In cases of suspected extraintestinal Whipple's disease, it is advisable to obtain specimens from the affected anatomic sites, in addition to intestinal biopsy specimens. This strategy applies to initial presentations with minimal or no apparent intestinal involvement [ 15 , 27 ]; in addition, it applies to patients after treatment of Whipple's disease, when either clinical findings persist or new atypical presentations occur, as is illustrated by a case of extreme insomnia occurring 8 years after diagnosis and treatment of intestinal disease [ 18 ].
There are still no randomized, double-blind trials of different antibiotic regimens upon which to base recommendations for the treatment of Whipple's disease. On the basis of the combined observations from many case reports [ 6 ], several patient series [ 9—11 ], and retrospective analyses [ 30 , 31 ], the therapy most commonly associated with clinical success is initial iv treatment with penicillin G and streptomycin, or a third-generation cephalosporin, followed by administration of co-trimoxazole for at least 1 year table 2.
The main objectives of treatment of Whipple's disease are to eradicate primary usually intestinal disease and to prevent relapse. Considering the tropism of T. Well-established protocols for patient follow-up during and after therapy are also lacking. Routine periodic assessment of sites of frequent disease involvement, such as the abdominal lymph nodes, cardiovascular system, and CNS, would be prudent.
PAS-positive macrophages undergo morphological changes but persist for up to several years [ 25 ]; intact bacterial cells with status determined by means of electron microscopy are shorter lived, disappearing after a few months [ 28 ]. Positive results of PCR analysis of intestinal specimens results indicate bacterial DNA convert to negative results usually within 1—12 months after initiation of therapy [ 19 ].
One study suggested that PCR analysis of intestinal specimens may be useful for monitoring the efficacy of therapy [ 20 ], whereas another investigation found that some patients for whom the results of PCR analysis of intestinal samples are negative develop relapses in the CNS [ 19 ]. At present, there are no solid data that one can use to decide when antibiotic therapy should be terminated, but therapy with an overall duration of at least 1 year is considered necessary [ 30 , 31 ].
The currently available data, albeit scant, suggest that posttreatment progression and relapse of disease are caused by the original infecting bacterial strain see below , rather than by reinfection by a different strain.
The question of whether a disease or infection has been underdiagnosed naturally arises when new, more-sensitive diagnostic methods become available. One would expect that this circumstance imposes a bias on the recognition and description of the full spectrum of disease manifestations.
For example, Whipple's disease was retrospectively diagnosed in a specimen from that was stored at the Westminster Museum in London, by means of the newly available PAS stain [ 32 ].
By use of other diagnostic procedures e. These diagnosed cases might have been missed before the availability of these methods. At the same time, Whipple's disease is considered to be invariably fatal when it is not treated with antibiotics [ 6 ]. If a significant number of cases were unrecognized and untreated, one might expect some of them to be discovered at autopsy; however, this is not a common event.
It is possible that spontaneous remission or resolution of disease occurs, and it is conceivable that patients with unsuspected disease are cured when they undergo short courses of antibiotic therapy for other complaints. In this context, the observation by Fleming et al. Furthermore, it has been suspected that the frequent use of antibiotics in general medical practice, in dosages and durations inadequate for cure, may have altered the age of presentation with Whipple's disease during the past several decades [ 34 ].
Overall, it seems unlikely that a significant number of advanced cases of Whipple's disease go undiagnosed; however, it remains unclear whether this theory holds true for less severe cases and for those that may be cured by short courses of antibiotics.
Over a period of 30 years, Dobbins [ 6 ] noted a relatively stable incidence of Whipple's disease, with a ratio of 1 published case to every 4 unpublished cases. Given how little we know about the natural habitat of the organism see the Pathogenesis and Acquisition of Infection section and the route s of transmission to humans, it is even more unclear whether asymptomatic, transient, or persistent infections in privileged anatomic compartments those that are usually free of microorganisms are common occurrences.
Electron microscopy of tissue specimens from patients with Whipple's disease reveals uniformity in bacterial size 0. The bacteria are surrounded by an unusual outer membrane not found in other gram-positive bacteria and unlike those seen in gram-negative bacteria: it appears to lack lipopolysaccharide. Some investigators have concluded that this membrane may be of host origin [ 29 ]. As a result, the lack of a known close relative prevents meaningful inferences of physiology and function for T.
One notable report by Schoedon et al. Heart valve tissue specimens obtained from 2 infected patients were inoculated onto human macrophages that had been treated with IL-4 in cell culture. This treatment impairs the microbicidal killing mechanisms of macrophages and facilitates the growth of intracellular microorganisms. Accumulation of PAS-positive intracellular inclusions and the persistence of PCR-amplified product after cell passage were interpreted as being indicative of growth of T.
However, these results have not been reproduced by other researchers Maiwald and Relman, unpublished data; [ 37 ]. A nonvalidated PCR assay was used by Schoedon et al. Raoult et al. An aortic valve tissue sample from a patient with endocarditis was inoculated onto a human fibroblast cell line, without special pretreatment of the cells e. After 65 days of incubation, a cytopathic effect was observed, and microorganisms were seen by means of several staining procedures, including PAS staining.
Fibroblast culture material was passaged 7 times, and after days, a cm 2 infected cell monolayer was obtained from an initial inoculum of 1 cm 2 of cells. Several stains showed bacteria, and results of PCR analysis were positive for T. The doubling time of the bacteria was estimated to be 18 days under these particular growth conditions, which is slower than that of Mycobacterium leprae in a mouse model 12 days.
Immunofluorescence staining that used samples of the patient's serum as well as murine polyclonal antibodies raised against cultured material revealed bacteria in and on fibroblasts and in the original heart valve.
Serological tests were also performed using cultured material as antigen. Elevated titers of IgM antibody were detected in 7 of 9 serum samples from different patients with Whipple's disease and in 3 of 40 serum samples from controls, whereas titers of IgG antibody were elevated for all 9 patients with Whipple's disease and for 29 of 40 controls.
Taken together, there is good evidence that these investigators have propagated T. However, the story is not yet complete: there is no documentation, by use of a quantitative method e. Although the reported doubling time renders this culture method impractical for routine laboratories, this report may constitute an important step toward the ultimate goal of routine propagation of T.
Basic epidemiological tasks, such as tracking routes of infection and determining linkage between cases, require bacterial strain identification and discrimination. The first step toward strain typing of T. This sequence was initially determined from a specimen from 1 patient with Whipple's disease [ 35 ]; variability of the spacer sequence was addressed in subsequent studies [ 39—41 ].
One study [ 39 ] found homogeneity in the spacer sequences in 9 Swiss individuals; another study by the same group of investigators [ 40 ] found 3 different spacer types in 28 individuals whose geographic locations were not specified.
Specimens from different anatomic sites generally yielded the same spacer types in individual patients, which supports the concept of systemic dissemination of a single bacterial clone [ 41 ]. However, 1 intestinal biopsy sample from 1 patient contained 2 sequence types, which raised, for the first time, the possibility of double infection with T.
Despite these efforts, the 16S—23S rRNA intergenic spacer sequence with its 6 known variant types may not be adequate for discrimination between T. Maternity Services. Hip Replacement. Primary Care. Type 2 Diabetes. Surgical Services. Home Care. Support Groups. Stroke Awareness. Fitness Classes. Integrative Therapy.
Weight Management. Parking Information. Gift Shop. Patient Meals. Pay My Bill Online. Financial Assistance. Medical Records. Events Calendar. Contact Us. Hospital Leadership. This was interpreted as a possible defect of cell immunity. With this information, the diagnosis hypothesis was an articular manifestation of a systemic disease. Since HLA B27 was negative, the classic seronegative spondyloarthropathies ankylosing spondylitis, inflammatory bowel disease, Reactive Arthritis, Psoriatic Arthritis was less likely, but not impossible.
The patient received a written summary of the clinical features and an immediate request of upper gastrointestinal endoscopy with duodenal biopsy to specifically rule out Whipple's disease. Despite this evaluation, the patient did not follow the indications and he did not return. In , together with the articular features, he started a refractory very severe headache. Associated with the headache bursts, he developed a right hemiparesis and a left facial paralysis that remitted spontaneously.
In addition, he had episodes of diarrhea with hematochezia, nausea and vomiting, resulting in significant weight loss and muscle atrophy. He had intracranial hypertension due to cerebral edema, confirmed by magnetic resonance imaging MRI associated with dyspnea on minimal exertion, paroxysmal nocturnal dyspnea, prerenal failure, pleural effusion and generalized edema consistent with congestive heart failure.
The echocardiography showed a mitral valve vegetation and insufficiency. The medical team who conducted the case requested an upper gastrointestinal endoscopy with duodenal biopsy for Whipple's disease investigation after reviewing information collected in the consultation at the Internal Medicine Unit in J Clin Microbiol. Marked accumulation of PAS-positive macrophages white arrow on submucosa and presence of fibrosis black arrow suggesting a chronic process.
In view of the diagnosis, therapy was initiated with trimethoprim-sulfamethoxazole, soon interrupted due to severe gastrointestinal intolerance. Therapy was replaced with doxycycline mg orally 2 tablets bid and hydroxychloroquine mg orally once a day. The patient showed dramatic clinical improvement and was discharged for outpatient monitoring. Whipple's disease has a variable presentation of polyarthralgia, including symmetric and asymmetric forms of intermittent nature, sometimes being migratory or additive.
Clinical Review of 52 cases. Societe Nationale Francaise de Medecine Interne. Med Tropheryma Whipplei. The patient presented the polyarticular arthritis features about five years before the severe illness. Not much is known about the bacteria. Although they seem readily present in the environment, scientists don't know where they come from or how they're spread to humans. Not everyone who carries the bacteria develops the disease.
Some researchers believe that people with the disease may have a genetic defect in their immune system response that makes them more likely to become sick when exposed to the bacteria. Because so little is known about the bacteria that cause Whipple disease, risk factors for the disease haven't been clearly identified. Based on available reports, it appears more likely to affect:. The lining of your small intestine has fine, hairlike projections villi that help your body absorb nutrients.
Whipple disease damages the villi, impairing nutrient absorption. Nutritional deficiencies are common in people with Whipple disease and can lead to fatigue, weakness, weight loss and joint pain. Whipple disease is a progressive and potentially fatal disease. Although the infection is rare, associated deaths continue to be reported. This is due in large part to late diagnoses and delayed treatment.
Death often is caused by the spread of the infection to the central nervous system, which can cause irreversible damage. Our patients tell us that the quality of their interactions, our attention to detail and the efficiency of their visits mean health care like they've never experienced.
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