Endocarditis

This patient was a 60 year old man with a history of cigarette smoking and alcohol use, who visited his internist with complaints of shortness of breath, intermittent fever, fatigue and weight loss. The physical exam revealed splenomegaly (4 cm below the left costal margin), a holosystolic murmur, and bilateral pulmonary rales. His laboratory tests were significant only for “mild pancytopenia” and hematuria. His liver chemistry was within normal limits. A bone marrow exam was done and reported as reactive. An abdominal CT scan was considered unremarkable except for splenomegaly. The echocardiogram showed mild to moderate mitral valve regurgitation. He was given antibiotics and was referred to a pulmonary specialist and an oncologist with the diagnoses of chronic obstructive pulmonary disease and probable lymphoma.

A few months later, the patient called the paramedics with complaints of severe dyspnea. He was found agitated and in respiratory distress. During transportation to the hospital, the patient became apneic and was intubated. He arrived to the emergency room without vital signs. Defibrillation was attempted several times without success and the patient was pronounced dead.

Gross Description

The body measured 195 cm and weighed 85 kg. The thoracic cavity was unremarkable except for bilateral pleural adhesions. No fluid accumulation was present in the pleural cavities. The heart weighed 610 g. The left atrium was dilated, but free of thrombus. The right and left ventricles measured 0.6 and 1.8 cm in thickness, respectively. The valve leaflets were translucent except those of the mitral valve, which were thick and contained large vegetations. The largest vegetation, located on the anterior leaflet, showed evidence of re-endothelialization on the closing edge along with ulceration and hemorrhage (Figures 1 and 2). The chordae tendineae were short and focally fused. The myocardium was brown-red and of average consistency. The epicardium had multiple small abscesses, but the pericardium was smooth and shiny. The coronary arteries showed up to 70% stenosis by atheromatous plaques. There were no complete occlusions. The aorta and its branches were also affected by severe atherosclerosis with plaque ulceration and hemorrhage. The lungs were edematous and had a combined weight of 1700 g. Bilateral apical bullous emphysema was evident, and the rest of the parenchyma failed to show areas of consolidation. The liver showed signs of passive congestion with a weight of 2400 g. The spleen weighed 750 g and was significantly enlarged (20 cm in length). A 3.5 x 3 cm defect and a subcapsular hematoma were located on the posterior surface compatible with acute splenic rupture (Figure 3). In addition, there were multiple acute and subacute splenic infarcts, the largest of which measured 4.0 cm in its greatest dimension. There was evidence of retroperitoneal hemorrhage with approximately 500 g of clotted blood and 2 L of ascites. The kidneys weighed 460 g combined, and were grossly unremarkable except for a healed infarct in the cortex of the right kidney and a left cyst at the corticomedullary junction measuring 0.8 cm in diameter. The cervical, mediastinal and abdominal lymph nodes were not enlarged. The brain did not show any pathologic changes.

Figure 1 Infective endocarditis, mitral valve. A large vegetation is present to the atrial surface of the leaflet (arrow). there is associated hemorrhage and ulceration

Figure 2 Infective endocarditis. The anterior leaflet of the mitral  valve has a vegetation with evidence

of re-endothelialization (arrow).

Figure 3 Section of the spleen showing a subcapsular hematoma (arrow). There is also softening of the parenchyma due to septic splenitis

Microscopic Description

Sections of the heart, stained with H&E, showed active infective endocarditis of the mitral valve with septic vasculitis and acute epicarditis with microabscess formation. The lungs and liver had changes of chronic passive congestion. The lungs were also affected by centrilobular emphysema. Sections from the spleen revealed multiple infarcts with cavitation, as well as hemorrhage in the area of rupture and acute inflammation. The kidneys showed interstitial chronic nephritis, but no recent infarcts. The bone marrow and lymph nodes were reactive with no evidence of malignancy.

Case Analysis

This case represents another example of cardiovascular sudden death. However, in contrast to the common fatal ventricular arrhythmia discussed previously; the cause of death in this case was directly related to a sudden but unexpected, non-arrhythmic complication of infectious endocarditis (IE). It is reasonable to say that IE virtually never causes sudden death, with the rare exception of septic embolization of a coronary or cerebral artery, arising from an infected vegetation. This case represents a rare event, but one that is instructive regarding the often subtle and difficult diagnosis of IE.

The clinical and pathological features are a classic example of what previously was called subacute bacterial endocarditis, or SBE. Today, for reasons outlined below, the generally accepted designation is infectious endocarditis. This is an unusual patient because it illustrates so clearly how elusive the diagnosis of IE can be since it may mimic an indolent systemic disease of many different etiologies. The ‘take home message’ from this case is that if the possibility of IE is not considered, reaching the correct diagnosis will be very unlikely. The consequences of such an oversight, as exemplified here, can be devastating.

What is the difference between subacute bacterial endocarditis (SBE) and acute bacterial endocarditis (ABE), and why has there been a trend away from these designations? Historically, both SBE and ABE were described in the pre-antibiotic and pre-cardiac surgery era, at a time when there was no treatment for the valvular infection(s). Thus, the natural history was
dependent on the virulence of the infective organism, and the underlying valvular pathology. SBE was usually a slow, progressive, indolent infection of a valve. Most often it involved the mitral and/or aortic valves. The rightsided disease was uncommon. The mitral valve was the most frequently affected, since pre-existing chronic rheumatic mitral valvulitis with scarring and calcification was highly prevalent. The valvular damage allowed for infection by organisms that ordinarily could not colonize ‘healthy’ valvular tissues. These organisms include Streptococcus viridans (normal mouth flora), and Staphylococcus epidermidis (normal skin colonizer). Healthy valve tissue covered by endothelium (endocardium), does not routinely permit adherence of non-pathogenic organisms. In contrast, scarred and distorted valves with turbulent blood flow over the valve surface, serve as anchor areas for the development of pathological infectious vegetations. Even nonpathogenic organisms can adhere to sub-endocardial connective tissue; and colonize small platelet and fibrin vegetations that may develop on denuded valve linings. The bacteria, particularly S. viridans,  circulate in the bloodstream following oral manipulation as common as brushing teeth. With more vigorous dental work there may be a more significant bacteremia, which explains why patients with known valvular disease, must have antibiotic prophylaxis before and after dental procedures.

Infection of valvular tissue with a non-virulent organism leads to a smoldering infection, and a prolonged clinical course. Patients with such infections could often live for many months even before antibiotics were available. The causes of death were usually valve destruction, non-cardiac tissue damage, or systemic complications of sepsis. This was the classic SBE: infection of an (almost always) abnormal heart valve persisting for more than 6-8 weeks. With the persistent, often  low-grade infection, patients have indolent symptoms of chronic disease. These may include variable weight loss, anorexia, fatigue, intermittent fever, chills, and night sweats. These are symptoms remarkably similar to those seen with occult cancers, collagenvascular disease, and tuberculosis (today, we should also consider HIV/AIDS). The weight loss, anorexia, and fatigue could also be ascribed among others, to depression, diabetes mellitus, and adrenal cortical insufficiency. The clinical presentation might suggest SBE if there were typical findings of a heart murmur that was changing in intensity at different times. Additionally, patients with SBE may have small mucocutaneous hemorrhages peripherally, particularly in their nail beds or the so-called ‘splinter hemorrhages’, and cutaneous petechiae. These lesions are generally thought to be secondary to small non-infected emboli from the valve vegetation, although infected material or immune mediation may play a role. Since the spleen is frequently enlarged, patients may present with left upper quadrant pain and tenderness. Splenic involvement includes changes associated with sepsis (‘acute splenitis’), infarction and/or abscess formation (septic emboli). Moreover, when the infection has persisted for some time, the valves leaflets or cusps are destroyed, which results in valvular insufficiency, and ultimately in ventricular failure. Often, patients succumb secondary to systemic embolization, particularly to the brain, where they might develop cerebral infarctions, abscesses, and meningitis. Patients may also develop systemic disease related to the prolonged indolent course of their infection. Specifically, the subacute infection may lead to the development of antigen-antibody complexes, with the antigen being bacterial membrane protein. These complexes can circulate in the bloodstream, and ultimately deposit in small skeletal muscle and skin vessels, and in glomerular capillaries of the kidney. In the former sites, they may lead to a necrotizing vasculitis, with tissue inflammation and necrosis. When present in the palms, finger pulp, or soles of the feet, they are known as Osler’s nodes. In the kidney, a focal, necrotizing glomerulonephritis may develop, which is not secondary to embolism of vegetations (even though classically it has been called focal embolic glomerulonephritis). Other manifestations of immune complex disease include arthralgias and arthritis.

Despite the relative ease with which the diagnosis of SBE should be made in patients who present with these clinical signs and symptoms; the fact remains that, even in this modern era of echocardiography, it is still a disease associated with a high number of mis-diagnoses. The primary reason, other than physicians not considering it, is that many patients do not present with all of these classic features. Since the infection is often a subtle one, and given the intermittent nature of active bacterial release into the blood stream, negative blood cultures may be common, unless taken frequently. Furthermore, once the bacteria extend into the valve tissue, or into the perivalvular annulus, they are not released into the bloodstream. Clinically, there may be no changing murmur; petechiae may not be present, or in darkskinned patients, may be difficult to appreciate; and complications associated with immune complexes may not develop. However, non-specific clinical symptoms may suggest cancer, or systemic diseases like lupus erythematosus. Laboratory signs such as low-grade leukocytosis (with white blood cell counts between 10,000-15,000), and elevated erythrocyte sedimentation rate (ESR) are relatively non-specific, and may not be present. So again, as stated previously, if you don’t think of the diagnosis, you won't make it!

In contrast to SBE, acute bacterial endocarditis (ABE) has different features and pathogenesis. It is generally associated with infection by virulent organisms, particularly Staphylococcus aureus, Streptococcus pneumoniae (pneumococcus), enterococci, and a number of Gram-negative bacilli. As a result of the virulence of these or other pathogens, pre-existing valve damage may or may not be present. With aggressive, rapidly growing, and destructive organisms, there is an acute and progressive tissue disruption associated with collagenolysis of valvular and annular connective tissue. Intra-valvular and annular abscesses may occur. Large platelet and fibrin vegetations develop, which are very susceptible to fragmentation and embolization. The time course of the disease is rapid, often measured in days or few weeks. Moreover, signs and symptoms of valvular insufficiency are frequent and occur early. Systemic embolization to other organs, with tissue infarction and abscess formation, is common. Because of the acuteness of the disease, there is generally not sufficient time for the immune complexes to develop. Thus, the immune complications characteristic of SBE are usually absent. Historically, death ensues in a relatively short time, usually secondary to cardiac failure with valve destruction, or septicemia. With these features, ABE has been defined as: infection of a normal or abnormal heart valve by a virulent organism, with disease generally less than 4 weeks in duration.

With such a clear distinction between SBE and ABE, why are these designations inappropriate today? Why is the preferred terminology: active infectious endocarditis? The simple answer is because antibiotics, and earlier diagnoses with the advent of echocardiography, have modified the natural history of the disease. In addition, surgical intervention has had a
major impact in the course of this disease. Prolonged survival is now possible with non-virulent and virulent organisms, allowing for the possibility of immune-mediated complications to develop. Finally, as a result of intravenous drug use and the HIV/AIDS epidemic, infections with fungi (aspergillus and Candida species, in particular), rather than bacteria, have gained tremendous attention. Although it is still true, that infection with Staphylococcus aureus and pneumococcus is more severe and more destructive than infection with S. viridans, medical intervention has changed the classic features of SBE and ABE.

This patient presented in a terminal state, and had a cardio-pulmonary arrest during transportation to the hospital. Death was a result of septicemia, cardiac failure, and acute splenic rupture. It is unlikely that he had hypovolemia, as only 500 cc of blood were found in the retroperitoneal space. The presence of 2 liters of ascites in the peritoneum was most probably from congestive heart failure (there was no evidence of cirrhosis). His heart was almost twice normal size (610 g), with a dilated and hypertrophied left ventricle, as a result of prolonged mitral valve regurgitation. The regurgitation was secondary to active and healed vegetations of his mitral valve, with ulceration, and actual partial destruction of the anterior leaflet. Vegetations, infected and bland, embolized to distant organs like the spleen, where they produced septic infarctions, and infected vasculitis. The latter, is referred to as a mycotic aneurysm. They are called mycotic even though they are usually not the result of a fungal infection. They represent an infection of the vessel wall, with eventual arterial destruction, and the development of a pseudo-aneurysm, which has the potential to rupture. This patient’s partial valvular healing was most certainly due to the antibiotics he was given for intermittent fever during his lengthy clinical course (in retrospect, at least 3-4 months in duration). Unfortunately, though gram-positive cocci were found in the valve tissues, no culture was performed. It is most likely that the organism was one of the saprophytic ones, such as S. viridans. Even though the valve was significantly distorted by the infection, it appeared to have nonspecific leaflet thickening, and focal fusion of several chordae tendineae. The latter finding may result from chronic alcohol abuse. Prior valve damage may have predisposed this man to infection with S. viridans.

As a final point, it would be instructive to consider why he was followed for months with a diagnosis of probable lymphoma, or some other type of hematologic malignancy. A local physician, based on symptoms of fatigue, weight loss, and intermittent fever made this diagnosis. He was referred to an oncologist at the same hospital where his wife was employed. In contrast to the leukocytosis one would expect from a persistent infection, this patient was pancytopenic. However, chronic or overwhelming infection may, on occasions, have bone marrow suppression. The symptoms, the peripheral blood findings, and the splenomegaly are all consistent with a diagnosis of leukemia/lymphoma. Unfortunately, the presence of a holosystolic murmur, and the confirmation of mitral valve regurgitation, was disregarded. Since the vegetations on the mitral valve were not large, they were not identified on the echocardiogram. His bone marrow showed reactive changes, which are benign findings and not confirmatory of lymphoma or leukemia. He was short of breath, and this was thought to be due to COPD, rather than CHF. Thus, he was referred to a pulmonologist  for consultation, rather than a cardiologist. The diagnosis of active infectious Endocarditis was never entertained prior to his death several months later. Again, the lesson from this case is: if you do not think of the diagnosis, you will not make it.

Posted in: Endocarditis