Diagnosis -- Whipple's Endocarditis (Tropheryma whipplei)


Whipple's Endocarditis (Tropheryma whipplei)


Infectious endocarditis is characterized by inflammation involving the inner lining of the heart and heart valves. Streptococci, staphylococci, and enterococci together account for 80-90% of cases. The HACEK organisms including Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella have also been implicated. Diagnosis is based on the Modified Duke Criteria which are summarized in Figure 2. Treatment typically consists of targeted antibiotic therapy for 4-6 weeks depending on the organism identified. Cases resulting in impaired cardiac function may require surgical intervention. Complications include valvular dysfunction, heart failure, embolization, ischemic stroke, intracranial hemorrhage, and renal failure [1].

Blood Culture-Negative Endocarditis (BCNE) is endocarditis in which the causative microbe cannot be cultured in the laboratory. Reasons for this include prior antibiotic treatment or the fastidious nature of some organisms which significantly limits the ability to grow them in an in vitro setting. Though classically associated with the HACEK organisms listed above, improved culture techniques have more recently allowed for the successful identification of many of these organisms [3]. Organisms more commonly implicated in BCNE today include Coxiella burnetii, Mycoplasma hominis, Trophyrema whipplei, Bartonella spp, as well as streptococci, staphylococci, and enterococci in the setting of prior antibiotic use [4]. Molecular methods, including 16S ribosomal RNA (rRNA) sequencing have become increasingly important for the identification of such organisms. Valvular biopsies are the ideal specimen for performing such polymerase chain reaction (PCR) studies, though blood samples have also been used with varying success [5]. The 16S rRNA gene is highly conserved amongst all bacteria. It measures roughly 1,550 base pairs in length and contains regions that are highly conserved as well as regions of high variability which can be used for phylogenetic identification. Often, broad-range primers complementary to conserved regions are used allowing for amplification of a segment of the gene across a wide-range of bacterial species. Once the segment has been amplified, it can be sequenced and compared to a library of known 16S rRNA gene sequences for proper identification. Alternatively, if one desires to test for the presence of a specific organism, primers can be designed based on unique regions of the 16S rRNA gene that allow for amplification of only the targeted segment when present [6].

Whipple's disease is the clinical manifestation of Tropheryma whipplei infection. Classic Whipple's disease involves the gut and presents with joint pain, weight loss, diarrhea, and abdominal pain. Chronic infection can lead to endocarditis. A German cohort study involving microbiological analysis of 1,135 surgically removed heart valve specimens identified T. whipplei as the fourth most commonly encountered bacteria after streptococci, staphylococci, and enterococci though clinical manifestations in these cases varied [8]. Histologic diagnosis is made by the presence of periodic acid-Schiff (PAS) staining organisms within duodenal macrophages. The organism has been successfully cultured in the laboratory, however it is not routine practice as it is extremely slow growing and requires the use of specialized media or a living cell host. Diagnosis usually depends on a combination of histologic and molecular studies as outlined in Figure 3. The recommended treatment includes a combination of doxycycline and hydroxychloroquine for 12 months in cases of classic infection. Treatment duration can be extended to 18 months for chronic localized disease. Follow-up monitoring for response to therapy can be accomplished by performing quantitative PCR on fecal samples or other involved tissues [9].


  1. Yallowitz, A. W., Decker, L. C. Infectious Endocarditis. [Updated 2021 May 1]. In: StatPearls [Internet]/ Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557641/
  2. Topan, A., Carstina, D., Slavcovici, A., Rancea, R., Capalneanu, R., & Lupse, M. (2015). Assessment of the Duke criteria for the diagnosis of infective endocarditis after twenty-years. An analysis of 241 cases. Clujul medical (1957), 88(3): 321-326. https://doi.org/10.15386/cjmed-469
  3. Chambers, S. T., Murdoch, D., Morris, A., Holland, D., Pappas, P., Almela, M., Fernandez-Hidalgo, N., Almmirante, B., Bouza, E., Forno, D., Rio, A., del, Hannan, M. M., Harkness, J., Kanafani, Z. A., Lalani, T., Lang, S., Raymond, N., Read, K., Vinogradova, T., Woods, C. W., Wray, D., Corey, G. R., Chu, V. H. (2013). HACEK infective ENDOCARDITIS: Characteristics and outcomes from a large, Multi-National Cohort. PLoS ONE, 8(5). https://doi.org/10.1371/journal.pone.0063181
  4. Fournier, P. E., Gouriet, F., Casalta, J. P., Lepidi, H., Chaudet, H., Thuny, F., Collart, F., Habib, G., Raoult, D. (2017). Blood culture-negative endocarditis: Improving the diagnostic yield using new diagnostic tools. Medicine, 96(47), e8392. https://doi.org/10.1097/MD.0000000000008392
  5. Fournier, P. E., Thuny, F., Richet, H., Lepidi, H., Casalta, J. P., Arzouni, J. P., Maurin, M., Celard, M., Mainardi, J. L., Caus, T., Collart, F., Habib, G., Raoult, D. (2010). Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis, 51(2): 131-140. doi: 10.1086/653675
  6. Clarridge III, J. E. (2004). Impact of 16S rRNA Gene Sequence Analysis for Identification of Bacteria on Clinical Microbiology and Infectious Diseases. Clin Microbiol Rev, 17(4): 840-862. doi: 10.1128/CMR.17.4.840-862.2004
  7. Fukuda, K., Ogawa, M., Taniguchi, H., Saito, M. (2016). Molecular Approaches to Studying Microbial Communities: Targeting the 16S Ribosomal RNA Gene. Journal of UOEH, 38(3): 223-232.
  8. Geissdorfer, W., Moos, V., Moter, A., Loddenkemper, C., Jansen, A., Tandler, R., Morguet, A. J., Fenollar, F., Raoult, D., Bogdan, C., Schneider, T. (2012). High frequency of Trophyrema whipplei in culture-negative endocarditis. Journal of Clinical Microbiology, 50(2), 216-222. https://doi.org/10.1128/JCM.05531-11
  9. Dolmans, R. A. V., Boel, C. H. E., Lacle, M. M., Kusters, J. G. (2017). Clinical Manifestations, Treatment, and Diagnosis of Trophyrema whipplei Infections. Clin Microbol Rev, 30(2): 529-555. doi: 10.1128/CMR.00033-16

Contributed by Robert Bubar, MD and Bryan Stevens, MD

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