Open access peer-reviewed chapter

Tropheryma whipplei Endocarditis

Written By

Lara García-Álvarez and José Antonio Oteo

Submitted: 18 September 2020 Reviewed: 04 December 2020 Published: 04 January 2021

DOI: 10.5772/intechopen.95378

From the Edited Volume

Advanced Concepts in Endocarditis - 2021

Edited by Michael S. Firstenberg and Umashankar Lakshmanadoss

Chapter metrics overview

443 Chapter Downloads

View Full Metrics

Abstract

Tropheryma whipplei mainly known as the causative agent of classical Whipple’s disease, also produces acute, sub-acute and chronic localized forms of infection such as endocarditis. The development of molecular tools has allowed increasing the number of cases of endocarditis due to blood culture use to be negative in T. whipplei endocarditis and most of the cases are confirmed post-surgery when molecular analyses of heart valves are performed. Although, T. whipplei endocarditis is an uncommon condition with an atypical presentation it must be considered in the diagnosis of blood culture negative endocarditis and in patients with heart failure in which valve affectation is present. Other clinical features such as long lasting arthralgia can be present in a high percentage of the patients. It is important to know that few cases are diagnosed in the context of the classical Whipple’s disease. The prognosis is very good when an appropriate surgical management and antimicrobial-specific treatment is given. This chapter describes the epidemiological, clinical characteristics, diagnosis and treatments for T. whipplei endocarditis.

Keywords

  • Tropheryma whipplei
  • Tropheryma whipplei endocarditis
  • endocarditis
  • blood culture negative endocarditis
  • infectious endocarditis

1. Introduction

Tropheryma whipplei, formerly Tropheryma whipplei, is an intracellular gram-positive Actinobacteria ubiquitous in the environment that is involved in a large variety of clinical forms [1, 2]. The initial name was proposed by Relman et al. in 1992, and comes from the Greek trophe, nourishment, and eryma, barrier, due to the malabsorption it causes, and from the surname of George Hoyt Whipple [3]. In 2001, the name of the bacterium was slightly modified to conform to the proper spelling of Dr. George H. Whipple’s name [4].

Dr. Whipple was the first who reported, in 1907, a “hitherto undescribed disease” he named “intestinal lipodystrophy” in a 36-year-old man with malabsortion, weight loss, diarrhea, migratory polyarthritis, cough and mesenteric lymphadenopathy [5]. Now, we refer to this disease as Whipple’s disease. Although this disease was first described at the beginning of the last century, the hypothesis of its bacterial origin goes back to the late 40’s and was supported with use of periodic acid-Schiff (PAS) staining and the success of the first antibiotic treatment [6, 7]. Subsequently, the presence of the microorganism was confirmed by electron microscopy (rod-shaped organism), polymerase chain reaction (PCR) of the 16S rRNA and finally by culture [1, 3, 8, 9, 10, 11, 12]. The isolation and later sequencing of its genome made possible to define its antibiotic susceptibility [13, 14, 15, 16].

Until recently, T. whipplei was known to be only the causative agent of Whipple’s disease, now called by some authors “classical Whipple disease”, a rare chronic multisystemic infection [5]. Incidence of Whipple’s disease was reported in approximately 1 per 1.000.000, although it remains unclear and epidemiological estimates varies among different studies [17, 18, 19]. Classical form of Whipple’s disease usually involves the gastrointestinal tract, joints and central nervous system with malabsorption, diarrhea, abdominal pain and/or weight loss and arthralgia as prominent manifestations. Cardiac, ocular or other organs involvement has been also reported in patients with Whipple’s disease [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. The knowledge of the genome of T. whipplei has allowed developing specific and sensible tools that have let to involve this microorganism in a broad spectrum of clinical conditions [1314]. Therefore, T. whipplei can produce acute localized forms of infection such as pneumonia [30, 31], bacteremia [32], acute diarrhea [33, 34], uveitis [3536]; sub-acute forms such as adenitis [37] and chronic forms as uveitis [38], and, overall, endocarditis [39, 40].

T. whipplei has also been detected in asymptomatic carriers based, mainly, on stools and saliva analysis with very different prevalence among populations [41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52]. The carriage of T. whipplei varies considerably across studies and subjects. Many factors are involved in those differences such as the geographical region, exposure or the age of the studied subjects. The prevalence of asymptomatic carriers of T. whipplei in Africa and Asia is higher than in Europe and it is also higher in children than in adults [49, 50, 51, 53]. Actinobacteria are environmental microorganisms that can be found in freshwater, soil or seawater sediments, this fact could explain the high prevalence of T. whipplei in people expose to sewage and sewage plant workers [2, 41, 47, 54, 55]. People in contact with patients with Whipple’s disease, as patients’ relatives or carriers, or those with poor hygiene conditions such as homeless, also presents higher prevalences [56, 57, 58, 59]. Differences between the targets used for the PCR and the samples used have been also observed and could explain these reported differences [52, 60]. Li et al. assessed that genomic variants of T. whipplei are associated with neither the organotropism of the bacteria nor the geographical residence of the individuals [61], however later studies show that different genotypes are more frequent in some populations [34, 56, 58, 62]. Therefore, despite Whipple’s disease is rare, the high number of healthy carriers, the ubiquitous presence of the bacteria in the environment [41, 47, 57, 59] and the possibility of interhuman transmission [49, 56, 57, 58, 59, 63, 64] make T. whipplei a common bacterium in humans.

Advertisement

2. Epidemiology

First implication of T. whipplei as causative agent of infective endocarditis was reported in Switzerland in 1997, in a patient with blood culture negative endocarditis (BCNE) using a broad-range PCR followed by sequencing [64]. Curiously, first stable cultivation of the bacterium of Whipple’s disease was carried out in 2000, from the mitral valve of a patient with BCNE [1]. Since then, the number of cases has increased and to date T. whipplei endocarditis is one of the more frequent causes of BCNE in some areas [65, 66].

BCNE is a relative frequent condition among endocarditis representing 5–30% in big series [67, 68, 69, 70]. The main reasons are the previous administration of antimicrobials and fastidiously culture microorganisms [67, 68, 71, 72, 73, 74, 75]. The application of molecular tools has allowed doing new approximations to the etiology of BCNE and new agents have been involved [69].

Sporadic cases of T. whipplei endocarditis have been reported from different countries, but there are few published series of T. whipplei endocarditis. France, Spain, Germany and Switzerland have the largest number of diagnosed cases [3964, 65, 70]. This fact could be due to their larger experience in the knowledge and use of the molecular tools to heart valves [40]. The incidence of T. whipplei endocarditis among BCNE varies depending on the series. The incidence rate estimated varies between 2.6% and 7.1% depending on the country (France: 2.6% [76], Spain and Denmark: 3.5% [70, 77], Switzerland: 4.3% [78], Germany: 6.3% [65], Czech Republic: 7.1% [79]). However, it is difficult to know the true incidence of T. whipplei endocarditis since its study by molecular tools is not the rule in all hospitals. Thus, several parameters seem to affect the incidence of T. whipplei endocarditis such as the diagnostic tools available, the working group experience and the true incidence itself [39].

A total of 174 cases of T. whipplei endocarditis have been reported between 1999 and 2020 [21, 39, 65, 70, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117]. The vast majority of cases were men (>85% of the cases) and the average age was around 57 years (range: 33–81 years).

Advertisement

3. Clinical features

Comorbidities or other predisposing risk factors have been not uniformly reported in the literature [118]. Previous valvular affectation has been documented in 21% of the diagnosed cases, while prosthetic valve replacement previously to the event seems not an important condition (<5% of the available series). Alcohol abuse has been reported in very few cases, however alcohol intake (>60 g/d) was referred by the 23.5% of the patients in the Spanish series [70]. Previous cardiac condition or a cardiac event (i.e., coronary heart disease) has been observed in 50% of cases [66]. Data of historical immunosuppression forms (autoimmune disease or immunosuppressive therapies such as steroids or tumor necrosis factor inhibitors) have been reported in 21 cases (12%).

Classical Whipple’s disease has been reported as concomitant with the diagnose of endocarditis in few cases (6%) [66, 70]. However, in lot of cases this data is not available and in some of them although, classical Whipple’s Disease has not been diagnosed, it cannot be excluded.

The signs and symptoms T. whipplei endocarditis are not the typical ones. Fever has been only reported in 21% of the cases. Cardiac failure and arthralgia have been shown as the main presenting symptoms and have been described in 43% and 52% of patients, respectively. Cardiac failure is of special interest because it is the first manifestation in a high percentage of patients. Long lasting arthralgias presence as a prominent symptom varies depending on the series. While in the French series arthralgias were present in 75% of patients [39], in the Spanish one this condition was present in 53% [70]. These variations could be due to this symptom is sometimes weak and only detected after an exhaustive clinical research. Some authors suggest that, in those patients with sub-acute endocarditis and low-grade fever or not fever, if arthralgias are present, T. whipplei as causative agent should be suspected [39, 103]. Asthenia and malaise lasting more than six months were notified by the 41.2% of the patients in one series [70]. Other signs such as weight loss or gastrointestinal symptoms have been observed in 25% and 21% of the reported patients [118]. In addition, central nervous system manifestations (i.e., emboli) have been detected in 16% of patients.

The valve involved in patients with T. whipplei endocarditis has been predominantly the aortic (63%). Involvement of multiple valves (mainly aortic valve in combination with the mitral or tricuspid valve, and mitral-tricuspid affection) has been noticed in 23% of patients. Only mitral valve affectation has been observed in 20% of patients and tricuspid valve just in six of 174 patients (3%). Native valve was affected in the vast majority of cases.

Echocardiography features are one of the most valuable tools for suspecting infectious endocarditis. According to the literature, when these data were recorded, presence of vegetations was observed in more than the half of patients [66]. In our series, echocardiography was performed in all patients (both transthoracic and transesophageal in more than 80%) and allowed the diagnosis of infectious endocarditis in 70% of patients through the visualization of vegetations in the vast majority, or by indirect signs in a few [70]. Valve vegetation from a patient after cardiac valve surgery is shown in Figure 1. In the French series, echocardiography showed vegetations in 78% of the patients, but these data are not recorded in the German one [3965]. Data of vegetation appearance or size is rarely reported. Data of size vegetations when available, shown a minimum size of 5 mm and a maximum of 33 mm [118].

Figure 1.

Valve vegetation specimen obtained after surgery from a patient with T whipplei endocarditis.

The main laboratory recording abnormalities at the time of the diagnosis have been anemia, which was detected in 40% of patients but this date can reach 88.2% in some series, and increasing of C-reactive protein in range from 2.3 to 137 mg/L [70]. In patients who had heart failure, B-type natriuretic peptide (BNPs) of up to 2536 ng/L has been also reported [118].

Main characteristics of patients are shown in Table 1.

% (No.)
Patients (No.)174
Epidemiological data
Medium Age (years)57
Male gender85% (148)
Medical history
Immunosuppression12% (21)
Valvular abnormality21.8% (38)
Affected valve
Aortic63% (110)
Mitral20.7% (36)
Tricuspid3.4% (6)
Multiple valves22.9% (40)
Presenting symptoms
Arthralgia51.7% (90)
Heart failure43% (75)
Weight loss25.2% (44)
Fever21.3% (37)
Central nervous system16.1% (28)
Gastrointestinal symptoms20,7% (36)
Laboratory abnormalities
Anemia39,1% (68)
Outcome
Valve surgery73.5% (128)
Death17.8% (31)

Table 1.

Main clinical epidemiological, clinical and outcome characteristics of patients with T. whipplei endocarditis reported in the literature. Updated from McGee et al. [118].

Advertisement

4. Diagnosis

The suspicion and diagnosis of T. whipplei endocarditis is complicated. To date, 174 cases have been reported but, due to the difficulties for the identification of T. whipplei, the prevalence of the endocarditis it causes could be underestimated [119].

Diagnosis of T. whipplei endocarditis remains a challenge for several reasons. One of them is because this endocarditis does not exhibit the typical sings (no fever nor peripheral stigmata and low inflammatory response) and blood cultures used to be negative; therefore, modified Duke’s criteria are ineffective for diagnosis before heart valve analysis [39]. In this sense, some series have shown that only 3.6% patients met criteria for endocarditis according to the modified Duke criteria and 60.7% met for possible endocarditis [39]. It is very difficult to perform a microbiological or histological diagnose without analyzing the surgical remove valve. Routine blood and tissue culture are not often useful for the diagnosis. Thus, the diagnosis is often made post-surgery and valve analysis requires specialized laboratories, moreover if culture of the bacteria is intended to carry out.

Different targets have been used for molecular analyses. PCR based on the 16S rRNA amplification and subsequent sequencing has been widely used and has been the first-line screening in our series. However, some authors alert that this broad-spectrum PCR could have a limited sensitivity (value sensitivity 60%, specificity 100%) [120], while specific qPCR for T. whipplei have showed higher sensitivities [48, 60]. So, if 16S rRNA PCR has been negative, specific targets should be used in highly suspected cases of T. whipplei. At least 2 of the PCRs must be positive and their sequences have to show higher identity with the bacterium studied. PCR yield in other specimen different from valves varies depending on the specimen type and should be interpreted with caution according to the clinical context [66, 118]. A positive PCR result from a non-sterile site such as stool or saliva samples has been used to diagnose classical Whipple’s disease and to detect asymptomatic carriers, but is nor sensible nor specific for the diagnosis of T. whipplei endocarditis without clinical evidence of disease [42, 121, 122].

The role of serological tests in the diagnosis of Whipple’s disease is unclear because healthy carrier patients may paradoxically have a higher immune response to T. whipplei compared with patients with active Whipple’s disease [123]. Specific tools for an indirect diagnose for T. whipplei endocarditis are not available. This fact does not occur in other BCNE such as Q fever endocarditis or Bartonella spp. endocarditis. Curiously, a patient with Q fever and T. whipplei concomitant endocarditis has been described [124]. Valvular inflammatory infiltrates of T. whipplei–infected heart valves mainly consisted of foamy macrophages and lymphocytes. These macrophages have been observed in valvular tissue and in the vegetations on the surface of the heart valves. The dense and granular material that foamy histiocytes are filled with is strongly positive on PAS staining or immunopositive with a specific antibody against T. whipplei [39]. Thus, PAS staining and specific immunohistochemistry test (IHC) using specific antibodies against T. whipplei of cardiac valves could be useful for the diagnosis of T. whipplei endocarditis (Figure 2).

Figure 2.

PAS staining positive in valvular tissue and vegetation.

According to the literature, 156 patients have been diagnosed of definite T. whipplei endocarditis by direct examination of the valve, of which more than 70% had positive PCR, almost 40% reported PAS staining positive on valve tissue and around 50% showed positive IHC. Seven patients were diagnosed of possible endocarditis regarding to vegetations on valve imaging and classical Whipple’s disease concomitant diagnosis. In these last cases, 85% had positive PCR on different specimen such as duodenal sample, stool, saliva or central nervous system samples and more than 50% had positive PAS staining in other tissue specimen [118].

In summary, definitive T. whipplei endocarditis could considered if positive results of PAS staining and/or specific IHC test using specific antibodies against T. whipplei and/or 2 positive results of PCR assays targeting 2 different sequences in a cardiac valve specimen are met [60]. It is important to notice that in patients with subacute endocarditis with negative blood cultures and low-grade fever (or not fever), if arthralgias are present, T. whipplei as causative agent should be suspected [39, 103].

Advertisement

5. Treatment

The optimal treatment of IE caused by T. whipplei remains uncertain. Treatment options and duration are based on previous experience and expert opinion owing to the microorganism’s nature, the lack of large series (because of the low incidence) in which follow-up is documented and because clinical trials have not been developed [74]. Recommendations are mainly based on the experience obtained from the treatment of classical Whipple’s disease and other types of BCNE such as Q fever endocarditis [125, 126]. Two weeks treatment with ceftriaxone, followed by 1 year of trimethoprim/sulfamethoxazole, has been the most recommended treatment for years [126]. However, in vitro studies have shown best results with the combination of doxycycline and hydroxychloroquine [127, 128].

According to the literature, treatments used in T. whipplei endocarditis include, in most cases, two weeks of parenteral high dose of ceftriaxone (others such as meropenem, penicillin G have been also used) followed by an oral treatment strategy of 12 months with sulfamethoxazole (160/800 mg BID) or, at least, 18 months of doxycycline (100 mg BID) plus hydroxychloroquine (600 mg/d), in a smaller proportion [125, 129, 130]. Available data indicate that the average treatment length (range) has been 17 months (12 months to indefinite) [118].

Last European guidelines published in 2015, recommend doxycycline (200 mg/24 h) plus hydroxychloroquine (200–600 mg/24 h) orally for at least 18 months (in the case of central nervous system involvement, sulfadiazine 1.5 g/6 h orally must be added to doxycycline). As alternative therapy, 2–4 weeks of ceftriaxone (2 g/24 h intravenously) or 2–4 weeks of penicillin G (2 million U/4 h) and streptomycin (1 g/24 h) intravenously can be used, followed by, at least, 1 year of oral trimethoprim/sulfamethoxazole (800 mg/12 h) [74]. It is likely that this recommendation was included after taking into consideration an in vitro T. whipplei resistant to trimethoprim, a case report of a patient with clinically acquired resistance to trimethoprim/sulfamethoxazole and the cases of T. whipplei endocarditis relapses after treatment with trimethoprim/sulfamethoxazole which were apparently cured after two years of doxycycline and hidroxychloroquine [109, 114, 131, 132]. Furthermore, some authors do not recommend the use of trimethoprim/sulfamethoxazole because the clinical, microbiological and genetic data analyses show that it is an antibiotic not efficient for the management of T. whipplei endocarditis [109]. In fact, three T. whipplei endocarditis relapses after treatment with trimethoprim/sulfamethoxazole have been published.

After the end of treatment, some authors recommend checking for the presence of T. whipplei in blood, saliva, and fecal samples every six months for two years and every year for the entire life of the patient [39]. If colonization is detected, they recommend treating again, but there is not still evidence for this procedure.

Follow-up data and long-term outcome of the treatments used in this condition have not been widely reported. These data are well documented in the Spanish series. Although in this series only the 35% of the patients received treatment according to guidelines, all the treatment lines used in this cohort in the management of T. whipplei endocarditis were effective and well tolerated and therapeutic failures or relapses were not detected either during the treatment or after it was finished [133]. Furthermore, no major complications were detected once the treatment was established or during the follow-up. Even though, follow-up of all patients continues in order to identify possible late relapses. It has been demonstrated that doxycycline plus hydroxychloroquine treatment of duration shorter than 18 months was not associated with either relapses or fatal outcomes. Moreover, data suggest that, with a very careful post-treatment monitoring, in patients who require the replacement of the infected valve and without classical manifestation of Whipple’s disease, replacement of the affected valve and a shorter duration antimicrobial treatment might be sufficient [133].

Since T. whipplei is not present in the stool or saliva of patients with endocarditis caused by this microorganism and in the absence of other biological markers indicating the discontinuation of the antimicrobials, other tools are needed. In this regard, the role of PCR of urine should be explored both as a tool for monitoring patients post-treatment and the non-invasive diagnosis of T. whipplei endocarditis [134].

Advertisement

6. Conclusions

In the last years and with the development of molecular tools, new cases of T. whipplei endocarditis have been diagnosed. For this reason, although T. whipplei infective endocarditis is an infrequent condition has emerged as an important differential diagnosis for BCNE. Endocarditis due to T. whipplei is often slowly progressive, similar to that caused by Coxiella burnetii and Bartonella spp. and it could be diagnosed with specific procedures when BCNE undergo cardiac surgery. An early and appropriate diagnosis is required since this condition has a very good course and prognosis when the appropriate treatment is started (including surgery). In our opinion, patients with unexplained valve destruction which requires cardiac surgery, an exhaustive clinical investigation must be performed and removed valves should be studied by molecular tools for to rule out an underlying infectious endocarditis.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H, et al. Cultivation of the bacillus of Whipple’s disease. N Engl J Med. 2000;342:620-625.DOI: 10.1056/NEJM200003023420903.
  2. 2. Dutly F, Altwegg M. Whipple’s disease and “Tropheryma whippelii”. Clinical Microbiology Reviews. 2001;14:561-583. DOI: 10.1128/CMR.14.3.561-583.2001
  3. 3. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple’s disease. The New England Journal of Medicine. 1992;327:293-301. DOI: 10.1056/NEJM199207303270501
  4. 4. La Scola B, Fenollar F, Fournier PE, Altwegg M, Mallet MN, Raoult D. Description of Tropheryma whipplei gen. Nov., sp. nov., the Whipple’s disease bacillus. International Journal of Systematic and Evolutionary Microbiology. 2001;51:1471-1479. DOI: 10.1099/00207713-51-4-1471
  5. 5. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bulletin of the Johns Hopkins Hospital. 1907;18:382-393
  6. 6. Black-Schaffer B. The tinctoral demonstration of a glycoprotein in Whipple’s disease. Proc Soc Exp Biol. 1949;72:225-227. DOI: 10.3181/00379727-72-17388
  7. 7. Paulley JW. A case of Whipple’s disease (intestinal lipodystrophy). Gastroenterology. 1952;22:128-133
  8. 8. WJr C, Ashworth CT. Electron microscopy study of the intestinal mucosa in Whipple’s disease-demonstration of encapsulated bacilliform bodies in the lesion. Gastroenterology. 1961;41:129-138
  9. 9. Yardley JH, Hendrix TR. Combined electron and light microscopy in Whipple’s disease. Bulletin of the Johns Hopkins Hospital. 1961;109:80-98
  10. 10. Wilson KH, Blitchington R, Frothingham R, Wilson JA. Phylogeny of the Whipple’s-disease-associated bacterium. Lancet. 1991;338:474-475. DOI: 10.1016/0140-6736(91)90545-z
  11. 11. Cohen AS, Schimmel EM, Holt PR, Isselbacher KJ. Ultrastructural abnormalities in Whipple’s disease. Proceedings of the Society for Experimental Biology and Medicine. 1960;105:411-414. DOI: 10.3181/00379727-105-26126
  12. 12. Schoedon G, Goldenberger D, Forrer R, Gunz A, Dutly F, Höchli M, et al. Deactivation of macrophages with interleukin-4 is the key to the isolation of Tropheryma whippelii. The Journal of Infectious Diseases. 1997;176:672-677. DOI: 10.1086/514089
  13. 13. Raoult D, Ogata H, Audic S, Robert C, Suhre K, Drancourt M. Tropheryma whipplei twist: A human pathogenic actinobacteria with a reduced genome. Genome Research. 2003;13:1800-1809. DOI: 10.1101/gr.1474603
  14. 14. Bentley SD, Maiwald M, Murphy LD, Pallen MJ, Yeats CA, Dover LG, et al. Sequencing and analysis of the genome of the Whipple’s disease bacterium Tropheryma whipplei. Lancet. 2003;361:637-644. DOI: 10.1016/S0140-6736(03)12597-4
  15. 15. Boulos A, Rolain JM, Raoult D. Antibiotic susceptibility of Tropheryma whipplei in MRC5 cells. Antimicrobial Agents and Chemotherapy. 2004;48:747-752. DOI: 10.1128/aac.48.3.747-752.2004
  16. 16. Boulos A, Rolain JM, Mallet MN, Raoult D. Molecular evaluation of antibiotic susceptibility of Tropheryma whipplei in axenic medium. The Journal of Antimicrobial Chemotherapy. 2005;55:178-181. DOI: 10.1093/jac/dkh524
  17. 17. Sieracki JC. Whipple’s disease: Observations on systemic involvement. Cytologic observations. Amer Med Asso Arch Pathol. 1958;66:464-467
  18. 18. von Herbay A, Otto HF, Stolte M, Borchard F, Kirchner T, Ditton HJ, et al. Epidemiology of Whipple’s disease in Germany. Analysis of 110 patients diagnosed in 1965-95. Scandinavian Journal of Gastroenterology. 1997;32:52-57. DOI: 10.3109/00365529709025063
  19. 19. Biagi F, Balduzzi D, Delvino P, Schiepatti A, Klersy C, Corazza GR. Prevalence of Whipple’s disease in North-Western Italy. European Journal of Clinical Microbiology & Infectious Diseases. 2015;34:1347-1348. DOI: 10.1007/s10096-015-2357-2
  20. 20. Durand DV, Lecomte C, Cathebras P, Rousset H, Godeau P. Whipple disease: Clinical review of 52 cases. The SNFMI research group on Whipple disease. Société Nationale Française de Médecine interne. Medicine (Baltimore). 1997;76:170-184. DOI: 10.1097/00005792-199705000-00003.
  21. 21. Fenollar F, Lepidi H, Raoult D. Whipple’s endocarditis: Review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis. Clinical Infectious Diseases. 2001;33:1309-1316. DOI: 10.1086/322666
  22. 22. Enzinger FM, Helwig EB. Whipple’s disease: A review of the literature and report fifteen patients. Virchows Archiv für Pathologische Anatomie und Physiologie und für Klinische Medizin. 1963;336:238-269
  23. 23. Maizel H, Ruffin JM, Dobbins WO 3rd. Whipple’s disease: A review of 19 patients from one hospital and a review of the literature since 1950. Medicine (Baltimore). 1993;72:343-355
  24. 24. McAllister HAJ, Fenoglio JJJ. Cardiac involvement in Whipple’s disease. Circulation. 1975;52:152-156. DOI: 10.1161/01.cir.52.1.152
  25. 25. Hausser-Hauw C, Roullet E, Robert R, Marteau R. Oculo-facioskeletalmyorhythmia as a cerebral complication of systemic Whipple’s disease. Movement Disorders. 1988;3:179-184. DOI: 10.1002/mds.870030211
  26. 26. Adler CH, Galetta SL. Oculo-facial-skeletal myorhythmia in Whipple disease: Treatment with ceftriaxone. Annals of Internal Medicine. 1990;112:467-469. DOI: 10.7326/0003-4819-76-3-112-6-467
  27. 27. Simpson DA, Wishnow R, Gargulinski RB, Pawlak AM. Oculofacial-skeletal myorhythmia in central nervous system Whipple’s disease: Additional case and review of the literature. Movement Disorders. 1995;10:195-200. DOI: 10.1002/mds.870100210
  28. 28. Rickman LS, Freeman WR, Green WR, Feldman ST,Sullivan J,Russack V, et al. Brief report: uveitis caused by Tropheryma whippeli (Whipple’s bacillus). N Engl J Med. 1995;332:363-366. DOI: 10.1056/NEJM199502093320604.
  29. 29. Helliwella TR, Appleton RE, Mapstone NC, Davidson J, Walsh KP. Dermatomyositis and Whipple’s disease. Neuromuscular Disorders. 2000;10:46-51. DOI: 10.1016/s0960-8966(99)00054-1
  30. 30. Stein A, Doutchi M, Fenollar F, Raoult D. Tropheryma whipplei pneumonia in a patient with HIV-2 infection. American Journal of Respiratory and Critical Care Medicine. 2013;188:1036-1037. DOI: 10.1164/rccm.201304-0692LE
  31. 31. Bousbia S, Papazian L, Auffray JP, Fenollar F, Martin C, Li W, et al. Tropheryma whipplei in patients with pneumonia. Emerging Infectious Diseases. 2010;16:258-263. DOI: 10.3201/eid1602.090610
  32. 32. Fenollar F, Mediannikov O, Socolovschi C, Bassene H, Diatta G, Richet H, et al. Tropheryma whipplei bacteremia during fever in rural West Africa. Clinical Infectious Diseases. 2010;51:515-521. DOI: 10.1086/655677
  33. 33. Gautret P, Benkouiten S, Parola P, Brouqui P, Memish Z, Raoult D. Occurrence of Tropheryma whipplei during diarrhea in hajj pilgrims: A PCR analysis of paired rectal swabs. Travel Medicine and Infectious Disease. 2014;12:481-484. DOI: 10.1016/j.tmaid.2014.04.003
  34. 34. Raoult D, Fenollar F, Rolain JM, Minodier P, Bosdure E, Li W, et al. Tropheryma whipplei in children with gastroenteritis. Emerging Infectious Diseases. 2010;16:776-782. DOI: 10.3201/eid1605.091801
  35. 35. Nishimura JK. Cook BE Jr, Pach JM (1998). Whipple disease presenting as posterior uveítis without prominent gastrointestinal symptoms. American Journal of Ophthalmology. 1998;126:130-132. DOI: 10.1016/s0002-9394(98)00084-1
  36. 36. Drancourt M, Fenollar F, Denis D, Raoult D. Postoperative panophthalmitis caused by Whipple disease. Emerging Infectious Diseases. 2009;15:825-827. DOI: 10.3201/eid1505.081209
  37. 37. Al-Hamoudi W, Habbab F, Nudo C, Nahal A, Flegel K. Eosinophilic vasculitis: A rare presentation of Whipple’s disease. Canadian Journal of Gastroenterology. 2007;21:189-191. DOI: 10.1155/2007/326174
  38. 38. Thaler S, Grisanti S, Klingel K, Raible A, Kempf VA, Schulte B. Intermediate uveitis and arthralgia as early symptoms in Whipple’s disease. International Journal of Infectious Diseases. 2010;14:388-389. DOI: 10.1016/j.ijid.2009.11.038
  39. 39. Fenollar F, Célard M, Lagier JC, Lepidi H, Fournier PE, Raoult D. Tropheryma whipplei endocarditis. Emerging Infectious Diseases. 2013;19:1721-1730. DOI: 10.3201/eid1911.121356
  40. 40. Moos V, Schneider T. Changing paradigms in Whipple’s disease and infection with Tropheryma whipplei. Eur J Clin Microbiol Infect. 2011;30:1151-1158. DOI: 10.1007/s10096-011-1209-y
  41. 41. Maiwald M, Schuhmacher F, Ditton HJ, von Herbay A. Environmental occurrence of the Whipple’s disease bacterium (Tropheryma whipplei). Applied and Environmental Microbiology. 1998;64:760-762. DOI: 10.1128/AEM.64.2.760-762.1998.
  42. 42. Street S, Donoghue HD, Neild GH. Tropheryma whippelii DNA in saliva of healthy people. Lancet. 1999;354:1178-1179. DOI: 10.1016/s0140-6736(99)03065-2
  43. 43. Ehrbar HU, Bauerfeind P, Dutly F, Koelz HR, Altwegg M. PCR-positive tests for Tropheryma whippelii in patients without Whipple’s disease. Lancet. 1999;353:2214. DOI: 10.1016/S0140-6736(99)01776-6
  44. 44. Dutly F, Hinrikson HP, Seidel T, Morgenegg S, Altwegg M, Bauerfeind P. Tropheryma whippelii DNA in saliva of patients without Whipple’s disease. Infection. 2000;28:219-222. DOI: 10.1007/s150100070039
  45. 45. Maibach RC, Dutly F, Altwegg M. Detection of Tropheryma whipplei DNA in feces by PCR using a target capture method. Journal of Clinical Microbiology. 2002;40:2466-2471. DOI: 10.1128/jcm.40.7.2466-2471.2002
  46. 46. Amsler L, Bauernfeind P, Nigg C, Maibach RC, Steffen R, Altwegg M. Prevalence of Tropheryma whipplei DNA in patients with various gastrointestinal disease and in healthy controls. Infection. 2003;31:81-85. DOI: 10.1007/s15010-002-3083-0
  47. 47. Schoniger-Hekele M, Petermann D, Weber B, Muller C. Tropheryma whipplei in the environment—Survey of sewage plant influxes and sewage plant workers. Applied and Environmental Microbiology. 2007;73:2033-2035. DOI: 10.1128/AEM.02335-06
  48. 48. Fenollar F, Trani M, Davoust B, Salle B, Birg ML, Rolain JM, et al. Prevalence of asymptomatic Tropheryma whipplei carriage among humans and nonhuman primates. The Journal of Infectious Diseases. 2008;197:880-887. DOI: 10.1086/528693
  49. 49. Fenollar F, Trape JF, Bassene H, Sokhna C, Raoult D. Tropheryma whipplei in fecal samples from children, Senegal. Emerging Infectious Diseases. 2009;15:922-924. DOI: 10.3201/eid1506.090182
  50. 50. Keita AK, Bassene H, Tall A, Sokhna C, Ratmanov P, Trape JF, et al. Tropheryma whipplei: A common bacterium in rural Senegal. PLoS Neglected Tropical Diseases. 2011;5:e1403. DOI: 10.1371/journal.pntd.0001403
  51. 51. Ramharter M, Harrison N, Bühler T, Herold B, Lagler H, Lötsch F, et al. Prevalence and risk factor assessment of Tropheryma whipplei in a rural Community in Gabon: A community based cross-sectional study. Clinical Microbiology and Infection. 2014;20:1189-1194. DOI: 10.1111/1469-0691.12724
  52. 52. García-Álvarez L, Pérez-Matute P, Blanco JR, Ibarra V, Oteo JA. High prevalence of asymptomatic carriers of Tropheryma whipplei in different populations from the north of Spain. Enfermedades Infecciosas y Microbiología Clínica. 2016;34:340-345. DOI: 10.1016/j.eimc.2015.09.006
  53. 53. Keita AK, Dubot-Peres A, Phommasone K, Sibounheuang B, Vongsouvath M, Mayxay M, et al. High prevalence of Tropheryma whipplei in Lao kindergarten children. PLoS Neglected Tropical Diseases. 2015;9:e0003538. DOI: 10.1371/journal.pntd.0003538
  54. 54. Marth T, Raoult D. Whipple’s disease. Lancet. 2003;361:239-246. DOI: 10.1016/S0140-6736(03)12274-X
  55. 55. Marth T, Moos V, Müller C, Biagi F, Schneider T. Tropheryma whipplei infection and Whipple’s disease. The Lancet Infectious Diseases. 2016;16:e13-e22. DOI: 10.1016/S1473-3099(15)00537-X
  56. 56. Fenollar F, Keita AK, Buffet S, Raoult D. Intrafamilial circulation of Tropheryma whipplei, France. Emerging Infectious Diseases. 2012;18:949-955. DOI: 10.3201/eid1806.111038
  57. 57. Keita AK, Raoult D, Fenollar F. Tropheryma whipplei as a commensal bacterium. Future Microbiology. 2013;8:57-71. DOI: 10.2217/fmb.12.124
  58. 58. Keita AK, Brouqui P, Badiaga S, Benkouiten S, Ratmanov P, Raoult D, et al. Tropheryma whipplei prevalence strongly suggests human transmission in homeless shelters. International Journal of Infectious Diseases. 2013;17:e67-e68. DOI: 10.1016/j.ijid.2012.05.1033
  59. 59. Keita AK, Mediannikov O, Ratmanov P, Diatta G, Bassene H, Roucher C, et al. Looking for Tropheryma whipplei source and reservoir in rural Senegal. Am J Trop Med Hyg. 2013;88:339-343. DOI: 10.4269/ajtmh.2012.12-0614.
  60. 60. Fenollar F, Laouira S, Lepidi H, Rolain JM, Raoult D. 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. 2008;47:659-667. DOI: 10.1086/590559
  61. 61. Li W, Fenollar F, Rolain JM, Fournier PE, Feurle GE, Müller C, et al. Genotyping reveals a wide heterogeneity of Tropheryma whipplei. Microbiology. 2008;154:521-527. DOI: 10.1099/mic.0.2007/011668-0
  62. 62. Wetzstein N, Fenollar F, Buffet S, Moos V, Schneider T, Raoult D. Tropheryma whipplei genotypes 1 and 3, in Central Europe. Emerging Infectious Diseases. 2013;19:341-342. DOI: 10.3201/eid1902.120709
  63. 63. Fenollar F, Lagier JC, Raoult D. Tropheryma whipplei and Whipple’s disease. The Journal of Infection. 2014;69:103-112. DOI: 10.1016/j.jinf.2014.05.008
  64. 64. Goldenberger D, Künzli A, Vogt P, Zbinden R, Altwegg M. Molecular diagnosis of bacterial endocarditis by broad-range PCR amplification and direct sequencing. Journal of Clinical Microbiology. 1997;35:2733-2739. DOI: 10.1128/JCM.35.11.2733-2739.1997
  65. 65. Geissdörfer W, Moos V, Moter A, Loddenkemper C, Jansen A, Tandler R, et al. High frequency of Tropheryma whipplei in culture-negative endocarditis. Journal of Clinical Microbiology. 2012;50:216-222. DOI: 10.1128/JCM.05531-11
  66. 66. García-Álvarez L, Sanz M, Oteo JA. Tropheryma Whipplei endocarditis. An epidemiological, clinical and treatment review. Aperito J infect dis. Vaccine. 2015;1:103
  67. 67. Murdoch DR, Corey GR, Hoen B, Miró JM, Fowler VG Jr, Bayer AS, et al. Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: The international collaboration on endocarditis-prospective cohort study. Archives of Internal Medicine. 2009;169:463-473. DOI: 10.1001/archinternmed.2008.603.
  68. 68. Tattevin P, Watt G, Revest M, Arvieux C, Fournier PE. Update on blood culture-negative endocarditis. Médecine et Maladies Infectieuses. 2014;45:1-8. DOI: 10.1016/j.medmal.2014.11.003
  69. 69. Muñoz P, Kestler M, De Alarcon A, Miro JM, Bermejo J, Rodríguez-Abella H, et al. Current epidemiology and outcome of infective endocarditis: A multicenter, prospective. Cohort study. Med (Baltimore). 2015;94:e1816. DOI: 10.1097/MD.0000000000001816
  70. 70. García-Álvarez L, Sanz MM, Marín M, Fariñas M, Montejo M, Goikoetxea J, et al. Tropheryma whipplei endocarditis in Spain: Case reports of 17 prospective cases. Medicine (Baltimore). 2016;95(26):e4058. DOI: 10.1097/MD.0000000000004058
  71. 71. Cecchi E, Forno D, Imazio M, Migliardi A, Gnavi R, Dal Conte I, et al. New trends in the epidemiological and clinical features of infective endocarditis: Results of a multicenter prospective study. Italian Heart Journal. 2004;5:249-256
  72. 72. López-Dupla M, Hernández S, Olona M, Mercé J, Lorenzo A, Tapiol J, et al. Clinical characteristics and outcome of infective endocarditis in individuals of the general population managed at a teaching hospital without cardiac surgery facilities. Study of 120 cases. Rev Esp Cardiol. 2006;59:1131-1139
  73. 73. Baddour LM, Wilson WR, Bayer AS, Fowler VG Jr, Tleyjeh IM, Rybak MJ, et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications: A scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132:1435-1486. DOI: 10.1161/CIR.0000000000000296
  74. 74. Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, et al. 2015 ESC guidelines for the management of infective endocarditis: The task force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European association of NuclearMedicine (EANM). European Heart Journal. 2015;36:3075-3128. DOI: 10.1093/eurheartj/ehv319
  75. 75. Díez-Villanueva P, Muñoz P, Marín M, Bermejo J, de Alarcón González A, Fariñas MC, et al. Infective endocarditis: Absence of microbiological diagnosis is an independent predictor of inhospitalmortality. International Journal of Cardiology. 2016;220:162-165. DOI: 10.1016/j.ijcard.2016.06.129
  76. 76. Fournier PE, Thuny F, Richet H, Lepidi H, Casalta JP, Arzouni JP, et al. Comprehensive diagnostic strategy for blood culture–negative endocarditis: A prospective study of 819 new cases. Clinical Infectious Diseases. 2010;51:131-140. DOI: 10.1086/653675
  77. 77. Voldstedlund M, Norum PL, Baandrup U, Klaaborg KE, Fuursted K. Broad-range PCR and sequencing in routine diagnosis of infective endocarditis. APMIS. 2008;116:190-198. DOI: 10.1111/j.1600-0463.2008.00942.x
  78. 78. Bosshard PP, Kronenberg A, Zbinden R, Ruef C, Bottger EC, Altwegg M. Etiologic diagnosis of infective endocarditis by broadrange polymerase chain reaction: A 3-year experience. Clinical Infectious Diseases. 2003;37:167-172. DOI: 10.1086/375592
  79. 79. Grijalva M, Horvath R, Dendis M, Erny J, Benedik J. Molecular diagnosis of culture negative infective endocarditis: Clinical validation in a group of surgically treated patients. Heart. 2003;89:263-268. DOI: 10.1136/heart.89.3.263.
  80. 80. Pron B, Poyart C, Abachin E, Fest T, Belanger C, Bonnet C, et al. Diagnosis and follow-up of Whipple’s disease by amplification of the 16S rRNA gene of Tropheryma whippelii. European Journal of Clinical Microbiology & Infectious Diseases. 1999;18:62-65. DOI: 10.1007/s100960050228
  81. 81. Wolfert AL, Wright JE. Whipple’s disease presenting as sarcoidosis and valvular heart disease. Southern Medical Journal. 1999;92:820-825. DOI: 10.1097/00007611-199908000-00017
  82. 82. Smith MA. Whipple endocarditis without gastrointestinal disease. Annals of Internal Medicine. 2000;132:595. DOI: 10.7326/0003-4819-132-7-200004040-00025
  83. 83. Ferrari Mde L, Vilela EG, Faria LC, Couto CA, Salgado CJ, Leite VR, et al. Whipple’s disease. Report of five cases with different clinical features. Revista do Instituto de Medicina Tropical de São Paulo. 2001;43:45-50. DOI: 10.1590/s0036-46652001000100009
  84. 84. Charniot JC, Mouthon L, Martin A, Barthelemy B, Podeva JD, Artigou JY, et al. Valvular locations in Whipple’s disease: Report of two cases and review of the literature. Archives des Maladies du Coeur et des Vaisseaux. 2001;94:1117-1121
  85. 85. Geissdörfer W, Wittmann I, Seitz G, Cesnjevar R, Röllinghoff M, Schoerner C, et al. A case of aortic valve disease associated with Tropheryma whippelii infection in the absence of other signs of Whipple’s disease. Infection. 2001;29:44-47. DOI: 10.1007/s15010-001-0135-9.
  86. 86. Geissdörfer W, Wittmann I, Röllinghoff M, Schoerner C, Bogdan C. Detection of a new 16S-23S rRNA spacer sequence variant (type 7) of Tropheryma whippelii in a patient with prosthetic aortic valve endocarditis. European Journal of Clinical Microbiology & Infectious Diseases. 2001;20:762-763. DOI: 10.1007/s100960100588
  87. 87. Richardson DC, Burrows LL, Korithoski B, Salit IE, Butany J, David TE, et al. Tropheryma whippelii as a cause of afebrile culture-negative endocarditis: The evolving spectrum of Whipple’s disease. The Journal of Infection. 2003;47:170-173. DOI: 10.1016/s0163-4453(03)00015-x
  88. 88. Dreier J, Szabados F, von Herbay A, Kröger T, Kleesiek K. Tropheryma whipplei infection of an acellular porcine heart valve bioprosthesis in a patient who did not have intestinal Whipple’s disease. Journal of Clinical Microbiology. 2004;42:4487-4493. DOI: 10.1128/JCM.42.10.4487-4493.2004
  89. 89. Marrakchi C, Abdennadher M, Blin D. Endocarditis caused by Tropheryma whippelii. La Tunisie Médicale. 2004;82:781-784
  90. 90. Lepidi H, Fenollar F, Dumler JS, Gauduchon V, Chalabreysse L, Bammert A, et al. Cardiac valves in patients with Whipple endocarditis: Microbiological, molecular, quantitative histologic, and immunohistochemical studies of 5 patients. The Journal of Infectious Diseases. 2004;190:935-945. DOI: 10.1086/422845
  91. 91. Aïouaz H, Célard M, Puget M, Vandenesch F, Mercusot A, Fenollar F, et al. Whipple’s disease endocarditis: Report of 5 cases and review of the literature. La Revue de Médecine Interne. 2005;26:784-790. DOI: 10.1016/j.revmed.2005.07.012
  92. 92. Saba M, Rollot F, Park S, et al. Whipple disease. initially diagnosed as sarcoidosis. Presse Med. 2005;34:1521-1524
  93. 93. Marín M, Muñoz P, Sánchez M, et al. Grupo de Apoyo al Manejo de la endocarditis Infecciosa del Hospital Gregorio Marañón, Madrid, Spain. Tropheryma whipplei infective endocarditis as the only manifestation of Whipple’s disease. Journal of Clinical Microbiology. 2007;45:2078-2081
  94. 94. West D, Hutcheon S, Kain R, Reid T, Walton S, Buchan K. Whipple’s endocarditis. Journal of the Royal Society of Medicine. 2005;98:362-364. DOI: 10.1258/jrsm.98.8.362
  95. 95. Williams OM, Nightingale AK, Hartley J. Whipple’s disease. N Engl J Med 2007;356:1479-1480;author reply 1480-1. DOI: 10.1056/NEJMc070234.
  96. 96. Kolek M, Zaloudíková B, Freiberger T, Brát R. Aortic and mitral valve infective endocarditis caused by Tropheryma whipplei and with no gastrointestinal manifestations of Whipple’s disease. Klinická Mikrobiologie a Infekc̆ní Lékar̆ství. 2007;13:213-216
  97. 97. Le Scanff J, Gaultier JB, Durand DV, Durieu I, Celard M, Benito Y, et al. Tropheryma whipplei and Whipple disease: False positive PCR detections of Tropheryma whipplei in diagnostic samples are rare. La Revue de Médecine Interne. 2008;29:861-867. DOI: 10.1016/j.revmed.2008.02.020
  98. 98. Voldstedlund M, Pedersen LN, Baandrup U, Fuursted K. Whipple’s disease–a cause of culture-negative endocarditis. Ugeskrift for Laeger. 2004;166:3731-3732
  99. 99. Besnard S, Cady A, Flecher E, Fily F, Revest M, Arvieux C, et al. Should we systematically perform central nervous system imaging in patients with Whipple’s endocarditis? The American Journal of Medicine. 2010;123:962.e1-962.e4. DOI: 10.1016/j.amjmed.2010.04.030
  100. 100. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic Tropheryma whipplei: Clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine (Baltimore). 2010;89:337-345. DOI: 10.1097/MD.0b013e3181f204a8
  101. 101. Ansemant T, Celard M, Tavernier C, Maillefert JF, Delahaye F, Ornetti P. Whipple’s disease endocarditis following anti-TNF therapy for atypical rheumatoid arthritis. Joint, Bone, Spine. 2010;77:622-623. DOI: 10.1016/j.jbspin.2010.07.003
  102. 102. Escher R, Roth S, Droz S, Egli K, Altwegg M, Täuber MG. Endocarditis due to Tropheryma whipplei: Rapid detection, limited genetic diversity, and long-term clinical outcome in a local experience. Clinical Microbiology and Infection. 2010;16:1213-1222. DOI: 10.1111/j.1469-0691.2009.03038.x
  103. 103. Whistance RN, Elfarouki GW, Vohra HA. Livesey SA. A case of Tropheryma whipplei infective endocarditis of the aortic and mitral valves in association with psoriatic arthritis and lumbar discitis. The Journal of Heart Valve Disease. 2011;20:353-356
  104. 104. Chan V, Wang B, Veinot JP, Suh KN, Rose G, Desjardins M, et al. Tropheryma whipplei aortic valve endocarditis without systemic Whipple’s disease. International Journal of Infectious Diseases. 2011;15:e804-e806. DOI: 10.1016/j.ijid.2011.05.020
  105. 105. Agard C, Brisseau JM, Grossi O, Pattier S, Espitia-Thibault A, Le Goff B, et al. Two cases of atypical Whipple’s disease associated with cytoplasmic ANCA of undefined specificity. Scandinavian Journal of Rheumatology. 2012;41:246-248. DOI: 10.3109/03009742.2011.648656
  106. 106. Algin A, Wegdam-Blans M, Verduin K, Janssen H, van Dantzig JM. Tropheryma whipplei aortic valve endocarditis, cured without surgical treatment. BMC Research Notes. 2012;5:600. DOI: 10.1186/1756-0500-5-600
  107. 107. Love SM, Morrison L, Appleby C, Modi P. Tropheryma whipplei endocarditis without gastrointestinal involvement. Interactive Cardiovascular and Thoracic Surgery. 2012;15:161-163. DOI: 10.1093/icvts/ivs116
  108. 108. Weisman A, Rebick G, Morris A, Butany J, Liles WC. Whipple’s endocarditis: An enigmatic cause of culture-negative bacterial endocarditis. Can J Infect Dis Med Microbiol. 2013;24:e29-e30. DOI: 10.1155/2013/138746
  109. 109. Fenollar F, Lagier JC, Rolain JM, Célard M, Bouchot O, Eicher JC, et al. Tropheryma whipplei endocarditis relapses after treatment with trimethoprim/sulfamethoxazole. International Journal of Antimicrobial Agents. 2013;41:592-594. DOI: 10.1016/j.ijantimicag.2013.02.003
  110. 110. Herrmann MD, Neumayr A, Essig A, Spiess J, Merk J, Möller P, et al. Isolated Whipple’s endocarditis: An underestimated diagnosis that requires molecular analysis of surgical material. The Annals of Thoracic Surgery. 2014;98:e1-e3. DOI: 10.1016/j.athoracsur.2014.04.059
  111. 111. Loughran D, Beale L, Lodge F, et al. Whipple’s in the valleys: A case of Whipple’s with thrombocytopenia and endocarditis. Journal of Clinical Pathology. 2014;67:445-448
  112. 112. Borne RT, Babu A, Levi M, et al. Tropheryma whipplei endocarditis: A two-patient case series. The American Journal of Medicine. 2015;128:1364-1366
  113. 113. Alozie A, Zimpfer A, Köller K, Westphal B, Obliers A, Erbersdobler A, et al. Arthralgia and blood culture-negative endocarditis in middle age men suggest Tropheryma whipplei infection: Report of two cases and review of the literature. BMC Infectious Diseases. 2015;15:339. DOI: 10.1186/s12879-015-1078-6
  114. 114. Emonet S, Wuillemin T, Harbarth S, Wassilew N, Cikirikcioglu M, Schrenzel J, et al. Relapse of Tropheryma whipplei endocarditis treated by trimethoprim/sulfamethoxazole, cured by hydroxychloroquine plus doxycycline. International Journal of Infectious Diseases. 2015;30:17-19. DOI: 10.1016/j.ijid.2014.11.003
  115. 115. Jos SL, Angelakis E, Caus T, Raoult D. Positron emission tomography in the diagnosis of Whipple’s endocarditis: A case report. BMC Research Notes. 2015;8:56. DOI: 10.1186/s13104-015-1022-2
  116. 116. Damaraju D, Steiner T, Wade J, Gin K, FitzGerald JM. Clinical problem-solving. A surprising cause of chronic cough. The New England Journal of Medicine. 2015;373:561-566. DOI: 10.1056/NEJMcps1303787
  117. 117. Gruber JR, Sarro R, Delaloye J, Surmely JF, Siniscalchi G, Tozzi P, et al. Tropheryma whipplei bivalvular endocarditis and polyarthralgia: A case report. Journal of Medical Case Reports. 2015;9:259. DOI: 10.1186/s13256-015-0746-x
  118. 118. McGee M, Brienesse S, Chong B, Levendel A, Lai K. Tropheryma whipplei Endocarditis: Case Presentation and Review of the Literature. Open Forum Infect Dis 2018;6:ofy330. DOI: 10.1093/ofid/ofy330
  119. 119. Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference center: Etiologic diagnosis of 348 cases. Medicine (Baltimore). 2005;84:162-173. DOI: 10.1097/01.md.0000165658.82869.17
  120. 120. Greub G, Lepidi H, Rovery C, Casalta JP, Habib G, Collard F, et al. Diagnosis of infectious endocarditis in patients undergoing valve surgery. Am J Med. 2005;118:230-238. DOIi: 10.1016/j.amjmed.2004.12.014.
  121. 121. Grasman ME, Pettersson AM, Catsburg A, Koek AG, van Bodegraven AA, Savelkoul PHM. Tropheryma whipplei, a potential commensal detected in individuals undergoing routine colonoscopy. Journal of Clinical Microbiology. 2015;53:3919-3921. DOI: 10.1128/JCM.02630-15
  122. 122. Rolain JM, Fenollar F, Raoult D. False positive PCR detection of Tropheryma whipplei in the saliva of healthy people. BMC Microbiology. 2007;7:48. DOI: 10.1186/1471-2180-7-48
  123. 123. Fenollar F, Amphoux B, Raoult D. A paradoxical Tropheryma whipplei Western blot differentiates patients with whipple disease from asymptomatic carriers. Clinical Infectious Diseases. 2009;49:717-723. DOI: 10.1086/604717
  124. 124. Santibáñez P, Portillo A, Santibáñez S, García-Álvarez L, de Toro M, Oteo JA. Qué aporta la secuenciación masiva del gen ARNr 16S al estudio de endocarditis infecciosa en tejido valvular? In: Programme of the VIII Congreso de la Sociedad Española de Infecciones cardiovasculares (SEICAV); 16-17 November 2018; Seville, Spain. 2018. p. 30
  125. 125. Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D. Whipple’s disease: New aspects of pathogenesis and treatment. The Lancet Infectious Diseases. 2008;8:179-190. DOI: 10.1016/S1473-3099(08)70042-2
  126. 126. Feurle GE, Moos V, Bläker H, Loddenkemper C, Moter A, Stroux A, et al. Intravenous ceftriaxone, followed by 12 or three months of oral treatment with trimethoprim-sulfamethoxazole in Whipple’s disease. The Journal of Infection. 2013;66:263-270. DOI: 10.1016/j.jinf.2012.12.004
  127. 127. Fenollar F, Puéchal X, Raoult D. Whipple’s disease. The New England Journal of Medicine. 2007;356:55-66. DOI: 10.1056/NEJMra062477
  128. 128. Lagier JC, Fenollar F, Lepidi H, Raoult D. Failure and relapse after treatment with trimethoprim/sulfamethoxazole in classic Whipple’s disease. The Journal of Antimicrobial Chemotherapy. 2010;65:2005-2012. DOI: 10.1093/jac/dkq263
  129. 129. Raoult D, Ogata H, Audic S, Robert C, Suhre K, Drancourt M, et al. Tropheryma whipplei twist: A human pathogenic actinobacteria with a reduced genome. Genome Research. 2003;13:1800-1809. DOI: 10.1101/gr.1474603
  130. 130. Feurle GE, Junga NS, Marth T. Efficacy of ceftriaxone or meropenem as initial therapies in Whipple’s disease. Gastroenterology. 2010;138:478-486. DOI: 10.1053/j.gastro.2009.10.041
  131. 131. Fenollar F, Perreal C, Raoult D. Tropheryma whipplei natural resistance to trimethoprim and sulphonamides in vitro. International Journal of Antimicrobial Agents. 2014;43:388-390
  132. 132. Fenollar F, Rolain JM, Alric L, Papo T, Chauveheid MP, van de Beek D, et al. Resistance to trimethoprim/ sulfamethoxazole and Tropheryma whipplei. International Journal of Antimicrobial Agents. 2009;34:255-259. DOI: 10.1016/j.ijantimicag.2009.02.014
  133. 133. García-Álvarez L, Sanz MM, Marín M, Fariñas MC, Montejo M, Goikoetxea J, et al. Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience. The Journal of Antimicrobial Chemotherapy. 2019;74:1713-1717. DOI: 10.1093/jac/dkz059
  134. 134. Lagier JC, Raoult D. Whipple’s disease and Tropheryma whipplei infections: When to suspect them and how to diagnose and treat them. Current Opinion in Infectious Diseases. 2018;31:463-470. DOI: 10.1097/QCO.0000000000000489

Written By

Lara García-Álvarez and José Antonio Oteo

Submitted: 18 September 2020 Reviewed: 04 December 2020 Published: 04 January 2021