Enterococcus faecalis is the third leading cause of infective endocarditis (IE) worldwide. It is becoming increasingly relevant due to epidemiological changes among patients at risk.1,2E. faecalis is one of the most relevant microorganisms of gut commensal flora involved in human disease. It is located in the colon wall, where it is involved in various processes, including translocation leading to systemic infection.3 However, the most commonly reported portal of entry in the literature on E. faecalis infective endocarditis (EFIE) is the genitourinary tract, followed by unknown origin.4 Some preliminary data indicate that E. faecalis might be involved in the mutagenesis of colonic cells5 and that the presence of lesions affecting the intestinal mucosa may lead to higher rates of translocation of E. faecalis into the bloodstream. However, whereas the relationship between IE caused by Streptococcus bovis group and colon malignancies has been widely studied,6–8 the relationship between EFIE and colorectal neoplasms (CRNs) has not been thoroughly explored to date.

Colonoscopy is the gold standard for CRN screening.9 In a study performed in asymptomatic patients with undiagnosed CRN undergoing colonoscopy for colorectal carcinoma (CRC) screening in Spain, the disease was detected in 27 of 5059 patients undergoing colonoscopy (0.5%) and in 30 patients (4.5%) with positive fecal immunochemical testing and colonoscopy findings (n = 663); advanced colorectal adenomas (CRAs) were found in 493 (9.7%) and 252 (38%) patients and nonadvanced CRA in 1116 (22.1%) and 112 (16.9%) patients, respectively.10 The global prevalence of CRA and CRC differs significantly between men and women (about 30% vs 20% for CRA and 1.4% vs 0.6% for CRC).11,12 More than 70% of EFIE patients are men, with a median age of around 70 years.1,2 The prevalence of CRC among patients within the age range of standard EFIE patients (70-80 years) undergoing screening colonoscopy is 0.8%-3.2%.11

Our aim was to assess the prevalence of CRN, and specifically that of CRC, in patients with EFIE undergoing colonoscopy due to an unclear origin of infection and to compare it with that of patients with an identified portal of entry. We compared this prevalence with that of the Spanish general population to determine whether colorectal examination to rule out neoplasm is necessary in these patients.

We evaluated 170 patients to determine their eligibility for the study and excluded 16 (Figure): 8 had a previous episode of IE caused by S. bovis and were considered to be at higher risk for CRN at baseline, 5 had non-E. faecalis species enterococcal IE, and 3 lacked clinical data. The study population comprised 154 patients with EFIE: 109 had an unclear source of infection and 45 had an identified portal of entry (genitourinary tract, 34; catheter, 4; surgical wound, 4; biliary tract, 3).

Figure.

Patient disposition flowchart. CRD, colorectal disease; CRN, colorectal neoplasm; EFIE, Enterococcus faecalis infective endocarditis; IE, infective endocarditis.

(0.23MB).

The demographic data of the 154 cases of EFIE included in the analysis are shown in Table 1. The general characteristics correspond to that of a typical EFIE profile: elderly individuals with multiple comorbidities (median age-adjusted Charlson score ≥ 5 in both groups), with a predominance of native and aortic endocarditis. Of note, patients with an unknown origin were more frequently male and had acquired their disease in the community. Patients with a known source had higher rates of cancer and hemodialysis. As for clinical characteristics, treatment details, and outcomes (Table 2), patients with an identified portal of entry had significantly longer symptom duration prior to diagnosis; however, no other significant differences were found between the 2 cohorts.

Data on CRN diagnosis in the study cohort are shown in Table 3. Sixty-one patients with an unclear source of infection (56%; 44 men [72.1%] and 17 women [27.9%]; median age, 71 years [interquartile range, 46-68 years]) and 6 patients in those with an identified source underwent colonoscopy during the work-up (13.6%; 5 men [83.3%] and 1 woman [16.7%]; median age, 64.5 years [interquartile range, 63-79 years]). One patient diagnosed with CRC underwent colonoscopy more than 3 months after discharge (at 4 months) due to prolonged recovery in a rehabilitation center. Colorectal diseases were diagnosed in 48 of the 61 patients who underwent colonoscopy (78.7%, 95% confidence interval [95%CI], 68.20%-89.17%) in the group with an unknown source of infection. Colorectal neoplasm was identified in 31 patients who underwent colonoscopy in the group without a clear focus of infection (50.8%, 95%CI, 38.02%-63.62%) and in 1 of the 6 patients (16.7%, 95%CI, 0.00%-4.89%) with a known portal of entry. One male patient with an unknown source of infection and normal colonoscopy findings during the initial admission was diagnosed with CRC 4 months after discharge, giving a total of 5 cases of CRC in 109 patients with EFIE and an unknown source of infection (prevalence of 4.6%) and in 61 patients with colonoscopy results from the first admission (prevalence of 8.2%). The ages of the 5 patients with a diagnosis of CRC were 62, 68, 74, 77, and 81 years. Four of the 5 patients died within 2 years of receiving the CRC diagnosis (median survival time was 94 days), whereas 1 was still alive at the end of 2015 (2730 days of follow-up). Additionally, 12 patients in the unknown source group who did not undergo colonoscopy and 5 in the group with an identified source underwent a barium enema. One patient in the first group was diagnosed with CRA in a colonoscopy subsequent to the admission when the barium enema was carried out, whereas none in the second group were diagnosed with CRN.

Overall, 32 cases of CRN were diagnosed in the whole cohort during the time between admission and the 3-month follow-up; the overall prevalence of CRN was 20.8% (95%CI, 14.24%-27.32%), 23.6% in men and 14.6% in women (P = .202). If only CRA was taken into account, the overall prevalence was 19.8% in men and 14.6% in women (P = .436). When only patients with colonoscopy were taken into account, the prevalence of CRN was 51% in men and 38.9% in women (P = .378); in the case of CRA, the prevalence was 42.9% and 38.9% for men and women, respectively (P = .770). In-hospital mortality and 1-year mortality were significantly higher among patients not diagnosed with CRN than among those who were (27.9% vs 6.2%; P = .009; and 38.5% and 12.5%; P = .006, respectively), whereas relapses were not significantly more frequent among patients diagnosed with CRN (8.3% in patients without CRN and 3.1% in patients with CRN; P = .460). When patients with CRN were compared with those who did not have the disease, no significant differences were detected in the classic factors associated with poorer prognosis of IE (type of IE [native/pacemaker vs prosthetic], valve involvement, rates of cardiac surgery, systemic and central nervous system emboli, heart failure, renal failure, persistent bacteremia, periannular complications, and type of antibiotic treatment [ampicillin plus aminoglycoside vs ampicillin vs ceftriaxone]) or in baseline comorbidities (data not shown).

The prevalence of CRN in the group of EFIE patients with an unclear source of infection is substantially higher than that expected for similarly aged patients in the general population, approaching that reported in patients with S. bovis IE. The prevalence of CRN in patients with S. bovis undergoing colonoscopy is approximately 60%,8 and both American16 and European17 guidelines recommend systematic colonoscopy in these patients. Although the prevalence of CRN in the group of EFIE patients with an unknown source of infection was significantly higher than that in those with a clear focus (and this finding is reliable), the data from our study are not conclusive because only 6 of 45 patients with an identified focus underwent colonoscopy.

The prevalence of CRA in a cohort study based on an Austrian national screening colonoscopy program with 44 350 participants was 18.4% (95%CI, 16.7%-20.1%) for women and 32% (95%CI, 30%-34%) for men in the 70–74-year age group,11 whereas it was 44.3% (95%CI, 31.54%-56.98%) in our cohort for patients undergoing colonoscopy (45.5% for men and 41.2% for women) in the group with an unknown source of infection. In the Austrian study, and within the same age group, the prevalence of CRC was 0.7% (95%CI, 0.4%-1.2%) in women and 1.9% (95%CI, 1.4%-2.6%) in men.11 In contrast, it was 8.2% (95%CI, 1.17%-15.22%) in our cohort in patients with available colonoscopy results and 11.4% (95%CI, 1.79%-20.93%) in men. Because all patients with a diagnosis of CRC were men, our findings represent a 1.4-fold higher prevalence of CRA and 6-fold higher rate of CRC than in the Austrian cohort when only male sex is considered. In the case of female patients, the CRA rate was 2.2-fold higher.

Comparison with data on the prevalence of CRN diagnosed by colonoscopy in Spain reveals even greater differences. In the study by Quintero et al.,10 the prevalence of CRC in patients undergoing colonoscopy (with no previous fecal immunochemical testing) was 0.5%, whereas CRA was found in 31.8%. Thus, CRC was almost 17 times more frequent in our cohort (0.5% vs 8.2%) in patients with colonoscopy, whereas CRA was only slightly more frequent (31.8% vs 44.3%). However, the mean age of the participants in the study by Quintero et al. was significantly lower than that of patients in our cohort (59.2 ± 5.5 years vs 69 ± 12.4 years in patients undergoing colonoscopy in our study).

A more recent study showed that the CRC rate among patients undergoing surveillance colonoscopy (follow-up colonoscopy in individuals with abnormal results in the baseline colonoscopy) was 9.5 cases per 10 000 persons-years in patients aged 70 to 74 years.20 Thus, even if we considered only the CRC cases diagnosed during follow-up, the incidence of CRC would still be considerably higher in our cohort of EFIE patients with an unknown source of infection undergoing colonoscopy than in patients at higher baseline risk of CRC due to a previous abnormal colonoscopy result within the same age range.

The diagnosis of CRN was not associated with poorer outcomes during admission and at 1 year or with a higher relapse rate. In contrast, mortality was significantly higher in the group without CRN, likely because a relevant percentage of patients presenting with severe courses of IE or poor baseline status did not undergo colonoscopy and thus were not diagnosed with CRN. The absence of an impact of EFIE on the prognosis of CRN is consistent with data from patients with IE due to the S. bovis group, who rarely die of CRN-related complications.15 On the other hand, EFIE and the S. bovis group IE might constitute, respectively, late and early markers of CRC due to the different temporal patterns of presentation. However, the differences between both entities could be due to a wide variety of reasons (eg, the epidemiology of our centers; the recent switch of EFIE from a subacute, community-acquired entity to an acute, health care-associated infection; and nonsystematic performance of colonoscopy in EFIE until recent years). These findings require confirmation in further studies. In this regard, we found a shorter duration of symptoms in patients with EFIE with unknown origin than in those with an identified focus of infection; community acquisition was more frequent in the former, and health care-associated acquisition was more frequent in the latter. We hypothesize that the diagnosis of IE was reached later in patients with health care-associated acquisition and an identified focus because they were mainly patients with invasive urinary procedures or a chronic urinary catheter with recurrent urinary infections. These cases of EFIE were partially treated as urinary infections, thus hindering the early detection of E. faecalis in blood cultures and suspicion of IE.

In our cohort, 17 patients with EFIE and an unknown source of infection underwent barium enema, and none were diagnosed with colorectal diseases. Given the high prevalence of colorectal diseases found in these patients using colonoscopy, we conclude that the sensitivity of barium enema is very low. Even though barium enema is no longer used as a screening tool for CRN in most countries, it remains crucial to highlight that the test of choice for ruling out CRN in patients with EFIE should always be colonoscopy.

Our findings could have a considerable impact not only on the diagnostic assessment of EFIE, but also on its management. If possible, colonoscopy should be performed early after the diagnosis of EFIE because the presence of an advanced neoplasm might change the performance or timing of invasive procedures (namely, cardiac surgery, which could be cancelled despite being indicated or postponed until after the initial treatment of the CRC). However, due to the risk of fluid overload in frail patients with valve regurgitation, as well as the difficulties of performing colonoscopy in critically ill patients, it is unlikely that all patients with EFIE will undergo colonoscopy in an early stage of the episode. In 3 of the patients of our cohort undergoing 18F-FDG positron emission tomography/computed tomography (PET/CT) (performed in most patients with possible or definite IE in Hospital Clínic since 2013) in the initial phase of the diagnostic process, focal colonic uptake aroused early suspicion of CRN, which was later confirmed by colonoscopy and histopathological findings (Supplementary material). 18F-FDG PET/CT is efficacious in IE, not only for diagnosis of prosthetic valve endocarditis, but also for early detection of septic embolisms and neoplasms.21,22 However, 18F-FDG PET/CT cannot replace colonoscopy as a diagnostic tool for CRN in these patients but can only act as an additional approach for confirmation and detection of metastases from the neoplasm. This is especially relevant when treating patients with a high risk of CRN and comorbidities, such as patients with EFIE, because it might determine operability and timing in patients with an indication for cardiac surgery. These “special situations” in IE have not been addressed by recent American16 and European17 guidelines or in the comments of the Spanish Society of Cardiology on the European guidelines.23 As stated elsewhere, we advocate including these considerations in future guidelines and recommendations.24

In conclusion, the prevalence of CRN in EFIE with unknown origin was 50.8% in patients undergoing colonoscopy. When compared with patients with EFIE and an identified focus of infection, the CRN rate was significantly higher in the group of patients with an unclear source of infection. The prevalence of CRN was also higher than in the general population. Colorectal adenoma was only slightly higher than in the Spanish population, whereas CRC was 17-fold higher. In light of these preliminary data, colonoscopy should be recommended in all patients with EFIE and an unclear source of infection until further studies on the relationship between EFIE and CRC are available.

This work was supported in part by a grant from the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Madrid, Spain), the Spanish Network for Research in Infectious Diseases (REIPI RD06/0008), and the “Fundación Máximo Soriano Jiménez” (Barcelona, Spain). While the manuscript was being drafted, J.M. Pericàs received an “Emili Letang” Postresidency Scholarship (2013-14) from Hospital Clínic, Barcelona (Spain) and a “Río Hortega” Research Grant (CM14/00135; 2015-16) from Instituto de Salud Carlos III and the Ministerio de Economia and Competitividad, Madrid (Spain). J.M.M. received a personal intensification research grant #INT15/00168 during 2016 from Instituto de Salud Carlos III, Madrid, Spain. The European Regional Development Fund (ERDF) “A way to build Europe” also provided funding”. None of the sponsors/funders had a significant role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

J.M. Miró has received consulting honoraria and/or research grants from AbbVie, Bristol-Myers Squibb, Cubist, Novartis, Gilead Sciences, and ViiV. F. Marco has received consulting honoraria from Novartis and Janssen-Cilag. C.A. Mestres has received consulting honoraria from Novartis and Edwards Lifesciences LLC.