactions. The fact that we removed rheumatoid factor from the serum samples may have controlled for the rare false positive result. In fact, in one patient, the presence of antineutrophil cytoplasmic autoantibodies made it impossible to interpret the results. However, the difference between the two groups was of borderline significance (P=0.052). The serologic data are preliminary, and it would be interesting to learn whether patients have higher titers of IgM antibodies early in the course of the disease.
Our results are encouraging, and the establishment of the strain will enable researchers to define the role of this microorganism in several clinical syndromes. It may also be useful in developing an animal model of Whipple's disease as well as for antibiotic-susceptibility testing. Finally, the purification of the strain will clear the way for genetic studies, so that specific gene sequences can be obtained, in contrast to the current ones, which are based on universal primers.
We are indebted to Dr. D. Ross and Dr. R. Baskett of the Division of Cardiovascular Surgery at Dalhousie University, to Dr. A. Raza of the Department of Pathology at Dalhousie University, and to C. Capo for the confocal-microscopy images.
Source Information
From the Unité des Rickettsies, Université de la Méditerranée, Faculté de Médecine, Marseilles, France (D.R., M.L.B., B.L., P.E.F., M.E., H.L., V.R.); the Service de Médecine Interne, Groupe Hospitalier Pitié–Salpêtrière, Paris (J.-C.P.); the Laboratoire de Bactériologie, Hôpital Louis Pradel, Lyons, France (F.V.); the Service de Médecine Interne, Centre Hospitalier Lyon Sud, Lyons, France (D.V.-D.); and the Department of Medicine, University of Alberta, Edmonton, Canada (T.J.M.).
Address reprint requests to Dr. Raoult at the Unité des Rickettsies, Université de la Méditerranée, Faculté de Médecine, CNRS UPRESA 6020, 27 Blvd. Jean Moulin, 13385 Marseilles, France, or at didier.raoult@medecine.univ-mrs.fr.
- References
References
1
Vital-Durand D ,Lecomte C ,Cathebras P ,Rousset H ,Godeau P . Whipple disease: clinical review of 52 cases. Medicine (Baltimore) 1997;76:170-184
CrossRef | Web of Science | Medline2
Ratliff NB ,McMahon JT ,Naab TJ ,Cosgrove DM . Whipple's disease in the porcine leaflets of a Carpentier-Edwards prosthetic mitral valve. N Engl J Med 1984;311:902-903
Full Text | Web of Science | Medline3
Maizel H ,Ruffin JM ,Dobbins WO III . Whipple's disease: a review of 19 patients from one hospital and a review of the literature since 1950. Medicine (Baltimore) 1970;49:175-205
Web of Science | Medline4
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;18:382-391
Web of Science5
Yardley J ,Hendrix TR . Combined electron and light microscopy in Whipple's disease: demonstration of “bacillary bones“ in the intestine. Bull Johns Hopkins Hosp 1961;109:80-98
Web of Science | Medline6
Black-Schaffer B . The tinctoral demonstration of a glycoprotein in Whipple's disease. Proc Soc Exp Biol Med 1949;72:225-227
Web of Science | Medline7
Wilson KH ,Blitchington R ,Frothingham R ,Wilson JAP . Phylogeny of the Whipple's-disease-associated bacterium. Lancet 1991;338:474-475
CrossRef | Web of Science | Medline8
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
Full Text | Web of Science | Medline9
Renne R ,Zhong W ,Herndier B , et al. Lytic growth of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in culture. Nat Med 1996;2:342-346
CrossRef | Web of Science | Medline10
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
Web of Science | Medline11
Relman DA . The Whipple bacillus lives (ex vivo)! J Infect Dis 1997;176:752-754
CrossRef | Web of Science | Medline12
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
CrossRef | Web of Science | Medline13
Hinrikson HP ,Dutly F ,Nair S ,Altwegg M . Detection of three different types of `Tropheryma whippelii' directly from clinical specimens by sequencing, single-strand conformation polymorphism (SSCP) analysis and type-specific PCR of their 16S-23S ribosomal intergenic spacer region. Int J Syst Bacteriol 1999;49:1701-1706
CrossRef | Medline14
Woods GL ,Walker DH . Detection of infection or infectious agents by use of cytologic and histologic stains. Clin Microbiol Rev 1996;9:382-404
Web of Science | Medline15
La Scola B ,Michel G ,Raoult D . Isolation of Legionella pneumophila by centrifugation of shell vial cell cultures from multiple liver and lung abscesses. J Clin Microbiol 1999;37:785-787
Web of Science | Medline16
La Scola B ,Raoult D . Diagnosis of Mediterranean spotted fever by cultivation of Rickettsia conorii from blood and skin samples using the centrifugation-shell vial technique and by detection of R. conorii in circulating endothelial cells: a 6-year follow-up. J Clin Microbiol 1996;34:2722-2727
Web of Science | Medline17
Gimenez DF . Staining rickettsiae in yolk-sac cultures. Stain Technol 1964;39:135-140
Web of Science | Medline18
La Scola B ,Birtles RJ ,Mallet MN ,Raoult D . Massilia timonae gen. nov., sp. nov., isolated from blood of an immunocompromised patient with cerebellar lesions. J Clin Microbiol 1998;36:2847-2852
Web of Science | Medline19
La Scola B ,Raoult D . Culture of Bartonella quintana and Bartonella henselae from human samples: a 5-year experience (1993 to 1998). J Clin Microbiol 1999;37:1899-1905
Web of Science | Medline20
Celard M ,de Gevigney G ,Mosnier S , et al. Polymerase chain reaction analysis for diagnosis of Tropheryma whippelii infective endocarditis in two patients with no previous evidence of Whipple's disease. Clin Infect Dis 1999;29:1348-1349
CrossRef | Web of Science | Medline21
La Scola B ,Michel G ,Raoult D . Use of amplification and sequencing of the 16S rRNA gene to diagnose Mycoplasma pneumoniae osteomyelitis in a patient with hypogammaglobulinemia. Clin Infect Dis 1997;24:1161-1163
CrossRef | Web of Science | Medline22
Bostwick DG ,Bensch KG ,Burke JS , et al. Whipple's disease presenting as aortic insufficiency. N Engl J Med 1981;305:995-998
Full Text | Web of Science | Medline23
Rose A . Mitral stenosis in Whipple's disease. Thorax 1978;33:500-503
CrossRef | Web of Science | Medline24
Silva MT ,Macedo PM ,Moura Nunes JF . Ultrastructure of bacilli and the bacillary origin of the macrophagic inclusions in Whipple's disease. J Gen Microbiol 1985;131:1001-1013
Medline25
Murray RGE ,Schleifer KH . Taxonomic notes: a proposal for recording the properties of putative taxa of procaryotes. Int J Syst Bacteriol 1994;44:174-176
CrossRef | Medline26
Shepard CC . The experimental disease that follows the injection of human leprosy bacilli into foot-pads of mice. J Exp Med 1960;112:445-454
CrossRef | Web of Science | Medline27
Slater LN ,Welch DF ,Hensel D ,Coody DW . A newly recognized fastidious gram-negative pathogen as a cause of fever and bacteremia. N Engl J Med 1990;323:1587-1593
Full Text | Web of Science | Medline28
Marshall B . Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983;1:1273-1275
Web of Science | Medline29
Weiss E ,Dressler HR . Centrifugation of rickettsiae and viruses onto cells and its effect on infection. Proc Soc Exp Biol Med 1960;103:691-695
Web of Science | Medline
- Citing Articles (110)
Citing Articles
1
Sofia Rocha, Luísa Lobato, Maria João Carvalho, Jorge Malheiro, Ramón Vizcaíno, Anabela Rodrigues, António Cabrita. (2011) Renal transplantation in AA amyloidosis associated with Whipple’s disease. Amyloid 18:4, 240-244
CrossRef2
Jean-Marc Rolain, Florence Fenollar, Didier Raoult. (2011) In vitro activity of pentamidine against Tropheryma whipplei. International Journal of Antimicrobial Agents 38:6, 545-547
CrossRef3
V. Moos, T. Schneider. (2011) Changing paradigms in Whipple’s disease and infection with Tropheryma whipplei. European Journal of Clinical Microbiology & Infectious Diseases 30:10, 1151-1158
CrossRef4
Wazim Mohamed, Erin Neil, William J. Kupsky, Csaba Juhász, Sandeep Mittal, Sunitha Santhakumar. (2011) Isolated inctracranial Whipple's disease—Report of a rare case and review of the literature. Journal of the Neurological Sciences 308:1-2, 1-8
CrossRef5
V. Moos, C. Loddenkemper, T. Schneider. (2011) Infektionen mit Tropheryma whipplei. Der Pathologe 32:5, 362-370
CrossRef6
K. Al Moussawi, N. Malou, J.-L. Mege, D. Raoult, B. Desnues. (2011) An Experimental Mouse Model to Establish Tropheryma whipplei as a Diarrheal Agent. Journal of Infectious Diseases 204:1, 44-50
CrossRef7
W.-J. Mayet. (2011) Rheumatologische Symptome bei gastroenterologischen Erkrankungen. Der Gastroenterologe 6:4, 307-315
CrossRef8
Shoo Siah, Han Siah. 2011. Tropheryma. , 181-188.
CrossRef9
K. Eggeling, T. Marth. (2011) Morbus Whipple. Der Gastroenterologe 6:2, 124-126
CrossRef10
Florence Fenollar, François Nicoli, Claire Paquet, Hubert Lepidi, Patrick Cozzone, Jean-Christophe Antoine, Jean Pouget, Didier Raoult. (2011) Progressive dementia associated with ataxia or obesity in patients with Tropheryma whipplei encephalitis. BMC Infectious Diseases 11:1, 171
CrossRef11
Robert E. Petras. 2011. Gastrointestinal Pathology. , 699-716.
CrossRef12
Benoit Desnues, Khatoun Al Moussawi, Florence Fenollar. (2010) New insights into Whipple’s disease and Tropheryma whipplei infections. Microbes and Infection 12:14-15, 1102-1110
CrossRef13
George T. Fantry. 2010. Whipple Disease. , 258-261.
CrossRef14
J.-C. Lagier, F. Fenollar, H. Lepidi, D. Raoult. (2010) Failure and relapse after treatment with trimethoprim/sulfamethoxazole in classic Whipple's disease. Journal of Antimicrobial Chemotherapy 65:9, 2005-2012
CrossRef15
Jean-Christophe Lagier, Hubert Lepidi, Didier Raoult, Florence Fenollar. (2010) Systemic Tropheryma whipplei. Medicine 89:5, 337-345
CrossRef16
Payam Afshar, David C. Redfield, Philip A. Higginbottom. (2010) Whipple’s Disease: A Rare Disease Revisited. Current Gastroenterology Reports 12:4, 263-269
CrossRef17
R. Escher, S. Roth, S. Droz, K. Egli, M. Altwegg, M. G. Täuber. (2010) Endocarditis due to Tropheryma whipplei: rapid detection, limited genetic diversity, and long-term clinical outcome in a local experience. Clinical Microbiology and Infection 16:8, 1213-1222
CrossRef18
Christos St. Basagiannis, George S. Panagoulias, Nicholas Tentolouris, Stavros Basoukeas, Dimitrios Sambaziotis, Spiros D. Ladas. (2010) Whipple Disease. Southern Medical Journal 103:4, 353-356
CrossRef19
N. H. Cox, I. H. Coulson. 2010. Systemic Disease and the Skin. , 1-113.
CrossRef20
Matthias Maiwald. 2010. Tropheryma. .
CrossRef21
Patricia S. Conville, Frank G. Witebsky. 2010. Nocardia and other Aerobic Actinomycetes. .
CrossRef22
Gerhard E. Feurle, Natascha S. Junga, Thomas Marth. (2010) Efficacy of Ceftriaxone or Meropenem as Initial Therapies in Whipple's Disease. Gastroenterology 138:2, 478-486
CrossRef23
Verena Moos, Carsten Schmidt, Anika Geelhaar, Désirée Kunkel, Kristina Allers, Katina Schinnerling, Christoph Loddenkemper, Florence Fenollar, Annette Moter, Didier Raoult, Ralf Ignatius, Thomas Schneider. (2010) Impaired Immune Functions of Monocytes and Macrophages in Whipple's Disease. Gastroenterology 138:1, 210-220
CrossRef24
Francis Amoo, Di Zhao, Ingram M. Roberts. 2010. Celiac Disease, Tropical Sprue, Whipple Disease, Lymphangiectasia, Immunoproliferative Small Intestinal Disease, and Nonsteroidal Anti-Inflammatory Drugs. , 291-296.
CrossRef25
G. B. Rogers, M. P. Carroll, K. D. Bruce. (2009) Studying bacterial infections through culture-independent approaches. Journal of Medical Microbiology 58:11, 1401-1418
CrossRef26
X. Puéchal. (2009) Maladie de Whipple. La Revue de Médecine Interne 30:3, 233-241
CrossRef27
Malgorzata Kowalczewska, Claude Villard, Daniel Lafitte, Florence Fenollar, Didier Raoult. (2009) Global proteomic pattern of Tropheryma whipplei: A Whipple's disease bacterium. PROTEOMICS 9:6, 1593-1616
CrossRef28
J. Le Scanff, I. Durieu. (2009) Malattia di Whipple. EMC - AKOS - Trattato di Medicina 11:3, 1-5
CrossRef29
L. C. Kramer, T. A. J. M. Manschot, J. N. M. Barendregt, J. M. Smit. (2008) Whipple's disease: often a late diagnosis and a rare cause of nephropathy. NDT Plus 2:1, 55-58
CrossRef30
Peter Jackuliak, Tomas Koller, Lahim Baqi, Lukas Plank, Zora Lasabova, Gabriel Minarik, Juraj Payer. (2008) Whipple’s Disease—Generalized Stage. Digestive Diseases and Sciences 53:12, 3250-3258
CrossRef31
S. Vehr, A. Nestler, A. Schütz, U. Halm, P. Meier. (2008) Uveitis intermedia bei Morbus Whipple. Der Ophthalmologe 105:11, 1046-1051
CrossRef32
Thomas E. Baudendistel, Nima Afshar, Lawrence M. Tierney. (2008) One hundred years later. Journal of Hospital Medicine 3:6, 483-488
CrossRef33
J. Le Scanff, J.B. Gaultier, D. Vital Durand, I. Durieu, M. Celard, Y. Benito, F. Vandenesch, H. Rousset. (2008) Tropheryma whipplei et maladie de Whipple : résultats de la recherche par polymerase chain reaction (PCR) dans les échantillons à visée diagnostique. La Revue de Médecine Interne 29:11, 861-867
CrossRef34
José Ramón Blanco, Isabel Jado, Mercedes Marín, Isabel Sanfeliu, Aránzazu Portillo, Pedro Anda, Immaculada Pons, José Antonio Oteo. (2008) Diagnóstico microbiológico de las infecciones por patógenos bacterianos emergentes: Anaplasma, Bartonella, Rickettsia, Tropheryma whipplei. Enfermedades Infecciosas y Microbiología Clínica 26:9, 573-580
CrossRef35
C. J. Bonhomme, P. Renesto, S. Nandi, A. M. Lynn, D. Raoult. (2008) Serological microarray for a paradoxical diagnostic of Whipple’s disease. European Journal of Clinical Microbiology & Infectious Diseases 27:10, 959-968
CrossRef36
Florence Fenollar, Sonia Laouira, Hubert Lepidi, Jean‐Marc Rolain, Didier Raoult. (2008) Value of Tropheryma whipplei Quantitative Polymerase Chain Reaction Assay for the Diagnosis of Whipple Disease: Usefulness of Saliva and Stool Specimens for First‐Line Screening. Clinical Infectious Diseases 47:5, 659-667
CrossRef37
Nawal Bakkali, Florence Fenollar, Silpak Biswas, Jean‐Marc Rolain, Didier Raoult. (2008) Acquired Resistance to Trimethoprim‐Sulfamethoxazole during Whipple Disease and Expression of the Causative Target Gene. The Journal of Infectious Diseases 198:1, 101-108
CrossRef38
Malgorzata Kowalczewska, Florence Fenollar, Claude Villard, Saïd Azza, Maurice Roux, Didier Raoult. (2008) An immunoproteomic approach for identification of clinical biomarkers of Whipple's disease. PROTEOMICS – CLINICAL APPLICATIONS 2:4, 504-516
CrossRef39
Florence Fenollar, Michèle Trani, Bernard Davoust, Bettina Salle, Marie‐Laure Birg, Jean‐Marc Rolain, Didier Raoult. (2008) Prevalence of Asymptomatic Tropheryma whipplei Carriage among Humans and Nonhuman Primates. The Journal of Infectious Diseases 197:6, 880-887
CrossRef40
Thomas Marth, Thomas Schneider. (2008) Whipple disease. Current Opinion in Gastroenterology 24:2, 141-148
CrossRef41
Thomas Schneider, Verena Moos, Christoph Loddenkemper, Thomas Marth, Florence Fenollar, Didier Raoult. (2008) Whipple's disease: new aspects of pathogenesis and treatment. The Lancet Infectious Diseases 8:3, 179-190
CrossRef42
Malgorzata Kowalczewska, Didier Raoult. (2007) Advances in Tropheryma whipplei research: the rush to find biomarkers for Whipple’s disease. Future Microbiology 2:6, 631-642
CrossRef43
Jean-Marc Rolain, Philippe Colson, Didier Raoult. (2007) Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. International Journal of Antimicrobial Agents 30:4, 297-308
CrossRef44
Véronique Vincent, Laurent Zabraniecki, Emmanuelle Uro-Coste, Olivia Lemaire, Bernard Fournié. (2007) Whipple disease revealed by musculocutaneous symptoms, with muscle biopsy cultures positive for Tropheryma whipplei. Joint Bone Spine 74:5, 506-508
CrossRef45
Chih-wei Wang, Thomas V. Colby. (2007) Histiocytic lesions and proliferations in the lung. Seminars in Diagnostic Pathology 24:3, 162-182
CrossRef46
Györgyi Műzes, Hajnal Székely, Zsolt Tulassay. (2007) A Whipple-kór aktuális kérdései. Orvosi Hetilap 148:26, 1225-1230
CrossRef47
Xavier Puéchal, Florence Fenollar, Didier Raoult. (2007) Cultivation ofTropheryma whipplei from the synovial fluid in Whipple's arthritis. Arthritis & Rheumatism 56:5, 1713-1718
CrossRef48
Hiroyuki Ogata, Patricia Renesto. 2007. Genomics of Rickettsial Agents. , 345-360.
CrossRef49
Aaron R Kosmin, Bennett Lorber. 2007. Specific Tests in the Diagnosis of Fever of Unknown Origin. , 159-208.
CrossRef50
John L. Brusch. 2007. Microbiology of Infective Endocarditis and Clinical Correlates: Gram-Negative and Other Organisms. , 51-100.
CrossRef51
Fenollar, Florence, Puéchal, Xavier, Raoult, Didier, . (2007) Whipple's Disease. New England Journal of Medicine 356:1, 55-66
Full Text52
S R Owens, J K Greenson. (2007) The pathology of malabsorption: current concepts. Histopathology 50:1, 64-82
CrossRef53
Marie Puget, Jean Iwaz, Anne Tristan, Nathalie Streichenberger. (2006) Whipple's disease with muscle impairment. Muscle & Nerve 34:6, 794-798
CrossRef54
Y. Juárez, S. España, M.ªL. Fernández-Díaz, M. Lueiro. (2006) Escorbuto e ictiosis adquirida asociadas a enfermedad de Whipple. Actas Dermo-Sifiliográficas 97:9, 587-590
CrossRef55
Raoult, Didier, Fenollar, Florence, Birg, Marie-Laure. (2006) Culture of T. whipplei from the Stool of a Patient with Whipple's Disease. New England Journal of Medicine 355:14, 1503-1505
Full Text56
Pedro Bermejo, Aurora Burgos. (2006) Enfermedad de Whipple y sistema nervioso central. Medicina Clínica 127:10, 379-385
CrossRef57
Mara M. Lugassy, Elan D. Louis. (2006) Neurologic manifestations of Whipple’s disease. Current Infectious Disease Reports 8:4, 301-306
CrossRef58
Sylvie Revaz, Jean Dudler, Alexander Kai-Lik So. (2006) Fever and musculoskeletal symptoms in an adult: differential diagnosis and management. Best Practice & Research Clinical Rheumatology 20:4, 641-651
CrossRef59
Malgorzata Kowalczewska, Florence Fenollar, Daniel Lafitte, Didier Raoult. (2006) Identification of candidate antigen in Whipple's disease using a serological proteomic approach. PROTEOMICS 6:11, 3294-3305
CrossRef60
A. Kalt, T. Schneider, S. Ring, J. Hoffmann, M. Zeitz, A. Stallmach, D. H. Persing, T. Marth. (2006) Decreased levels of interleukin-12p40 in the serum of patients with Whipple’s disease. International Journal of Colorectal Disease 21:2, 114-120
CrossRef61
Klaus Mönkemüller, Lucía C. Fry, Steffen Rickes, Peter Malfertheiner. (2006) Whipple’s disease. Current Infectious Disease Reports 8:2, 96-102
CrossRef62
Andrew Mark Morris. (2006) How best to deal with endocarditis. Current Infectious Disease Reports 8:1, 14-22
CrossRef63
H. Aïouaz, M. Célard, M. Puget, F. Vandenesch, A. Mercusot, F. Fenollar, F. Delahaye, JF. Obadia, J. Tebib, H. Rousset. (2005) Endocardites de la maladie de Whipple : cinq observations et revue de la littérature. La Revue de Médecine Interne 26:10, 784-790
CrossRef64
Rene Mahnel, Anja Kalt, Sabine Ring, Andreas Stallmach, Warren Strober, Thomas Marth. (2005) Immunosuppressive Therapy in Whipple's Disease Patients is Associated with the Appearance of Gastrointestinal Manifestations. The American Journal of Gastroenterology 100:5, 1167-1173
CrossRef65
Pierre Houpikian, Didier Raoult. (2005) Blood Culture-Negative Endocarditis in a Reference Center. Medicine 84:3, 162-173
CrossRef66
R. Mahnel, T. Marth, F. Fenollar, D. Raoult. 2004. Tropheryma whipplei. , 1292-1296.
CrossRef67
O. Gout, G. Besson, J. Croizé. (2004) Troubles de la marche d’aggravation rapide chez un homme de 68 ans. Revue Neurologique 160:11, 1096-1101
CrossRef68
Hassane Izzedine, Irina Buhaescu, Bahram Bodaghi, Valerie Martinez, Eric Caumes, Phuc LeHoang, Gilbert Deray. (2004) Oculo-renal Disorders in Infectious Diseases. International Ophthalmology 25:5-6, 299-319
CrossRef69
A.C. Friedmann, G.K. Perera, A. Jayaprakasam, I. Forgacs, J.R. Salisbury, D. Creamer. (2004) Whipple's disease presenting with symmetrical panniculitis. British Journal of Dermatology 151:4, 907-911
CrossRef70
Stefan Martin Kröber, Edwin Kaiserling, Hans-Peter Horny, Achim Weber. (2004) Primary diagnosis of Whipple’s disease in bone marrow. Human Pathology 35:4, 522-525
CrossRef71
J. Fernández Castroagudín, C. Durana Tonder, J.E. Domínguez Muñoz. (2004) Síndrome de malabsorción intestinal (2). Formas de afectación intestinal primaria en el adulto. Medicine - Programa de Formación Médica Continuada Acreditado 9:3, 172-184
CrossRef72
Didier Raoult, Pierre Edouard Fournier, Michel Drancourt. (2004) What does the future hold for clinical microbiology?. Nature Reviews Microbiology 2:2, 151-159
CrossRef73
Tatsuji YOGI, Akira HOKAMA, Fukunori KINJO, Ryosaku TOMIYAMA, Michio KOIDE, Kazuto KISHIMOTO, Tomoko MAKISHI, Masaru OSHIRO, Satoru MIYAGI, Chiharu KOBASHIGAWA, Ryo TAKAKI, Takashi NAKAYAMA, Atsushi SAITO. (2004) Whipple's Disease: the First Japanese Case Diagnosed by Electron Microscopy and Polymerase Chain Reaction. Internal Medicine 43:7, 566-570
CrossRef74
Tahir Tak, Sumeesh Dhawan, Cory Reynolds, Sanjay K Shukla. (2003) Current diagnosis and treatment of infective endocarditis. Expert Review of Anti-infective Therapy 1:4, 639-654
CrossRef75
B Bodaghi, B Wechsler, L.T.H Du-Boutin, N Cassoux, P LeHoang, J.-C Piette. (2003) Uvéites chroniques sévères : classification, démarche diagnostique et principes thérapeutiques. La Revue de Médecine Interne 24:12, 794-802
CrossRef76
Elan D. Louis. (2003) Whipple disease. Current Neurology and Neuroscience Reports 3:6, 470-475
CrossRef77
Florence Fenollar, Didier Raoult. (2003) Whipple’s disease. Current Gastroenterology Reports 5:5, 379-385
CrossRef78
Romana C. Maibach, Martin Altwegg. (2003) Cloning and sequencing an unknown gene of Tropheryma whipplei and development of two LightCycler® PCR assays. Diagnostic Microbiology and Infectious Disease 46:3, 181-187
CrossRef79
G. VESTRIS, J. M. ROLAIN, P. E. FOURNIER, M. L. BIRG, M. ENEA, J. Y. PATRICE, D. RAOULT. (2003) Seven Years' Experience of Isolation of Rickettsia spp. from Clinical Specimens Using the Shell Vial Cell Culture Assay. Annals of the New York Academy of Sciences 990:1, 371-374
CrossRef80
Hubert Lepidi, Florence Fenollar, Rene Gerolami, Jean-Louis Mege, Marie-France Bonzi, Marc Chappuis, José Sahel, Didier Raoult. (2003) Whipple’s disease: immunospecific and quantitative immunohistochemical study of intestinal biopsy specimens. Human Pathology 34:6, 589-596
CrossRef81
Dumler, J. Stephen, Baisden, Blaire L., Yardley, John H., , Raoult, Didier, . (2003) Immunodetection of Tropheryma whipplei in Intestinal Tissues from Dr. Whipple's 1907 Patient. New England Journal of Medicine 348:14, 1411-1412
Full Text82
Bernard La Scola, Jean‐Marc Rolain, Max Maurin, Didier Raoult. (2003) Can Whipple’s Disease Be Transmitted by Gastroscopes? • . Infection Control and Hospital Epidemiology 24:3, 191-194
CrossRef83
Stephen D Bentley, Matthias Maiwald, Lee D Murphy, Mark J Pallen, Corin A Yeats, Lynn G Dover, Halina T Norbertczak, Gurdyal S Besra, Michael A Quail, David E Harris, Axel von Herbay, Arlette Goble, Simon Rutter, Robert Squares, Stephen Squares, Bart G Barrell, Julian Parkhill, David A Relman. (2003) Sequencing and analysis of the genome of the Whipple's disease bacterium Tropheryma whipplei. The Lancet 361:9358, 637-644
CrossRef84
Andreas Schaffner, Markus Schneemann. (2003) Whipple's disease—from enigma to genomics. The Lancet 361:9358, 632
CrossRef85
Marianna Papadopoulou, Michael Rentzos, Chryssoula Nicolaou, Vassiliki Ioannidou, Anastassios Ioannidis, Stylianos Chatzipanagiotou. (2003) Cerebral Whipple???s???Disease Diagnosed Using PCR. Molecular Diagnosis 7:3, 209-211
CrossRef86
Matthias Maiwald, Paul W. Lepp, David A. Relman. (2003) Analysis of Conserved Non-rRNA Genes of Tropheryma whipplei. Systematic and Applied Microbiology 26:1, 3-12
CrossRef87
Sabine Ring, Thomas Schneider, Thomas Marth. (2003) Mucosal immune response to Tropheryma whipplei. International Journal of Medical Microbiology 293:1, 69-76
CrossRef88
John Lynch, Timothy Lynch. 2003. Whipple's Disease. , 748-750.
CrossRef89
ANTOINE GERARD, FRANCOISE SARROT-REYNAULD, ERIC LIOZON, PASCAL CATHEBRAS, GERARD BESSON, CHRISTOPHE ROBIN, ALAIN VIGHETTO, JEAN-FRANCOIS MOSNIER, ISABELLE DURIEU, DENIS VITAL DURAND, HUGUES ROUSSET. (2002) Neurologic Presentation of Whipple Disease. Medicine 81:6, 443-457
CrossRef90
Hubert Lepidi, David T Durack, Didier Raoult. (2002) Diagnostic methods. Infectious Disease Clinics of North America 16:2, 339-361
CrossRef91
Pierre Houpikian, Didier Raoult. (2002) Diagnostic methods. Infectious Disease Clinics of North America 16:2, 377-392
CrossRef92
D.G James, M.C.I Lipman. (2002) Whipple's disease: a granulomatous masquerader. Clinics in Chest Medicine 23:2, 513-519
CrossRef93
Xavier Puéchal. (2002) Whipple’s disease. Joint Bone Spine 69:2, 133-140
CrossRef94
John H. Yardley, Hubert Lepidi, Blaire L. Baisden, Didier Raoult, Pedram Argani, J. Stephen Dumler. (2002) 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. American Journal of Clinical Pathology 118:5, 742-748
CrossRef95
Silvia Morgenegg, Romana Maibach, David-Nicolas Chaperon, Kathrin Herzog, Martin Altwegg. (2001) Antibodies against recombinant heat shock protein 65 of Tropheryma whipplei in patients with and without Whipple's disease. Journal of Microbiological Methods 47:3, 299-306
CrossRef96
Theodore F. Beals, MD, Serhan Alkan, MD, Bertram Schnitzer, MD. (2001) Primary Diagnosis of Whipple Disease Manifesting as Lymphadenopathy. American Journal of Clinical Pathology 116:6, 898-904
CrossRef97
Mylonakis, Eleftherios, Calderwood, Stephen B., . (2001) Infective Endocarditis in Adults. New England Journal of Medicine 345:18, 1318-1330
Full Text98
Thomas Marth. (2001) The diagnosis and treatment of whipple’s disease. Current Allergy and Asthma Reports 1:6, 566-571
CrossRef99
Florence Fenollar, Hubert Lepidi, Didier Raoult. (2001) Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture–Positive Endocarditis. Clinical Infectious Diseases 33:8, 1309-1316
CrossRef100
Florence Fenollar, Didier Raoult. (2001) Molecular techniques in Whipple's disease. Expert Review of Molecular Diagnostics 1:3, 299-309
CrossRef101
Raoult, Didier, Lepidi, Hubert, , Harle, Jean Robert, . (2001) Tropheryma whipplei Circulating in Blood Monocytes. New England Journal of Medicine 345:7, 548-548
Full Text102
Nicole Müller, Th. Schneider, M. Zeitz, Th. Marth. (2001) La maladie de Whipple: nouveaux aspects de la pathogénie et du diagnostic. Acta Endoscopica 31:3, 243-253
CrossRef103
Judith B. Scott, Mark C. Flemmer, Edward Oldfield. (2001) In pursuit of Doctor Whipple's nemesis. The American Journal of Gastroenterology 96:3, 915-916
CrossRef104
Thomas James. (2001) Coronary Artery Disease 12:2, 115-125
CrossRef105
L. J. Strausbaugh, M. Maiwald, D. A. Relman. (2001) Whipple's Disease and Tropheryma whippelii: Secrets Slowly Revealed. Clinical Infectious Diseases 32:3, 457-463
CrossRef106
Xavier Pu??chal. (2001) Whipple disease and arthritis. Current Opinion in Rheumatology 13:1, 74-79
CrossRef107
Michael Levy, Claire Poyart, Dominique Lamarque, Jean-Charles Delchier. (2000) Whipple's disease: acquired resistance to trimethoprim-sulfamethoxazole. The American Journal of Gastroenterology 95:9, 2390-2391
CrossRef108
Mark C. Flemmer, Ronald W. Flenner. (2000) Toward a new understanding of Whipple’s disease. Current Gastroenterology Reports 2:4, 299-304
CrossRef109
J.P. Cervoni, F. Brisset, L. Larvol, H. Levecq, R. Damade. (2000) Ascite et amaigrissement. La Revue de Médecine Interne 21, 350s-355s
CrossRef110
Swartz, Morton N., . (2000) Whipple's Disease — Past, Present, and Future. New England Journal of Medicine 342:9, 648-650
Full Text
