Correspondence
Whipple's Disease
N Engl J Med 2007; 356:1479-1481April 5, 2007
- Article
To the Editor:
In their Medical Progress article on Whipple's disease, Fenollar and colleagues (Jan. 4 issue)1 raise important issues regarding culture-negative endocarditis. We report on a 38-year-old-man with a 6-month history of polyarthralgia. He had clubbing of the fingers as well as aortic and mitral regurgitant murmurs. Transesophageal echocardiography showed vegetations on both the mitral and aortic (bicuspid) valves. Multiple blood cultures and routine serologic tests were negative. A species-specific polymerase-chain-reaction (PCR) assay for Tropheryma whipplei and broad-range PCR for 16S ribosomal DNA2 on whole blood were negative.
After replacement of the aortic and mitral valves, tissue samples from both valves were found to be positive for T. whipplei on broad-range PCR assay2 (with sequence analysis) and species-specific PCR assay. Macrophages with positive inclusions on periodic acid–Schiff (PAS) staining were confirmed as the organisms seen on electron microscopy (Figure 1Figure 1
Electron Micrograph of Valvular Tissue Showing Rodlike Organisms with the Characteristic Trilamellar Cell Wall of Tropheryma whipplei.).The modified Duke criteria3 are often unreliable in detecting culture-negative endocarditis; our patient was clinically categorized as having possible endocarditis (one major and one minor sign). We suggest that other clinical signs (including clubbing4) and serologic5 and molecularly based tests should be included as part of the initial diagnostic workup for patients with suspected infective endocarditis and that valvular tissue removed during surgery should be investigated with the use of molecular techniques.
5 ReferencesOwen M. Williams, Ph.D.
Health Protection Agency South West Regional Laboratory, Bristol BS2 8HW, United Kingdom
martinx.williams@ubht. nhs. uk Angus K. Nightingale, M.D.
Bristol Heart Institute, Bristol BS2 8HW, United KingdomJohn Hartley, M.R.C.Path.
Great Ormond Street Hospital, London WC1N 3JH, United Kingdom1
Fenollar F ,Puechal X ,Raoult D . Whipple's disease. N Engl J Med 2007;356:55-66
Full Text | Web of Science | Medline2
Harris KA ,Hartley JC . Development of broad range 16s rDNA PCR for use in the routine diagnostic clinical microbiology service. J Med Microbiol 2003;52:685-691
CrossRef | Web of Science | Medline3
Li JS ,Sexton DJ ,Mick N , et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:633-638
CrossRef | Web of Science | Medline4
Lamas CC ,Eykyn SJ . Suggested modifications to the Duke criteria for the clinical diagnosis of native valve and prosthetic valve endocarditis: analysis of 118 pathologically proven cases. Clin Infect Dis 1997;25:713-719
CrossRef | Web of Science | Medline5
Raoult D ,Casalta JP ,Richet H , et al. Contribution of systematic serological testing in diagnosis of infective endocarditis. J Clin Microbiol 2005;43:5238-5242
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To the Editor:
Fenollar and colleagues propose treatment with doxycycline plus hydroxychloroquine for Whipple's disease without neurologic involvement. In our view, it is difficult to exclude the central nervous system as a sanctuary for T. whipplei. Neither histopathological examination nor PCR on cerebrospinal fluid is sufficiently sensitive for technical reasons (low number of cells in cerebrospinal fluid for PAS staining, and inhibition of the PCR reaction).1 Given a relapse rate of 32% after tetracycline treatment (as shown in Table 4 of the article) and the high mortality among patients with cerebral relapse, we suggest that it is prudent to use antibiotics with therapeutic cerebrospinal fluid concentrations (e.g., cotrimoxazole) as standard practice for all patients with Whipple's disease.2
T. whipplei resides in subgingival dental plaque in up to one third of the white population in Central Europe.3 This suggests that T. whipplei is common in the environment. Therefore, reinfection is a real concern for patients with treated Whipple's disease, considering that they may have an immune defect.4 We recommend lifelong follow-up of patients who have been treated for Whipple's disease and consideration of antibiotic prophylaxis.
Matthias Bramkamp, M.D.
Fabio Ruggieri, M.D.
Markus Schneemann, M.D.
University Hospital of Zurich, 8091 Zurich, SwitzerlandDr. Schneemann reports receiving lecture fees and travel grants from Merck Sharp & Dohme, Pfizer, and Bristol-Myers Squibb.
4 References1
Wilson IG . Inhibition and facilitation of nucleic acid amplification. Appl Environ Microbiol 1997;63:3741-3751
Web of Science | Medline2
Gerard A ,Sarrot-Reynauld F ,Liozon E , et al. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine (Baltimore) 2002;81:443-457
CrossRef | Web of Science | Medline3
Zinkernagel AS ,Gmur R ,Fenner L ,Schaffner A ,Schoedon G ,Schneemann M . Marginal and subgingival plaque -- a natural habitat of Tropheryma whipplei? Infection 2003;31:86-91
CrossRef | Web of Science | Medline4
Desnues B ,Ihrig M ,Raoult D ,Mege JL . Whipple's disease: a macrophage disease. Clin Vaccine Immunol 2006;13:170-178
CrossRef | Web of Science | Medline
Author/Editor Response
Williams and colleagues report a case of blood culture–negative endocarditis caused by T. whipplei. We agree that the Duke criteria perform poorly for patients with endocarditis associated with Whipple's disease, as previously reported.1 The Duke criteria are the absence of fever (major criterion), previous valve lesion (minor criterion), and available microbiologic tests — blood culture (major criterion) and serologic findings (minor criterion). Thus, additional criteria are welcome. Among them, arthralgias, as reported in their patient, are important. The prevalence of long-lasting arthralgias in the history is very high and should trigger a suspicion of Whipple's disease. Valve examination remains the key to the diagnosis, since duodenal biopsies and blood tests may be negative on PCR assay. Thus, PCR assay cannot be proposed as a reliable diagnostic test; a reliable blood test is urgently needed.
Bramkamp and colleagues suggest that cotrimoxazole should be added to the treatment of all patients with Whipple's disease and that such patients may benefit from long-term follow-up. We agree that patients should have lifelong follow-up to detect late relapses. However, with respect to cotrimoxazole, one should remember that only sulfamides are active against T. whipplei, whereas trimethoprim is not.2 We have documented treatment failures associated with specific mutations in the genome of T. whipplei (unpublished data), and relapses have been documented. Therefore, in our view, alternatives to cotrimoxazole would be useful, because the treatment conundrum remains unsolved. We suggest avoiding cotrimoxazole in the absence of neurologic symptoms plus a negative result of a PCR assay performed on cerebrospinal fluid. As we stated in our article, preliminary results with a regimen of doxycycline and hydroxychloroquine appear to be encouraging. One hopes that further studies will clarify the best strategies for curing this difficult disease.
2 ReferencesDidier Raoult, M.D., Ph.D.
Florence Fenollar, M.D., Ph.D.
Université de la Méditerranée, 13385 Marseille, France
didier.raoult@medecine. univ-mrs. fr Xavier Puéchal, M.D., Ph.D.
Le Mans General Hospital, 72037 Le Mans, France1
Raoult D . Afebrile blood culture-negative endocarditis. Ann Intern Med 1999;131:144-146
Web of Science | Medline2
Boulos A ,Rolain JM ,Mallet MN ,Raoult D . Molecular evaluation of antibiotic susceptibility of Tropheryma whipplei in axenic medium. J Antimicrob Chemother 2005;55:178-181
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
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
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