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Ann Thorac Surg 2004;78:1623-1629
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Latent Infective Endocarditis: Epidemiology and Clinical Characteristics of Patients With Unsuspected Endocarditis Detected After Elective Valve Replacement

Nadiv Shapira, MDa, Ofer Merin, MDa, Eliezer Rosenmann, MDb, Ilia Dzigivker, MDa, Dan Bitran, MDa, Amos M. Yinnon, MDc,*, Shuli Silberman, MDa

a Department of Cardiothoracic Surgery, Jerusalem, Israel
b Department of Pathology, Jerusalem, Israel
c Infectious Disease Unit, Shaare Zedek Medical Center, Jerusalem, Israel

Accepted for publication May 14, 2004.

* Address reprint requests to Dr Yinnon, Infectious Disease Unit, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel
yinnon{at}szmc.org.il


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: The diagnosis of infective endocarditis is usually made on the basis of clinical and laboratory criteria and may be confirmed by histologic examination or culture of excised valves. We tried to determine the incidence and significance of inflammatory changes in valves excised during operations for reasons other than infective endocarditis.

METHODS: The charts and histopathology of all patients undergoing valve replacement during a 10-year period (1993–2002) were reviewed. A total of 868 patients underwent a total of 970 valve replacements during this period, of whom 11 patients (1.3%) were for endocarditis, with the remaining 857 (98.7%) for other indications. All excised valves were cultured and examined histologically for the presence of inflammatory infiltrates, vegetations, and microorganisms.

RESULTS: In 8 of 857 patients (0.9%), the histologic examination unexpectedly demonstrated an infiltrate suggestive of endocarditis. Blood and valve cultures, and serologic tests for Mycoplasma, Chlamydia, Legionella, Q fever, Brucella, Rickettsiae, VDRL, and Bartonella were negative in all but 1 patient, who was found to have Q fever. All received a prolonged course of antibiotics. Six patients had an uneventful recovery; 1 had intramyocardial abscesses and expired during cardiac reoperation; and 1 had recurrent fever and dehiscence of the aortic and mitral valve prostheses and after two cardiac reoperations remains in severe heart failure.

CONCLUSIONS: The presence of an unexpected inflammatory infiltrate in heart valves excised for reasons other than endocarditis may occur in 0.9% of such operations; these infiltrates could indicate presence of endocarditis. A microbial origin should be sought, and patients should receive empiric antibiotic treatment for endocarditis.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Despite dramatic improvements in the natural history of infective endocarditis subsequent to the introduction of antimicrobial therapy [1], this entity remains a serious disease that requires surgical intervention in up to 40% of involved patients [2]. In general, patients who have been referred for surgery combine manifestations of both infection and valvular dysfunction. Two recent publications [3, 4] have drawn attention to a unique category of patients: those who were referred for valve replacement with a diagnosis other than infective endocarditis, but, unexpectedly, the histopathologic examination of their excised valve indicated infective endocarditis. Unfortunately, the latter reports did not elaborate on the clinical course or the outcome of these patients. Therefore, it remains unknown whether the presence of such an inflammatory infiltrate is accidental and meaningless or clinically and prognostically significant.

During the years, we have encountered occasional cases in which an inflammatory infiltrate was unexpectedly found in the histologic examination of cardiac valves that were replaced for reasons other than infective endocarditis. For this study, the histopathology slides of the excised valves of all patients who have undergone valve replacement in our institution in a 10-year period (1993–2002) were reviewed to identify those with an unexpected valvular inflammatory infiltrate. Records from the original hospitalizations and follow-up visits were reviewed. This review enabled us to determine the incidence, clinical significance, and possible implications of this finding. Furthermore, because the mere presence of an inflammatory infiltrate in an electively excised valve is not sufficient for making the diagnosis of infective endocarditis according to the classic von Reyn [5] or the more recent Duke University criteria [6], the results of this study may imply a need for modification of these criteria.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Between January 1, 1993, and December 31, 2002, 868 patients (416 women, 452 men) underwent valve replacement in our institution. Age range was 17 to 87 years (mean, 63 ± 14 years). A total of 970 valves were replaced; in 374 patients (43.1%) the aortic valve, in 371 (42.7%) the mitral valve, in 105 (12.1%) both aortic and mitral valves, and in 18 (2.1%) other valves.

Surgery was performed using uniform technique in all. Care was taken to achieve complete decalcification of excised valve annuli, and implanted valves were carefully sized, with tendency to undersize rather than oversize the valve. All excised valves were routinely divided on the operating table, and placed in two sterile containers: one for pathologic examination, the other for microbiologic studies. On receiving the histopathologic examination report regarding the presence of an unexpected infiltrate, patients were evaluated by an infectious disease consultant to substantiate or exclude the diagnosis of endocarditis. At least three blood cultures were drawn and held for 4 weeks to detect possible HACEK organisms [7]; in addition, serologic tests for Mycoplasma, Chlamydia, Legionella, Coxiella burnetii (Q fever), Brucella, Rickettsiae, Bartonella, and VDRL were obtained. Tests to rule out anticardiolipin syndrome and thrombophilias were acquired as well.

For this study we reviewed the histopathologic slides of all patients undergoing valve replacement during the 10-year study period for the presence of an inflammatory infiltrate, vegetations, or microorganisms. Those patients whose excised valves revealed the presence of a dense infiltrate consisting of neutrophils, granulation tissue, lymphocytes, plasma cells, or macrophages were defined as having occult or latent infective endocarditis and were included in this review. Patients referred to surgery because of endocarditis were excluded.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Eleven of the 868 patients (1.3%) who underwent valve replacement were referred to surgery with a diagnosis of native valve endocarditis (Fig 1). These patients, 10% of 108 patients who were diagnosed and treated for infective endocarditis in our institution during that period, were not included in this report [8]. Thus, 857 patients were referred for surgery for indications other than endocarditis, and were not suspected to have such a process. In 8 of these patients (0.9%), the histologic examination unexpectedly revealed findings indicative of infective endocarditis. The remaining 849 patients did not have any histopathologic evidence of endocarditis.



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  		Fig 1. Indications for valve surgery and results of routine histologic examination for 10 years (1993–2002). *During this period, 108 patients received the diagnosis of definite or probable endocarditis by Duke University criteria, of whom these 11 patients (10%) were referred for valve replacement [8].

 
All 8 patients were operated on electively. The principal clinical features of these patients are depicted in Table 1. During the 6 months preceding surgery, none of these patients had had fever, loss of weight, malaise, night sweats, or rigors, and none had undergone dental work or other invasive procedures. Preoperative transthoracic or transesophageal echocardiogram examinations were negative for findings that may indicate endocarditis [6]. Preoperative leukocyte counts ranged from 4,800 to 10,600 cells/mL, and none had anemia. Patients received routine prophylactic antibiotic coverage, consisting of intravenous cefazolin (1.0 g three times per day), starting 30 minutes before surgery with discontinuation after 48 hours. Given their intraoperative gross appearance, the surgeon did not expect the valve(s) in any of these 8 patients to be infected. The results of the histopathologic reports suggesting endocarditis were received 4 to 12 days after operation, at which time an infectious disease consultant examined each patient. The physical examination was negative in all for Osler's nodes, Janeway nodules, conjunctival petechiae, retinal Roth spots, clubbing, and splenomegaly. After obtaining blood cultures and serologic tests, intravenous treatment with empiric antibiotics was initiated. Cultures of the excised valves, as well as cultures taken from the valve annuli and all blood and serologic tests, were negative in all patients except 1 in whom Q fever was diagnosed (patient no. 7). Gram stain, periodic acid–Schiff, and Giemsa staining, performed in all, did not reveal the presence of microorganisms. Antibiotic treatment was continued for 4 to 6 weeks.


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  		Table 1. Principal Clinical and Laboratory Features of 8 Patients With Occult Endocarditis

 
The main features of these patients are shown in Table 1. As shown, 6 of these patients did well and completely recovered after intravenous antimicrobial therapy; 1 died postoperatively, and 1 had severe paravalvular leaks and, after two reoperations, remains in severe heart failure. Four patients had unique features, which we will briefly describe.

Patient no. 1, a 44-year-old woman, was referred for replacement of her aortic and mitral valve because of significant regurgitation. Her history was significant only for a febrile respiratory disease, possible Mycoplasma pneumonia, 1 year before the present admission, which had been treated with roxithromycin. In the following year, she remained afebrile but exhibited symptoms of heart failure. Her valvular disease was attributed to possible past endocarditis or rheumatic carditis; however, there were no historic, physical, or laboratory clues of an infectious process at the time of surgery. She underwent an uneventful aortic and mitral valve replacement using mechanical prostheses. At surgery, both valves appeared fibrotic with "rolled over" edges. The heart was covered with extensive and dense adhesions, and the aorta was unusually thick. The histopathologic results (Fig 2) demonstrated chronic inflammation including granulation tissue, microvegetations, and extensive myxomatous changes involving both valves, and she received a 6-week course of cefazolin, gentamicin, and doxycycline. After 6 months aortic regurgitation was diagnosed and heart failure developed, and 1 year later, she underwent primary reattachment of the partially dehisced aortic valve prosthesis. However, regurgitation reoccurred, and an echocardiogram revealed paraprosthetic leaks of both valves, which were replaced again. Cultures taken from the valve annuli during both operations were negative. The patient was treated with intravenous vancomycin, ciprofloxacin, and doxycycline for 6 weeks, and was discharged in good condition to continue ciprofloxacin and doxycycline orally. Eleven years after the last operation, because of severe perivalvular leaks and class IV heart failure, she underwent successful valve replacements, and 6 months after operation, she remains symptom free.



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  		Fig 2. Histopathologic examination of heart valve of patient no. 1, showing chronic inflammatory infiltrate, granulation tissue, extensive myxomatous changes, and microvegetations.

 
Patient no. 4, a 58-year-old man who presented with congestive heart failure owing to severe aortic stenosis and moderate insufficiency, underwent an uneventful aortic valve replacement with a prosthetic biologic valve, and coronary artery bypass grafting. The aortic valve appeared heavily calcified and bicuspid. On the fifth postoperative day, a first-degree atrioventricular block developed in the patient, which deteriorated to second-degree block and on the next day, fever and leukocytosis, and he was empirically treated with vancomycin and amikacin. Blood cultures remained sterile. Histopathologic examination (Fig 3) showed calcified cusps with chronic infiltrate, granulation tissue, abundant plasma cells, and neutrophils. On the twelfth day he experienced shivering, and echocardiography revealed a vegetation on the anterior mitral leaflet and an abscess in the aortic-mitral continuity. On the thirtieth postoperative day he experienced a cerebral embolic event and underwent reoperation. At surgery, a large abscess was detected at the aortic-mitral continuity. The anterior mitral annulus and the adjacent aortic valve–supporting tissue were destroyed and required reconstruction. The aortic and mitral valves were replaced by mechanical prostheses. Disseminated intravascular coagulopathy ensued with severe bleeding, and the patient died a few hours later. Histologic examination of the mitral valve showed leaflets partially destroyed by vegetations, with granulation tissue and chronic and acute inflammatory infiltrates. This patient possibly suffered from postoperative prosthetic valve endocarditis. However, in view of the presence of an inflammatory infiltrate in the resected native valve, we believe that the catastrophic postoperative course was the result of a preexisting infection.



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  		Fig 3. Histopathologic examination of heart valve of patient no. 4, showing extensive calcifications and acute and chronic inflammatory infiltrate, with abundant plasma cells and granulation tissue.

 
Patient no. 6, a 75-year-old man, was referred for elective mitral valve replacement. Nine months earlier, he had been hospitalized with an acute febrile disease; Streptococcus pneumoniae, with a minimal inhibitory concentration of 0.01 µg/mL, had been isolated from several blood cultures and the cerebrospinal fluid culture. A transesophageal echocardiogram revealed moderate mitral regurgitation, similar to that detected 2 years earlier. At the time the patient received 2 weeks of intravenous penicillin and completely recovered. During the 6 months before admission he exhibited shortness of breath on exertion, without fever. Echocardiography revealed significant mitral regurgitation, without vegetations. He underwent an uneventful valve replacement with a bioprosthetic valve and coronary artery bypass grafting. Pathologic examination revealed an ulcerated mitral valve, with fibrinous vegetation and mixed inflammatory infiltrate. The patient received a 4-week course of ceftriaxone and completely recovered. He died 7 years later of cancer. In retrospect, this patient may have suffered from pneumococcal endocarditis, partially treated with 2 weeks of intravenous penicillin, and subsequently developed latent endocarditis and progressive mitral insufficiency. Pneumococcal endocarditis in the antibiotic era is rare and generally manifests acutely, similar to staphylococcal endocarditis, although rare instances of a more insidious course have been described [9–11].

Patient no. 7, a 58-year-old man, was referred for elective aortic valve replacement because of a 3-year history of shortness of breath on effort. Echocardiography before surgery revealed severe aortic stenosis and moderate regurgitation. At surgery he was found to have a thickened bicuspid valve. He underwent an uneventful valve replacement with a bioprosthesis. Gross examination at surgery was unremarkable; however, histologic examination (Fig 4) revealed a fibrotic and calcified valve and fibrinous vegetations with a neutrophilic infiltrate. Infectious disease consultation did not reveal any clue for endocarditis in the patient's history, physical examination, or laboratory tests. Before surgery his hemoglobin was 13.2 g/dL and the white blood cell count was 4,700/mL. Blood cultures remained sterile. After these histologic results, serologic tests revealed very high titers of Q fever immunoglobin G antibodies (immunoglobin G phase I, >1:32,000; immunoglobin G phase II, 1:8,000; immunoglobin M phase I and II, 1:20). There was no known exposure to pets. The patient was diagnosed as having Q fever endocarditis and was discharged on doxycycline and hydroxychloroquine [12], which he is scheduled to receive for at least 3 years; a future negative Q fever titer may be the most important determinant for discontinuation of treatment. He is currently 6 months after surgery and asymptomatic. Latent Q fever endocarditis, detected at elective surgery, has been rarely described in the literature [13].



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  		Fig 4. Histopathologic examination of heart valve of patient no. 7, showing fibrosis, calcifications, and fibrinoid vegetations with neutrophilic infiltrate.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Only one major inclusion criterion was applied in this review [6]: the unexpected histopathologic finding of an inflammatory infiltrate in a heart valve that was excised for reasons other than endocarditis. We detected 8 such patients, who constituted 0.9% of 857 patients who underwent valve replacement during a 10-year period for indications other than endocarditis. In none of these patients did the preoperative clinical presentation and the laboratory evaluation suggest that an infectious process might be present, nor were any of the Duke criteria for endocarditis present, including patient no.1, in whom the possibility of bacterial endocarditis had been entertained preoperatively. Thus, the diagnosis of infectious endocarditis was made solely on the basis of histologic findings.

Two groups [3, 4] have described patients with a similar clinicopathologic picture. The first one conducted a histologic examination of 150 excised aortic valves, which were replaced for a diagnosis other than infective endocarditis, and in 17 (11.3%) found acute (n = 7) or chronic (n = 10) endocarditis [3]. The second paper summarizes the results of a similar study of 35 aortic or mitral valves, and in 4 (11.4%) histologic findings were consistent with endocarditis [4]. Neither report provided information regarding the postoperative clinical course, whether the findings influenced the management of these patients, or whether the findings affected the patients' outcome. We cannot explain the difference between the incidence of latent endocarditis in these two studies and ours (0.9%). The paucity of publications on latent endocarditis probably indicates an overall low prevalence, and, therefore, our low figure may be more representative.

The fact that in all 8 patients the cultures of valve tissue were negative, and that pathologic examination revealed bacteria in none, was particularly problematic in the 2 patients (nos.1 and 4) who exhibited early symptoms of infection of the newly implanted valves. The first had partial prosthetic aortic valve dehiscence 6 months after surgery, and the second had vegetations with an intramyocardial abscess in the immediate postoperative period. The timing of these events—within days to a few months after surgery—and their location—around the sewing rings of the newly placed prosthetic valves—strongly suggest that they were not endocarditis de novo, but rather preexisting processes that already involved the native valves. This conclusion is consistent with the fact that all blood cultures in these patients were sterile, even those that were obtained when they demonstrated clinical signs of active infection, suggesting a direct extension of a preexisting infection. There are several possible explanations for the fact that blood and valve cultures were negative. First, it is possible that the single dose of antibiotic prophylaxis could have prevented growth of organisms from the excised valves [14]. Second, a small inoculum, and especially the presence of nonstaining pathogens, could also possibly explain lack of detection by microscopy, as exemplified by patient no. 6, who may have had partially treated pneumococcal endocarditis. Third, fastidious organisms that are difficult to isolate may have caused valvular infection: patient no. 7 with Q fever endocarditis may belong to this category.

Is latent infective endocarditis a clinically significant entity? The high proportion of infective endocarditis involving the newly placed prosthetic valve in our series, in 2 of 8 patients (25%), is strongly indicative that these valves were indeed inserted within an infected area. This proportion is far higher than the expected risk of prosthetic valve endocarditis in patients with no prior endocarditis quoted in the literature: 3% at 12 months and less than 1% per patient-year in the long term [15–17], and higher than the overall 0.9% observed rate of early postoperative endocarditis seen in our patients, which was less than 1%. It is also much higher than the 2-year actuarial freedom from recurrent endocarditis, 95% per patient-year, among patients who undergo valve replacement with a preoperative diagnosis of infective endocarditis [18, 19]. These figures reflect the significant risk these patients were exposed to by being operated on during unrecognized and untreated infective endocarditis. We, therefore, believe this is a clinically meaningful entity rather than an accidental laboratory finding.

The considerable improvement in the prognosis of infective endocarditis can be attributed to two key elements: effective antimicrobial therapy [1], and the feasibility and the relative safety of valvular replacement in the face of active infection in those who develop severe valvular dysfunction [2, 20]. Because an active infective process was not suspected in any of these patients, they received routine perioperative antibiotic prophylaxis, which was discontinued within 48 hours after operation. The histologic results were received between the fourth and twelfth postoperative days. Therefore, there was a window of 2 to 10 days during which they were not treated with any antimicrobial agent. Unfortunately, because the bacteriologic and serologic workup and the cultures of excised valves were negative in all but 1 patient, the choice of antibiotic regimen was empiric, similar to the management of culture-negative endocarditis [21]. If the diagnosis of endocarditis had been known or suspected preoperatively, their management would have been substantially different; first, they would have been treated with antibiotics for 2 to 6 weeks before surgery instead of a single dose, as recommended by American Heart Association guidelines [22]. Second, the antibiotic regimen would have been selected according to microbiologic evaluation rather than using a standard protocol for culture-negative endocarditis. Third, the postoperative hiatus of 2 to 10 days without antibiotic therapy would have been avoided. Because all patients received prolonged intravenous antibiotic therapy, it is impossible to conclude whether the 6 who completely recovered did so because or in spite of this treatment.

On the basis of the Duke criteria [5, 6], the 8 patients presented in this manuscript would not be diagnosed as having infective endocarditis. Published case definition criteria do not allow for diagnosis based only on positive histopathologic examination of excised valve tissue, unless a vegetation or intracardiac abscess is present [23, 24]. Therefore, in the current era of cardiac surgery, published diagnostic criteria may not be sufficiently sensitive, and their strict application could lead to underdiagnosis, as in the 8 patients described in this report.

Patients undergoing surgery for endocarditis present a well-defined group, and protocols for their management have been well established. Patients who are diagnosed as having endocarditis at surgery will fall into the same therapeutic category. However, a third group of patients, such as those described in this manuscript, do not have any preoperative or operative findings indicative of valve infection, and endocarditis is diagnosed only after the fact. In our series they represent nearly 1% of all patients undergoing valve surgery without clinical evidence of endocarditis. Although overall they constitute a small group, their clinical outcome does warrant special attention. Although one cannot establish strict guidelines on the basis of such a small number of patients, we believe it preferable to possibly err on the side of caution in view of the potentially catastrophic consequences of untreated endocarditis, and to treat these patients as having culture-negative endocarditis. It would take a much larger number of patients in a prospective, randomized study to draw further conclusions regarding the most appropriate therapeutic approach. This is beyond the scope of this manuscript in which we call attention to an as yet inadequately recognized entity.

In summary, we described 8 patients who underwent elective valve replacement for diagnoses other than infective endocarditis, in whom routine pathologic examination of the excised valve unexpectedly revealed an inflammatory infiltrate. None of these patients met the standard criteria for diagnosis of infective endocarditis. They received the diagnosis of latent infective endocarditis and received antibiotic treatment for culture-negative endocarditis, except 1 patient with Q fever endocarditis who received commensurate therapy. Although 6 of the 8 patients had an uneventful recovery, the other 2 had a calamitous postoperative course, attributed to infection. This complication rate is significantly higher than that observed in our surgical practice for elective valve replacement. The value of microbiologic and histologic evaluation of valves removed because of endocarditis has been demonstrated [25]. We suggest that all resected valves, regardless of the indication, should be sent for routine histologic examination, and, if an infiltrate is detected, an underlying microbial cause should be sought and appropriate antibiotic therapy instituted. If no organism is identified, these patients should be treated as having culture-negative endocarditis.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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