**4. Diagnosis**

**% (No.)**

*Advanced Concepts in Endocarditis - 2021*

**Patients (No.)** 174

Medium Age (years) 57

Male gender 85% (148)

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

Immunosuppression 12% (21) Valvular abnormality 21.8% (38)

Aortic 63% (110) Mitral 20.7% (36) Tricuspid 3.4% (6) Multiple valves 22.9% (40)

Arthralgia 51.7% (90) Heart failure 43% (75) Weight loss 25.2% (44) Fever 21.3% (37) Central nervous system 16.1% (28) Gastrointestinal symptoms 20,7% (36)

Anemia 39,1% (68)

Valve surgery 73.5% (128) Death 17.8% (31)

*Main clinical epidemiological, clinical and outcome characteristics of patients with* T. whipplei *endocarditis* 

**Epidemiological data**

**Figure 1.**

**Medical history**

**Affected valve**

**Presenting symptoms**

**Laboratory abnormalities**

*reported in the literature. Updated from McGee et al. [118].*

**Outcome**

**74**

**Table 1.**

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 broadspectrum 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

**Figure 2.** *PAS staining positive in valvular tissue and vegetation.*

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**).

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].

### **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

**77**

endocarditis [134].

Tropheryma whipplei *Endocarditis*

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

of doxycycline and hydroxychloroquine [127, 128].

(range) has been 17 months (12 months to indefinite) [118].

trimethoprim/sulfamethoxazole have been published.

treatment might be sufficient [133].

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

According to the literature, treatments used in *T. whipplei* endocarditis include,

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

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*

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

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

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

*Advanced Concepts in Endocarditis - 2021*

*PAS staining positive in valvular tissue and vegetation.*

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**).

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

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

**76**

suspected [39, 103].

**5. Treatment**

**Figure 2.**

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].
