LymphedemaV1, Istex, Corpus, bibRecord, 004389

Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive

Identifieur interne : 004389 ( Istex/Corpus ); précédent : 004388; suivant : 004390

Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive

Auteurs : Florence Fenollar ; Hubert Lepidi ; Didier Raoult

Source :

Clinical Infectious Diseases [ 1058-4838 ] ; 2001-10-15.

RBID : ISTEX:8FF75F546EC4D4B2F2CEF0311439891CD6892D58

Abstract

Whipple's disease is a systemic infection sometimes associated with cardiac manifestations. Recently, there has been an increase in the number of reported cases of Whipple's endocarditis. The purpose of our study was to describe this entity. Data from 35 well-described cases of Whipple's endocarditis were collected and compared with those of blood culture-positive endocarditis, Q fever endocarditis, and Bartonella endocarditis. Some patients with generalized Whipple's disease presented with cardiac involvement, among other symptoms. Others presented with a nonspecific, blood culture-negative endocarditis with no associated symptoms. In comparison with cases of endocarditis due to other causes, congestive heart failure, fever, and previous valvular disease were less frequently observed in the cases of Whipple's endocarditis. Without examination of the excised valves, the diagnosis of infective endocarditis could not have been confirmed in most cases. Treatment is not well established. Whipple's endocarditis is a specific entity involving minor inflammatory reactions and negative blood cultures, and its incidence is probably underestimated.

Url:

https://api.istex.fr/document/8FF75F546EC4D4B2F2CEF0311439891CD6892D58/fulltext/pdf

DOI: 10.1086/322666

Links to Exploration step

ISTEX:8FF75F546EC4D4B2F2CEF0311439891CD6892D58

Le document en format XML

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<front><div type="abstract">Whipple's disease is a systemic infection sometimes associated with cardiac manifestations. Recently, there has been an increase in the number of reported cases of Whipple's endocarditis. The purpose of our study was to describe this entity. Data from 35 well-described cases of Whipple's endocarditis were collected and compared with those of blood culture-positive endocarditis, Q fever endocarditis, and Bartonella endocarditis. Some patients with generalized Whipple's disease presented with cardiac involvement, among other symptoms. Others presented with a nonspecific, blood culture-negative endocarditis with no associated symptoms. In comparison with cases of endocarditis due to other causes, congestive heart failure, fever, and previous valvular disease were less frequently observed in the cases of Whipple's endocarditis. Without examination of the excised valves, the diagnosis of infective endocarditis could not have been confirmed in most cases. Treatment is not well established. Whipple's endocarditis is a specific entity involving minor inflammatory reactions and negative blood cultures, and its incidence is probably underestimated.</div>
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<issn pub-type="ppub">1058-4838</issn>

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<article-title>Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, <italic>Bartonella</italic>
 Infection, and Blood Culture—Positive</article-title>

</title-group>

<contrib-group>

<contrib contrib-type="author" corresp="yes">

<name>

<surname>Fenollar</surname>

<given-names>Florence</given-names>

</name>

<xref rid="aff1" ref-type="aff">1</xref>

<xref rid="cor1" ref-type="corresp"></xref>

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<contrib contrib-type="author">

<name>

<surname>Lepidi</surname>

<given-names>Hubert</given-names>

</name>

<xref rid="aff1" ref-type="aff">1</xref>

<xref rid="aff2" ref-type="aff">2</xref>

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<contrib contrib-type="author">

<name>

<surname>Raoult</surname>

<given-names>Didier</given-names>

</name>

<xref rid="aff1" ref-type="aff">1</xref>

</contrib>

<aff id="aff1"><label>1</label>
<institution>Unité des Rickettsies, Centre Nationale de Recherche Scientifique</institution>
, <addr-line>Unité Mixte de Recherche 6020, France</addr-line>
</aff>

<aff id="aff2"><label>2</label>
<institution>Laboratoire d'histologie, Faculté de médecine, Université de la Méditerraneé</institution>
, <addr-line>Marseille, France</addr-line>
</aff>

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<author-notes>

<corresp id="cor1">Reprints or correspondence: Dr. Didier Raoult, Unité des Rickettsies, CNRS: UPRESA 6020, Faculté de médecine, Université de la Méditerranée, 27 Boulevard Jean Moulin, 13385 Marseille Cedex 05, France (<email>Didier.Raoult@medecine.univ-mrs.fr</email>
).</corresp>

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<day>15</day>

<month>10</month>

<year>2001</year>

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<fpage>1309</fpage>

<lpage>1316</lpage>

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<date date-type="received">

<day>15</day>

<month>12</month>

<year>2000</year>

</date>

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<day>5</day>

<month>4</month>

<year>2001</year>

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<copyright-statement>© 2001 by the Infectious Diseases Society of America</copyright-statement>

<copyright-year>2001</copyright-year>

<abstract>

<p>Whipple's disease is a systemic infection sometimes associated with cardiac manifestations. Recently, there has been an increase in the number of reported cases of Whipple's endocarditis. The purpose of our study was to describe this entity. Data from 35 well-described cases of Whipple's endocarditis were collected and compared with those of blood culture-positive endocarditis, Q fever endocarditis, and <italic>Bartonella</italic>
 endocarditis. Some patients with generalized Whipple's disease presented with cardiac involvement, among other symptoms. Others presented with a nonspecific, blood culture-negative endocarditis with no associated symptoms. In comparison with cases of endocarditis due to other causes, congestive heart failure, fever, and previous valvular disease were less frequently observed in the cases of Whipple's endocarditis. Without examination of the excised valves, the diagnosis of infective endocarditis could not have been confirmed in most cases. Treatment is not well established. Whipple's endocarditis is a specific entity involving minor inflammatory reactions and negative blood cultures, and its incidence is probably underestimated.</p>

</abstract>

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<body>

<p>Whipple's disease is an uncommon, chronic systemic illness that was first described in 1907 as occurring in a missionary who died after the occurrence of chronic arthralgias, weight loss, and abdominal discomfort [<xref rid="ref1" ref-type="bibr">1</xref>
]. Whipple accurately described the “phagocytic mononuclear cells” in the walls of the intestine and the mesenteric lymph nodes, as well as the rodlike bacilli in a small node, but he did not conclude that the disease was due to a bacterium [<xref rid="ref1" ref-type="bibr">1</xref>
]. In 1961, electron microscopy demonstrated for the first time that rod-shaped structures in the intestinal mucosa and within macrophages had the structural characteristics of bacteria [<xref rid="ref2" ref-type="bibr">2</xref>
, <xref rid="ref3" ref-type="bibr">3</xref>
]. In 1991 and 1992, the phylogenetic position of the bacterium that causes the disease was established [<xref rid="ref4" ref-type="bibr">4</xref>
], and the agent was named <italic>Tropheryma whippelii</italic>
 [<xref rid="ref5" ref-type="bibr">5</xref>
]. A successful attempt to culture the organism was reported in 1997 [<xref rid="ref6" ref-type="bibr">6</xref>
], but the work could not be reproduced or pursued as reported by the authors [<xref rid="ref7" ref-type="bibr">7</xref>
].</p>

<p>In 2000, successful isolation and establishment of a strain of the Whipple's disease bacterium were reported and confirmed by representatives of the independent French national culture collection [<xref rid="ref8" ref-type="bibr">8</xref>
]. In 1907, valvular lesions were found by Whipple, but they were not linked to the disease [<xref rid="ref1" ref-type="bibr">1</xref>
]. Cardiological changes associated with Whipple's disease were first described by Upton [<xref rid="ref9" ref-type="bibr">9</xref>
] in 1952. Endocarditis with negative blood cultures is considered by some authors to be the most usual clinical finding among cardiovascular lesions associated with the disease [<xref rid="ref10" ref-type="bibr">10</xref>
]. In the early stages of the disease, the diagnosis is difficult. Although the efficacy of antibiotic treatment for Whipple's disease has been recognized since 1952 [<xref rid="ref11" ref-type="bibr">11</xref>
], the optimal treatment has not yet been established. The purpose of our study was to examine in detail the clinical, biological, and histopathological features of Whipple's disease endocarditis reported in the literature since 1907 and to compare them with those of endocarditis due to other bacteria [<xref rid="ref12" ref-type="bibr">12</xref>
–<xref rid="ref14" ref-type="bibr">14</xref>
].</p>

<sec sec-type="methods" id="sec1">

<title>Methods</title>

<p>A MEDLINE search of reports that were published from 1966 through 1999 was performed with use of the keywords <italic>“T. whippelii,”</italic>
 “Whipple's disease,” and “endocarditis.” We then identified additional cases from these reports by cross-referencing.</p>

<p>The criteria for inclusion in our study were based on valve histology during necropsy or valve replacement. Valve studies should show principally (1) infiltration by foamy macrophages containing granules positive on periodic acid-Schiff (PAS) staining, (2) an inflammatory reaction or positive PCR amplification of DNA extracted from the valve or a vegetation, and (3) negative blood culture. Only patients for whom a diagnosis of Whipple's disease endocarditis was confirmed and clinical details were sufficient were considered for the analysis. Indeed, we selected only patients for whom the presence or absence of clinical manifestations, such as arthralgia, diarrhea, weight loss, pigmentation, lymphadenopathy, fever, dyspnea, and cachexia, had been reported.</p>

<p>In order to define Whipple's disease endocarditis better, we also compared these data with those from a large series of cases of blood culture-positive endocarditis [<xref rid="ref14" ref-type="bibr">14</xref>
] and with those concerning the 2 most frequent causes of blood culture-negative endocarditis, <italic>Bartonella</italic>
 species and <italic>Coxiella burnetii</italic>
 [<xref rid="ref12" ref-type="bibr">12</xref>
, <xref rid="ref13" ref-type="bibr">13</xref>
].</p>

</sec>

<sec sec-type="results" id="sec2">

<title>Results</title>

<p><bold><italic>Patients' characteristics</italic>
</bold>
. In the literature review, 35 cases were identified for inclusion in the analysis of Whipple's endocarditis. Of these 35 patients, 31 (89%) were male, and the age range at the time of diagnosis was 36–66 years (mean, 49 years).</p>

<p><bold><italic>Clinical presentation</italic>
</bold>
. Clinical features of the 35 patients with Whipple's disease endocarditis are presented in <xref rid="tab1" ref-type="fig">table 1</xref>
 [<xref rid="ref1" ref-type="bibr">1</xref>
, <xref rid="ref8" ref-type="bibr">8</xref>
, <xref rid="ref9" ref-type="bibr">9</xref>
, <xref rid="ref15" ref-type="bibr">15</xref>
–<xref rid="ref41" ref-type="bibr">41</xref>
]. Signs were related either to the heart (heart failure in 7 patients) or to a general disease. Common symptoms (those that affected >60% of patients) were arthralgias, diarrhea, and weight loss; less common symptoms (those that affected 40%–60% of patients) included abnormal cutaneous pigmentation, lymphadenopathy, and hypotension. Fever was observed in only one-third of patients. Cardiac features are also summarized in <xref rid="tab1" ref-type="fig">table 1</xref>
; underlying heart disease was not usually found. Endocarditis lesions affected the aortic valve in 14 patients (40%), the mitral valve in 6 (17%), the tricuspid valve in 2 (6%), mitral and aortic valves in 5 (14%), mitral and tricuspid valves in 3 (9%), mitral as well as aortic and tricuspid valves in 4 (11%), and mitral as well as aortic, tricuspid, and pulmonary valves in 1 (3%). A single case of endocarditis involving a mitral bioprosthesis valve has been reported [<xref rid="ref30" ref-type="bibr">30</xref>
]. Endocarditis was associated with pericarditis in 16 cases (46%) and with myocarditis in 5 cases (14%).</p>

<p>Despite being reported by several authors, 23 cases of Whipple's disease endocarditis were excluded from our study; either clinical details about general manifestations were not specified or, as in large studies, such as the series of Vital-Durand et al. [<xref rid="ref10" ref-type="bibr">10</xref>
] and Enzinger and Helwig [<xref rid="ref42" ref-type="bibr">42</xref>
], the presence or absence of general symptoms in each patient was not indicated [<xref rid="ref10" ref-type="bibr">10</xref>
, <xref rid="ref42" ref-type="bibr">42</xref>
]. In a clinical review of 52 cases of Whipple's disease selected from the period of 1964–1994, 3 cases of endocarditis (6%) were reported [<xref rid="ref10" ref-type="bibr">10</xref>
]. Fibrosis, deformity, and positive macrophages on PAS staining of ⩾1 cardiac valve were noted in 10 (53%) of 19 cases selected from the files of the Armed Forces Institute of Pathology [<xref rid="ref43" ref-type="bibr">43</xref>
]. In a series of 15 autopsied patients, 6 (40%) had endocarditis [<xref rid="ref42" ref-type="bibr">42</xref>
]. By studying the systemic lesions of Whipple's disease, Farnan found 2 cases of endocarditis among 7 patients (29%) [<xref rid="ref44" ref-type="bibr">44</xref>
]. Finally, by means of molecular techniques, including broad-range PCR and direct sequencing, among 18 cases of endocarditis, 1 case of Whipple's disease endocarditis was diagnosed [<xref rid="ref45" ref-type="bibr">45</xref>
]. In addition to these confirmed cases, there are 2 reports that strongly suggest the occurrence of endocarditis in 3 patients with Whipple's disease. Two patients had multiple emboli, whereas a third had a modification of a known heart murmur for which a necropsy was not performed [<xref rid="ref46" ref-type="bibr">46</xref>
–<xref rid="ref48" ref-type="bibr">48</xref>
].</p>

<p><bold><italic>Biological findings</italic>
</bold>
. Laboratory results for the 35 patients are summarized in <xref rid="tab1" ref-type="fig">table 1</xref>
. Increased erythrocyte sedimentation or C-reactive protein concentration was found in 13 (77%) of 17 patients, and anemia was frequently observed. Leukocytosis was present in 6 (40%) of 15 patients, and hypereosinophilia was a surprising observation in 4 (40%) of 10 patients.</p>

<p><bold><italic>Supplementary investigation</italic>
</bold>
. Echocardiography was performed on 12 of 35 patients with Whipple's disease: transthoracic echocardiography for 1 patient, transesophageal echocardiography for 5 patients, both types for 3 patients, and unspecified for 3 patients. Endocarditis and vegetation were observed in 9 patients (75%).</p>

<p><bold><italic>Positive diagnosis</italic>
</bold>
. Valves were obtained either by necropsy (20 cases) or by surgery (15 cases). Diagnosis was confirmed by histologic examination in 34 cases, PCR in 8, and culture in 2. In the case that we described elsewhere [<xref rid="ref8" ref-type="bibr">8</xref>
], antibodies to the isolate were detected in the patient serum (IgM titer, >1:400). At histologic examination, 26 patients had foamy macrophages associated with deposits of fibrin or inflammatory cells and 1 patient had only foamy macrophages. Deposits of fibrin and platelets on the valves were present in 13 cases. The presence of polymorphonuclear neutrophils or lymphocytes was observed in 10 and 4 patients, respectively. For 9 cases, the various types of inflammatory cells were not defined, and general terms, such as “chronic endocarditis” and “chronic inflammatory infiltrate,” were used. The histologic findings in 1 case were not described, but vegetations were seen macroscopically.</p>

<p><bold><italic>Treatment and outcomes</italic>
</bold>
. In this study, 20 (57%) of 35 patients died; of these 20 patients, 7 were not treated and 10 underwent symptomatic treatment. Eighteen patients received antibiotic treatment (maximum duration of treatment, 27 months). Eleven patients were treated with cotrimoxazole, 3 received doxycycline, 1 received doxycycline plus ofloxacin, 1 received penicillin plus gentamicin, 1 received ciprofloxacin, and 1 received an unspecified drug. The duration and outcome of treatment and follow-up for the 17 patients whose prescribed treatment was known are summarized in <xref rid="tab2" ref-type="fig">table 2</xref>
. One of the patients who had previously been treated for Whipple's disease developed endocarditis in the porcine leaflets of a Carpentier-Edwards prosthetic mitral valve only 23 months after the original cardiac surgery, which was performed because of complications of childhood rheumatic fever [<xref rid="ref30" ref-type="bibr">30</xref>
]. Fifteen patients had surgical therapy with valvular replacement.</p>

</sec>

<sec sec-type="discussion" id="sec3">

<title>Discussion</title>

<p>Epidemiological data for patients with Whipple's disease endocarditis are similar to those for patients with generalized Whipple's disease; each disease is associated predominately with male patients and each occurs worldwide [<xref rid="ref10" ref-type="bibr">10</xref>
]. It is of interest that many of the recently described cases of Whipple's disease endocarditis have been reported from southern Germany, the eastern part of Switzerland, and France [<xref rid="ref37" ref-type="bibr">37</xref>
, <xref rid="ref38" ref-type="bibr">38</xref>
, <xref rid="ref41" ref-type="bibr">41</xref>
]. This fact leads one to ask whether the bacterium is particularly prevalent in this area or whether its prevalence is the result of medical interest in Whipple's disease endocarditis in this area. An oral infectious route is suspected, and the bacterium's phylogenetic neighbors are soil bacteria; it can be speculated that this is true of the Whipple's bacterium. Indeed, specific DNA has been detected in waste-water samples [<xref rid="ref49" ref-type="bibr">49</xref>
].</p>

<p>Two studies have revealed a positive result of PCR of gastric juice and duodenal biopsy specimens [<xref rid="ref50" ref-type="bibr">50</xref>
] as well as saliva specimens [<xref rid="ref51" ref-type="bibr">51</xref>
] obtained from healthy people. The Whipple's disease bacterium may therefore be present in a substantial fraction of the population in the absence of Whipple's disease. However, the PCR-based data from the aforementioned studies must be considered only preliminary.</p>

<p>Typically, Whipple's disease is characterized by a prodromal period of polyarthritis, weight loss, and anemia, followed by a syndrome of abdominal pain, diarrhea, and cachexia. On physical examination, lymphadenopathy and hyperpigmentation are frequent findings [<xref rid="ref10" ref-type="bibr">10</xref>
, <xref rid="ref52" ref-type="bibr">52</xref>
]. Chronicity is a cardinal feature of the spontaneous evolution of this disease [<xref rid="ref10" ref-type="bibr">10</xref>
, <xref rid="ref52" ref-type="bibr">52</xref>
]. CNS involvement, especially progressive dementia, ocular disturbances, and cerebellar symptoms, is common [<xref rid="ref10" ref-type="bibr">10</xref>
, <xref rid="ref52" ref-type="bibr">52</xref>
]. Ophthalmological manifestations, such as uveitis, are usually associated with CNS manifestations [<xref rid="ref10" ref-type="bibr">10</xref>
]. Another characteristic finding is a chronic cough [<xref rid="ref42" ref-type="bibr">42</xref>
]. Cardiovascular manifestations are also common in patients with Whipple's disease. Cardiac involvement has been noted in 20%–55% of patients [<xref rid="ref10" ref-type="bibr">10</xref>
], and certain autopsy studies have shown almost constant involvement of at least 1 of the 3 cardiac layers [<xref rid="ref43" ref-type="bibr">43</xref>
]. Constrictive pericarditis, endocarditis, myocarditis, coronary arteritis, congestive heart failure, and sudden death have been documented [<xref rid="ref53" ref-type="bibr">53</xref>
].</p>

<p>We compared patients who have Whipple's disease with a large series of patients with blood culture-positive endocarditis, excluding persons with a prosthesis and injection drug users, who would have presented a bias in the epidemiological data. We also compared those patients who have Whipple's disease endocarditis with patients infected with <italic>Bartonella</italic>
 and <italic>Coxiella burnetii</italic>
 that had caused blood culture-negative endocarditis [<xref rid="ref12" ref-type="bibr">12</xref>
<xref rid="ref13" ref-type="bibr">13</xref>
-<xref rid="ref14" ref-type="bibr">14</xref>
]. Male patients are more frequently affected by Whipple's disease endocarditis than are female patients. Whipple's disease endocarditis occurs in 88% of patients with native valves without underlying disease. This is remarkably different from the percentage associated with endocarditis due to other causes. Indeed, only 11% of patients with Q fever endocarditis, 46% of patients with blood culture-positive endocarditis, and 22% of patients with <italic>Bartonella henselae</italic>
 endocarditis had a native valve without previous disease [<xref rid="ref12" ref-type="bibr">12</xref>
<xref rid="ref13" ref-type="bibr">13</xref>
-<xref rid="ref14" ref-type="bibr">14</xref>
]. Although it has been found that 82% of patients who developed <italic>Bartonella quintana</italic>
 endocarditis had a native valve with no previous disease, the patients are usually homeless and alcoholic [<xref rid="ref12" ref-type="bibr">12</xref>
]. General symptoms of Whipple's disease are often present, but congestive heart failure and fever are observed less frequently in patients with Whipple's disease than they are in patients with other causes of endocarditis. In patients with Whipple's disease, it is more usual for >1 valve to be infected in the same patient. Eosinophilia was also observed in patients with Whipple's disease.</p>

<p>Whipple's disease results in a higher mortality rate, but this finding may be influenced by the fact that many diagnoses were determined after necropsy. In addition, patients with Whipple's disease endocarditis may be sicker than are patients with other forms of endocarditis, progressing to surgery or death and, consequently, to histologic diagnosis. Physicians frequently use the Duke criteria to diagnose endocarditis [<xref rid="ref54" ref-type="bibr">54</xref>
]. Excluding histologic examination, these comprise 2 major criteria (blood culture findings typical of infective endocarditis and vegetation findings on an echocardiograph) and 7 minor criteria (positive blood culture, fever, previous heart disease, arterial embolism, serological test results that are positive for endocarditis bacterial pathogens, immunologic disorders, and atypical but compatible findings on an echocardiograph) [<xref rid="ref54" ref-type="bibr">54</xref>
]. Patients with Whipple's disease endocarditis have no previous heart disease and are most often afebrile; their blood cultures are negative, and vegetation is observed on an echocardiograph in only 75% of cases. Thus, in many cases, the Duke criteria could not confirm the diagnosis of endocarditis. Several cases of Whipple's disease endocarditis without gastrointestinal involvement that occurred during a short period of time have been described recently [<xref rid="ref8" ref-type="bibr">8</xref>
, <xref rid="ref37" ref-type="bibr">37</xref>
, <xref rid="ref38" ref-type="bibr">38</xref>
, <xref rid="ref41" ref-type="bibr">41</xref>
].</p>

<p>These last observations strongly suggest that 2 entities of Whipple's disease endocarditis exist: one in which valve involvement is part of the generalized disease and another in which it is the only symptom, in the absence of systemic multiorgan infection. Before the pathologic examination, 1 patient fulfilled no criteria, 1 patient fulfilled a minor criterion, 2 patients fulfilled 1 major criterion, 2 patients fulfilled 2 criteria (1 major and 1 minor), and 1 patient fulfilled 3 criteria (1 major and 2 minor). This emphasizes the fact that the prevalence of the disease is probably underestimated and that physicians must actively search for this etiology.</p>

<p>Although a clinical profile may suggest a diagnosis of Whipple's disease, confirmation of the disease corresponds with the presence of characteristic histologic features on microscopic examination. In a typical case of the disease, the most severe changes are seen in the small intestine and mesenteric lymph nodes, where examination of a biopsy specimen often reveals foamy macrophages containing PAS-positive granulations. These PAS-positive cells can also be detected in practically all organs. However, PAS-positive cells are not pathognomonic of Whipple's disease and have been seen not only in healthy persons but also in those with infection due to <italic>Mycobacterium avium-Mycobacterium intracellulare</italic>
 [<xref rid="ref55" ref-type="bibr">55</xref>
–<xref rid="ref58" ref-type="bibr">58</xref>
].</p>

<p>Cardiac involvement in patients with Whipple's disease includes the pericardium, the myocardium, and the cardiac valves, usually the mitral and aortic valves. Cardiac valve pathological findings are described in detail in few reports [<xref rid="ref27" ref-type="bibr">27</xref>
, <xref rid="ref29" ref-type="bibr">29</xref>
, <xref rid="ref33" ref-type="bibr">33</xref>
, <xref rid="ref43" ref-type="bibr">43</xref>
]. Surgically removed valves have thickened cusps, are distorted and fibrotic, and have vegetation of variable sizes on the valvular surface. Calcific deposits may occur. Valvular tissue is very inflamed and vascularized. The pattern of inflammation is key to formulating a diagnosis and consists of a predominantly mononuclear cell infiltrate with numerous foamy macrophages (<xref rid="fig1" ref-type="fig">figure 1</xref>
). The microorganism in infected tissues can also be visualized using silver stains. With the successful isolation and cultivation of the Whipple's disease agent, polyclonal antibodies to the bacterium can be generated in mice and rabbits [<xref rid="ref8" ref-type="bibr">8</xref>
]. With use of these antibodies for immunohistology, the bacterium can be detected in tissues, as demonstrated in a case of Whipple's disease endocarditis (<xref rid="fig2" ref-type="fig">figure 2</xref>
) [<xref rid="ref8" ref-type="bibr">8</xref>
].</p>

<p>Diagnosis may not be possible by means of histological examination, especially with unusual manifestations of the disease, such as cardiac lesions, CNS manifestations, ocular abnormalities, pulmonary lesions, generalized adenopathy, and chronic fever [<xref rid="ref56" ref-type="bibr">56</xref>
]. In all such cases, the diagnosis can now be established on the basis of PCR of tissue (duodenal biopsy, lymph node, or cardiac valve specimen) or puncture fluid (CSF or pleural effusion) specimens [<xref rid="ref59" ref-type="bibr">59</xref>
, <xref rid="ref60" ref-type="bibr">60</xref>
]. Some reports suggest that PCR analysis of blood samples may sometimes yield a diagnosis [<xref rid="ref61" ref-type="bibr">61</xref>
], but this technique must be validated. Recently, the PCR methodology—in particular, all the sequences of PCR primers available for diagnosis of Whipple's disease—has been described elsewhere [<xref rid="ref62" ref-type="bibr">62</xref>
, <xref rid="ref63" ref-type="bibr">63</xref>
].</p>

<p>One significant limitation of PCR seems to be several problems involving specificity. First, PCR results have been positive for healthy people [<xref rid="ref50" ref-type="bibr">50</xref>
, <xref rid="ref51" ref-type="bibr">51</xref>
]. Second, if Whipple's disease bacterium is present in water, PCR contamination may easily occur. Third, amplified bands of presumably appropriate fragment length may be nonspecific. Therefore, a second step, direct sequencing or hybridization, is necessary after PCR to confirm the identity of the amplified products. Thus, interpretation of PCR results without histologic confirmation should be done cautiously. Serologic testing could be useful. With culture of Whipple's disease bacterium, antigens could be produced to perform a serological test that would allow easier diagnosis. Preliminary screening studies demonstrated that IgG antibodies to the bacillus were detected in most serum samples, including those obtained from control subjects, but that IgM antibodies were more specific [<xref rid="ref8" ref-type="bibr">8</xref>
]. Two patients with endocarditis had positive IgM antibody titers [<xref rid="ref8" ref-type="bibr">8</xref>
]. Large-scale studies are necessary to confirm these results. Culture may be attempted with a biopsy specimen using the human fibroblast cell lines HEL and MRC5, grown in minimum essential medium with 10% fetal calf serum and 2 m<italic>M</italic>
 L-glutamine [<xref rid="ref8" ref-type="bibr">8</xref>
, <xref rid="ref62" ref-type="bibr">62</xref>
, <xref rid="ref63" ref-type="bibr">63</xref>
]. The limitations of this technique are the length of bacterial growth required, the necessity of having qualified personnel, and the limited availability of appropriate laboratory facilities.</p>

<p>During the first half of the 19th century, Whipple's disease was usually fatal [<xref rid="ref64" ref-type="bibr">64</xref>
]. Because the disease is rare, there are no results of large-scale, controlled therapy studies available, and recommendations are therefore based on observations in single cases. Tests to determine resistance to antibiotics have not yet been possible, and almost all antibiotics have been used in the treatment of Whipple's disease. Tetracycline has been used for many years, but clinical resistance or relapses with diverse frequency (range, 8%–35%) have been reported [<xref rid="ref52" ref-type="bibr">52</xref>
, <xref rid="ref55" ref-type="bibr">55</xref>
, <xref rid="ref65" ref-type="bibr">65</xref>
]. Only these frequently occurring relapses and a greater awareness of the involvement of the CNS have led to a rethinking of antimicrobial strategy.</p>

<p>The currently recommended treatment for Whipple's disease is daily parenteral administration of streptomycin (1 g) and benzylpenicillin (penicillin G; 1.2 million units) during a period of 14 days, followed by oral cotrimoxazole (trimethoprim-sulfamethoxazole; 160 mg/800 mg b.i.d.) for 1 year (or 2 years if there is supplementary impairment of the immune system) [<xref rid="ref10" ref-type="bibr">10</xref>
, <xref rid="ref66" ref-type="bibr">66</xref>
]. The specific treatment of Whipple's disease endocarditis is still unclear, but the outcome of cases that have been diagnosed and treated since 1990 has been considerably better than that for cases reported before this date. Among the patients who received antibiotics, follow-up data were available for only 3. Two patients were observed for 3 years: one received penicillin plus gentamicin for 6 weeks, followed by cotrimoxazole for 2 years, and the other received cotrimoxazole for 1 year. The data from these 2 patients suggest that the drug used against systemic Whipple's disease can be used against endocarditis, even though 2 patients died a few days after the beginning of adequate therapy. For the third patient, the follow-up was of only 6 months' duration, and he received ampicillin plus streptomycin for 1 month, followed by ciprofloxacin for 27 months. There are no reliable parameters indicating when treatment should end, but the length of treatment must be at least 1 year.</p>

<p>With regard to surgical therapy, it should be emphasized that until now, valvular histology, culture, and PCR were the only methods available to establish the diagnosis of Whipple's endocarditis. Thus, it is difficult to speculate whether valvular surgery is always necessary to cure Whipple's endocarditis. One report suggests that a patient with Whipple's disease who requires a prosthetic cardiac valve has a high risk of developing specific endocarditis [<xref rid="ref30" ref-type="bibr">30</xref>
].</p>

<p>Whipple's bacterium should be added to the list of agents that cause blood culture-negative endocarditis, and Whipple's disease endocarditis can be considered as an entity. We believe that it is important to draw clinicians' attention to the significant number of patients with Whipple's disease who may have endocarditis that is not associated with the usual findings of the disease. They must be made aware that minor inflammatory reactions appear to be its hallmark. Presently, we can speculate that cases of Whipple's disease endocarditis are underestimated.</p>

</sec>

</body>

<back>

<ack>

<title>Acknowledgments</title>

<p>We acknowledge Emma and Richard Birtles for reviewing the manuscript.</p>

</ack>

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<sec sec-type="display-objects">

<title>Figures and Tables</title>

<fig position="anchor" id="fig1">

<label>Figure 1</label>

<caption><p>Section of an aortic valve with superficial vegetation. Inflammatory infiltrate is composed of numerous foamy macrophages with a clear distended cytoplasm (<italic>asterisks;</italic>
 stain, hematoxylin and eosin; original magnification, ×100).</p>
</caption>

<graphic mimetype="image" xlink:href="33-8-1309-fig001.tif"></graphic>

</fig>

<fig position="anchor" id="fig2">

<label>Figure 2</label>

<caption><p>Demonstration of <italic>Tropheryma whippelii</italic>
 by immunochemistry in valvular tissues. Bacilli are packed as coarse, granular immunopositive material in foamy macrophage cytoplasm (<italic>arrows;</italic>
 polyclonal mouse antibody to <italic>T. whippelii</italic>
 used, at dilution of 1:500; hemalum counterstain; original magnification, ×250).</p>
</caption>

<graphic mimetype="image" xlink:href="33-8-1309-fig002.tif"></graphic>

</fig>

<fig position="anchor" id="tab1">

<label>Table 1</label>

<caption><p><bold>Clinical, cardiac, and laboratory features of patients with Whipple's disease endocarditis and blood culture-positive endocarditis, <italic>Bartonella</italic>
 endocarditis, and Q fever endocarditis.</bold>
</p>
</caption>

<graphic mimetype="image" xlink:href="33-8-1309-tbl001.tif"></graphic>

</fig>

<fig position="anchor" id="tab2">

<label>Table 2</label>

<caption><p><bold>Treatment, outcome, and follow-up data for 17 patients with Whipple's endocarditis who received antibiotics.</bold>
</p>
</caption>

<graphic mimetype="image" xlink:href="33-8-1309-tbl002.tif"></graphic>

</fig>

</sec>

</back>

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<mods version="3.6"><titleInfo><title>Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive</title>
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<titleInfo type="alternative" contentType="CDATA"><title>Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive</title>
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<name type="personal" displayLabel="corresp"><namePart type="given">Florence</namePart>
<namePart type="family">Fenollar</namePart>
<affiliation>Unité des Rickettsies, Centre Nationale de Recherche Scientifique, Unité Mixte de Recherche 6020, France</affiliation>
<affiliation>E-mail: Didier.Raoult@medecine.univ-mrs.fr</affiliation>
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<name type="personal"><namePart type="given">Hubert</namePart>
<namePart type="family">Lepidi</namePart>
<affiliation>Unité des Rickettsies, Centre Nationale de Recherche Scientifique, Unité Mixte de Recherche 6020, France</affiliation>
<affiliation>Laboratoire d'histologie, Faculté de médecine, Université de la Méditerraneé, Marseille, France</affiliation>
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<name type="personal"><namePart type="given">Didier</namePart>
<namePart type="family">Raoult</namePart>
<affiliation>Unité des Rickettsies, Centre Nationale de Recherche Scientifique, Unité Mixte de Recherche 6020, France</affiliation>
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<abstract>Whipple's disease is a systemic infection sometimes associated with cardiac manifestations. Recently, there has been an increase in the number of reported cases of Whipple's endocarditis. The purpose of our study was to describe this entity. Data from 35 well-described cases of Whipple's endocarditis were collected and compared with those of blood culture-positive endocarditis, Q fever endocarditis, and Bartonella endocarditis. Some patients with generalized Whipple's disease presented with cardiac involvement, among other symptoms. Others presented with a nonspecific, blood culture-negative endocarditis with no associated symptoms. In comparison with cases of endocarditis due to other causes, congestive heart failure, fever, and previous valvular disease were less frequently observed in the cases of Whipple's endocarditis. Without examination of the excised valves, the diagnosis of infective endocarditis could not have been confirmed in most cases. Treatment is not well established. Whipple's endocarditis is a specific entity involving minor inflammatory reactions and negative blood cultures, and its incidence is probably underestimated.</abstract>
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   |texte=   Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive
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Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive

Whipple's Endocarditis: Review of the Literature and Comparisons with Q Fever, Bartonella Infection, and Blood Culture—Positive

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