**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 [67–70]. The main reasons are the previous administration of antimicrobials and fastidiously culture microorganisms [67, 68, 71–75]. 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

**73**

Tropheryma whipplei *Endocarditis*

and the true incidence itself [39].

been reported in 21 cases (12%).

diagnosed, it cannot be excluded.

have been detected in 16% of patients.

affected in the vast majority of cases.

**3. Clinical features**

*DOI: http://dx.doi.org/10.5772/intechopen.95378*

[39, 64, 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

A total of 174 cases of *T. whipplei* endocarditis have been reported between 1999 and 2020 [21, 39, 65, 70, 78–117]. The vast majority of cases were men (>85% of the

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

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

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)

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

cases) and the average age was around 57 years (range: 33–81 years).

*Advanced Concepts in Endocarditis - 2021*

overall, endocarditis [39, 40].

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 [17–19]. 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 [20–29]. 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 [13, 14]. Therefore, *T. whipplei* can produce acute localized forms of infection such as pneumonia [30, 31], bacteremia [32], acute diarrhea [33, 34], uveitis [35, 36]; sub-acute forms such as adenitis [37] and chronic forms as uveitis [38], and,

*T. whipplei* has also been detected in asymptomatic carriers based, mainly, on stools and saliva analysis with very different prevalence among populations [41–52]. 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 [49–51, 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 [56–59]. 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, 56–59, 63, 64] make *T. whipplei* a common bacterium

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

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

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

**72**

in humans.

**2. Epidemiology**

of BCNE in some areas [65, 66].

new agents have been involved [69].

[39, 64, 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, 78–117]. The vast majority of cases were men (>85% of the cases) and the average age was around 57 years (range: 33–81 years).
