Case 29-2004 — A 75-Year-Old Woman with Acute Onset of Chest Pain Followed by Fever
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《新英格兰医药杂志》
Presentation of Case
Dr. Claudia U. Chae: A 75-year-old woman was admitted to the hospital because of chest pain. One week before admission she had had an illness characterized by fever, headache, nausea, malaise, and anorexia. On the night before admission, she awoke with a sensation of heaviness in her chest, dyspnea, and sweating, without nausea, vomiting, palpitations, or syncope. There was no improvement with the administration of sublingual nitroglycerin. She was admitted to the hospital.
The patient had had exertional chest pain for several years, which had been treated and controlled with sublingual nitroglycerin. Forty months before admission, a cardiac ultrasonographic study showed mild aortic stenosis. Eleven months before admission, she had had a non–Q-wave myocardial infarction. Cardiac catheterization revealed 65 percent stenosis of the proximal right coronary artery and severe stenosis of a circumflex obtuse marginal branch; percutaneous transluminal coronary angioplasty was performed, with stent placement. A cardiac ultrasonographic examination disclosed aortic stenosis with a valve area of 1 cm2 and a mean gradient of 28 mm Hg; the left ventricular systolic function was normal. On the day after the placement of the stent, the patient had episodes of tachycardia associated with dizziness; an electrophysiological study showed an easily inducible typical atrioventricular nodal tachycardia, and radiofrequency ablation was performed.
The patient had a history of hypothyroidism and in the past had had a transient cerebral ischemic attack, which had been managed by performing a left carotid endarterectomy. Her medications were atenolol, lisinopril, fluvastatin, levothyroxine, promethazine, and aspirin. She drank alcohol occasionally and had smoked cigarettes in previous years. Her mother had had diabetes mellitus and heart disease, and her father had died at 67 years of age from a myocardial infarction.
On physical examination, the jugular venous pressure was normal. The temperature was 37°C, the heart rate 68 beats per minute, and the respiratory rate 16 breaths per minute. The blood pressure was 140/70 mm Hg. The carotid pulses were + bilaterally. The lungs were clear. A systolic murmur, grade 2 of 6, was heard at the right upper sternal border, radiating to both carotid arteries; no pericardial rub was detected. The abdomen was unremarkable. There was no peripheral edema; the femoral pulses were + to ++ without bruits, and the pedal pulses were ++. No focal neurologic deficit was detected.
The urine was positive for protein (++), ketones (+++), and bilirubin (+); the sediment contained 50 to 100 white cells, 3 to 5 red cells, and moderate amounts of bacteria per high-power field. The levels of urea nitrogen, creatinine, conjugated and total bilirubin, phosphorus, magnesium, electrolytes, aspartate aminotransferase, alanine aminotransferase, amylase, lipase, creatine kinase, and creatine kinase MB were all normal. Other laboratory values are shown in Table 1 and Table 2.
Table 1. Hematologic Laboratory Data.
Table 2. Blood Chemical Values.
An electrocardiogram showed a normal rhythm at a rate of 78 beats per minute and right bundle-branch block with left anterior hemiblock; repeated tracings revealed normal rhythm and right bundle-branch block, with ST-segment depression of 0.5 mm inferiorly and as much as 1 mm in leads V4 through V6. A chest radiograph showed cardiomegaly; the mediastinal contour was within normal limits, and the lungs were clear.
Specimens of blood and urine were obtained for culture, and levofloxacin was begun as treatment for a possible urinary tract infection. The patient was treated with aspirin, beta-blockers, nitrates, and morphine in the emergency room, and her initial chest pain resolved over the course of four hours. She had recurrent chest pain on the first hospital day and two further episodes on the fourth hospital day; the patient reported that the pain resembled the angina she had had in the past, and it appeared to respond to treatment with nitrates. The troponin T level was elevated, at 0.21 ng per milliliter, on admission; it decreased to 0.17 ng per milliliter on the next day, was 0.19 ng per milliliter on the fourth hospital day, and then subsequently declined. The levels of creatine kinase and creatine kinase MB remained normal. Minidose heparin was injected for prophylaxis against deep venous thrombosis.
Twelve hours after admission, the temperature rose to 38.5°C, and a planned cardiac catheterization was aborted. The temperature rose daily thereafter to between 38.4 and 39.3°C, accompanied by shaking chills. Chest radiographs revealed that the heart and mediastinum were normal; there was mild atelectasis in the right lower lobe but no evidence of pneumonia. On the third hospital day, computed tomographic (CT) scanning of the abdomen and pelvis revealed no abnormalities.
On the fifth hospital day, two of the six cultures of blood drawn on the second hospital day yielded gram-positive cocci in pairs and short chains, which were later identified as Streptococcus anginosus (S. milleri group). Treatment with vancomycin was begun. A transthoracic ultrasonographic study disclosed valvular aortic stenosis with calcification of all three leaflets. An echolucent area, 2.3 cm by 0.92 cm, was present anterior to the right coronary cusp (Figure 1A and Video Clip 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org), and several small mobile echodensities on the atrial and ventricular side of the cusps were seen (Figure 1B and Video Clip 2 in the Supplementary Appendix). The peak transaortic gradient was 36 mm Hg and the mean gradient 20 mm Hg. There was moderate aortic regurgitation as visualized on Doppler ultrasonography. There was symmetrical left ventricular hypertrophy; the size and systolic function of the left ventricular cavity were normal. CT scanning of the brain revealed no abnormalities. Treatment with intravenous gentamicin and vancomycin was begun, and levofloxacin was discontinued.
Figure 1. Echocardiograms.
A parasternal, long-axis view (Panel A) from the transthoracic echocardiogram shows a lucent area adjacent to the aortic root, indicating an abscess of 2.3 cm by 0.92 cm (arrows). A color Doppler study (Panel B) shows a jet of aortic regurgitation (yellow-orange) and aortic insufficiency (blue). A transesophageal echocardiographic view of the aortic-valve leaflets (Panel C) demonstrates a shaggy thickening consistent with valvular vegetations (arrows). A transesophageal echocardiogram view of the aortic-valve leaflets as highlighted in a color-flow Doppler study (Panel D) shows evidence of aortic insufficiency. LA denotes left atrium, Ao aorta, and AoV aortic valve.
On the sixth hospital day, a transesophageal cardiac ultrasonographic study disclosed thickening of the aortic root and a hypoechoic area anterior to the aortic valve. Mobile, hyperechoic masses consistent with vegetations were present on the right coronary cusp; the largest measured 0.75 cm by 0.46 cm and was attached to the right aortic leaflet (Figure 1C and Video Clip 3 in the Supplementary Appendix). No evidence of leaflet perforation or fistula formation was detected. There was Doppler evidence of moderate aortic regurgitation (Figure 1D and Video Clip 4 in the Supplementary Appendix). Left ventricular size and systolic function were normal. There was a small pericardial effusion with evidence of right atrial inversion during a major portion of the cardiac cycle, consistent with elevation of pericardial pressure. Another chest radiograph disclosed mild cardiomegaly with clear lungs. Penicillin G was substituted for vancomycin, in response to results of tests to determine the sensitivity of the organism. The spiking fevers and chills continued. The results of cultures of blood from the fifth and sixth hospital days were negative.
On the seventh hospital day, chest radiographs showed an enlarged cardiac silhouette and bilateral pleural effusions with associated atelectasis. The temperature rose to 39.3°C, with rigor.
Differential Diagnosis
Dr. Chae: This 75-year-old woman with a history of coronary artery disease and aortic stenosis came to the hospital with chest pain of recent onset. The initial impression of the cardiology team was that she had unstable angina with a non–Q-wave myocardial infarction. As we were about to perform cardiac catheterization, she had a shaking chill, and fever developed. A chest radiograph showed no evidence of pneumonia. Our differential diagnosis at this point included subacute bacterial endocarditis, myopericarditis, and, possibly, cardiac ischemia due to increased physiological demand in the context of a febrile illness. On the fifth day, we received a report that two blood cultures were positive for gram-positive cocci, which were later identified as S. anginosus (S. milleri group). We then became very concerned about endocarditis, changed her antibiotic coverage, and obtained cardiac ultrasonographic studies.
May we see the imaging studies?
Dr. Nadeem A. Afridi: A transthoracic echocardiogram obtained in the parasternal long axis reveals a pericardial effusion and an echolucent space, consistent with an abscess cavity 2.3 cm by 0.92 cm, in the anterior aortic-root wall (Figure 1A and Video Clip 1 in the Supplementary Appendix). The aortic valve is thickened, with an attached substance suspected to be vegetations. Color Doppler visualization shows moderate-to-severe aortic regurgitation with no flow in the space, suggesting no direct communication between the abscess cavity and the aortic lumen (Figure 1B and Video Clip 2 in the Supplementary Appendix).
A transesophageal echocardiogram again shows the echolucent space with a mild pericardial effusion, suggesting a diagnosis of pericarditis in the setting of endocarditis. The valve leaflets are ragged and thickened and prolapse slightly into the outflow tract, affecting the integrity of the valve (Figure 1C and Video Clip 3 in the Supplementary Appendix) and inducing severe regurgitation (Figure 1D and Video Clip 4 in the Supplementary Appendix).
Dr. Chae: At this point, we knew that the patient had endocarditis; we believed she was receiving appropriate antibiotic therapy, and the blood cultures became negative. However, the findings on the transesophageal echocardiogram were highly worrisome, and on the seventh day, her fever spiked again, and a chest radiograph showed an enlarged cardiac silhouette. At this point, I sought urgent consultation from my colleagues in infectious diseases and cardiothoracic surgery, who had been involved in the patient's care since the first echocardiogram was performed. I would like to invite Dr. Karchmer to give us his thoughts on further evaluation and management of this case.
Dr. Adolf W. Karchmer: In a case such as this, the infectious-disease consultant needs to address several questions. What is the significance of the organism isolated from the patient's blood? Does this patient have endocarditis, and if so, what would be the optimal antimicrobial therapy? What is the meaning of the persistent fever and the echolucent area in the upper septum anterior to the right coronary cusp? What adjunctive therapy would be indicated and why, and when should it begin?
This patient's blood cultures grew S. anginosus, a member of the S. milleri group. This is the collective designation for three species, S. intermedius, S. constellatus, and S. anginosus. The organisms in this group are often -hemolytic, but occasionally they can be -hemolytic or nonhemolytic. They are found among the flora of the oral cavity and the gastrointestinal tract and are associated with abscesses and soft-tissue infections, which are often polymicrobial, in the abdominal cavity, lower respiratory tract, orofacial and sinus area, and skin. In addition, they can cause hematogenous, monomicrobial abscesses in the brain, liver, spleen, subdural space, and bone, and occasionally endocarditis.1
Does this patient have endocarditis? The modified Duke criteria2 require the presence of two major criteria or one major and three minor criteria to establish a definite clinical diagnosis of endocarditis (Table 3). This case illustrates the value of echocardiography in making the diagnosis of endocarditis. Because neither peripheral manifestations of endocarditis nor a diastolic murmur indicative of new aortic regurgitation was detected on physical examination, it remained unclear until echocardiography was performed whether the patient had S. milleri bacteremia and a focal extravascular infection or endocarditis. The echocardiographic findings and the positive blood cultures meet major criteria. If, for the sake of argument, the type of organism and the degree of bacteremia are not considered sufficient for a major criterion to be met, the bacteremia would meet a minor criterion. In the latter case, the patient's findings would satisfy three minor criteria: bacteremia, a predisposing condition (aortic stenosis), and persistent fever; the echocardiographic findings would constitute a major criterion. Thus, by the Duke criteria, the patient had definite endocarditis.
Table 3. Modified Duke Criteria for Endocarditis.
Is S. anginosus a probable cause of this patient's endocarditis? Viridans streptococci cause 30 to 50 percent of episodes of native-valve endocarditis,3,4 and the S. milleri group probably accounts for 1 to 2 percent of cases overall. A study of infective endocarditis caused by organisms of the S. milleri group5 found that in 25 percent of the cases there were extracardiac suppurative foci of infection, 14 percent had intracardiac abscesses, and 90 percent had valvular regurgitation. These cardiac findings are similar to those in the patient under discussion.
Organisms of the S. milleri group are generally susceptible to penicillin, but they may be relatively penicillin-insensitive (with a minimal inhibitory concentration of more than 0.1 μg per milliliter).6,7 All of the organisms in the S. milleri group are susceptible to vancomycin. As was done in this case, I would initiate therapy with vancomycin, establish the MIC of penicillin, and — if the isolate were susceptible — treat the infection with high-dose penicillin in the range of 16 to 24 million U daily. It is reasonable to add gentamicin, an aminoglycoside, to penicillin treatment in an attempt to enhance the bactericidal activity of penicillin, as long as the organism is not highly resistant to aminoglycosides. If the organism had been relatively resistant to penicillin, treatment with the combination of penicillin and gentamicin or with vancomycin should be considered.
This patient's fever persisted after three days of adequate therapy. Without complications, the time to defervescence in cases of endocarditis due to viridans streptococci is usually three days; fever persists for more than five days in only 10 percent of cases, and all patients should be afebrile by day 7.8 Fever that persists after more than seven days of appropriate antimicrobial therapy has been associated with increased mortality.8
In the context of persistent fever, there are several possibilities to consider: extensive intracardiac infection (intracardiac abscess accounts for 33 to 46 percent of such infections), embolic complications (15 to 20 percent), and drug hypersensitivity (approximately 20 percent). Nosocomial events, such as catheter-related bacteremia, diarrhea induced by Clostridium difficile, or pulmonary emboli, can cause persistent fever, as can extracardiac foci of infection, such as splenic abscesses, renal abscesses, and abscesses in other areas that might require drainage or special attention.9,10 The latter would be an important consideration in this patient with S. milleri endocarditis. We also should be concerned about inadequate therapy, either because the organism is resistant or because the initial microbiologic data were not accurate.
Abscesses are more common with infection of the aortic valve than with infection of other valves, and may be associated with new regurgitation, pericarditis, and conduction abnormalities.11,12,13,14 Conduction abnormalities were present in this patient but were preexisting and not progressive; however, the transthoracic echocardiogram showed an abscess. Transesophageal echocardiography is markedly more sensitive than transthoracic echocardiography for demonstrating intracardiac abscesses, with sensitivity rates of 87 to 100 percent and 28 to 36 percent, respectively.15,16 The echocardiogram revealed a newly dysfunctional aortic valve, continued normal left ventricular function, a perivalvular abscess, and a pericardial effusion with right atrial inversion during a substantial portion of the cardiac cycle. A chest radiograph suggested an increase in cardiomegaly or a pericardial effusion and bilateral pleural effusions. Taken together, these findings suggest an urgent need for cardiac surgery to débride the abscess and restore aortic-valve function.
Can this surgery be performed during active endocarditis? Three recent studies show that for patients with active native-valve or prosthetic-valve endocarditis who were operated on during the course of antibiotic therapy — often with recent positive cultures of blood or material from the site of infection — there was relatively low operative mortality.17,18,19 Recurrent endocarditis was infrequent. The timing of surgical intervention is very important. It is the patient's preoperative hemodynamic status that predicts postoperative mortality rates (not the duration of preoperative antibiotic therapy), and this should be the chief consideration in scheduling surgery. Delaying surgery when there is increasing ventricular decompensation may lead to an increase in the rate of mortality. Intracardiac abscesses are rarely cured by antibiotic therapy, particularly in the context of persistent fever, and delay may allow more tissue destruction by uncontrolled infection. This patient's abscess could rupture into the pericardial space or form an intracardiac fistula, or the aortic regurgitation could worsen. Finally, there is risk of an embolic complication.
In summary, this patient had intracardiac disease that would not respond to antimicrobial therapy, and the responsible organism, the S. milleri group, can cause infection in other sites, such as the liver and brain. Although surgery carries a small risk of death and of recurrent endocarditis, at this point I would recommend urgent cardiac surgical intervention.
Discussion of Management
Dr. Chae: I asked Dr. Torchiana to discuss how the decision was made whether and when to take this patient to surgery.
Dr. David F. Torchiana: Most patients with native-valve endocarditis are treated with antimicrobial therapy and do not need surgery.20,21 Surgery is most clearly indicated when there has been destruction of tissue by infection and when valvular insufficiency and congestive heart failure develop. Other possible indications for surgery in endocarditis are a resistant organism, persistent sepsis, extension of infection beyond the valve, and recurrent emboli. The term "complicated endocarditis" has been used to differentiate those cases in which one or more of these criteria are present.21 This patient had only modest aortic insufficiency, with little, if any, congestive heart failure. The infecting streptococcal organism was relatively sensitive, but she had extensive infection into the myocardium and persistent sepsis.
With a case of acute endocarditis and valvular insufficiency, the temptation is to treat with antibiotics and delay surgery if the patient's condition can be managed safely in the interim. Gaining control of acute sepsis renders surgery and cardiopulmonary bypass less hazardous. Sterilization of the field may reduce the risk of recurrent infection, especially if foreign material such as a valve prosthesis will be introduced. A sterilized field will have better tissue integrity, particularly if three or four weeks of antibiotic therapy can be instituted before surgery, allowing time for scarring and fibrosis to develop, which helps the valve sutures to hold.
There are pitfalls in delaying surgery, however, and vigilant follow-up is needed if this strategy is undertaken. Patients with aortic insufficiency, particularly younger patients, may appear to tolerate a severe valve lesion with relatively little evidence of clinical compromise, but their status may in reality be quite precarious. Recurrent emboli may be difficult to detect, particularly visceral emboli or central nervous system emboli in patients who already have an altered mental status. These issues must be kept in mind when following a patient with endocarditis, and they must be factored into decisions on the timing of surgery. As a general principle, patients with complicated endocarditis do better with surgery than without it, and delay makes no sense if the patient's health is deteriorating. In this patient, because of the extensive myocardial infection and persistent sepsis, I thought that surgery was indicated.
Once we decided that this patient would probably require surgery, a decision needed to be made whether to perform coronary angiography. In this case, the patient had two indications for coronary angiography. The first was known coronary artery disease and a prior coronary intervention. Obviously, the potential for new or progressive occlusive disease made coronary angiography beneficial in surgical planning. Second, this patient had an aortic-root abscess; knowledge of the relative size and course of the coronary arteries can be helpful in planning a complex aortic-root reconstruction. In the absence of risk factors for coronary disease and in younger patients, echocardiography is sufficient preoperative imaging. The necessity of administering a contrast agent to an already sick patient and the risk of causing embolization of aortic-valve vegetations are relative contraindications to angiography. Newer techniques for noninvasive coronary imaging, such as CT or magnetic resonance angiography, may have a role in management in the future. In this patient, we opted to do preoperative coronary angiography, which disclosed a 40 percent stenosis of the left main coronary artery and a 50 percent stenosis of the proximal right coronary artery.
The principles of valve surgery in endocarditis have changed relatively little since the first reported surgery in 1965.22 Infected tissue should be thoroughly débrided and cultured. There is no clear advantage in terms of the risk of recurrent infection with either mechanical or tissue prostheses.18,23,24,25 The lack of a need for anticoagulant treatment may make a tissue prosthesis a safer choice early on in complicated cases, in sick patients, and in intravenous-drug users in whom noncompliance increases the risks associated with warfarin.
The choice of prosthesis for patients with endocarditis is based on the same criteria as are used in the absence of infection. Valves that can be repaired should be repaired. When replacement is necessary, tissue valves are used in older patients and mechanical prostheses in younger patients. In cases of complicated infection of the aortic root, such as this, implantation of an aortic homograft (a nonviable, cryopreserved human aortic root) appears to be associated with better early results and a lower risk of recurrent infection.26 Both the pliability of the homograft tissue and the fact that the infected field is radically excluded from the bloodstream in this procedure probably contribute to its success rate in spite of the greater associated technical complexity.
At surgery, we found a large aortic-root abscess extending from the left main artery around to the origin of the right coronary artery, with purulent destruction of part of the interventricular septum. Because of the extent of tissue destruction, we used a homograft for root replacement. The left main coronary artery was reimplanted. The origin of the right coronary artery was surrounded by inflammatory tissue and induration, which precluded mobilization. This vessel was ligated proximally and bypassed with a saphenous-vein graft. The patient recovered uneventfully, was discharged on the sixth postoperative day, and went on to complete a six-week course of intravenous antibiotics. She is alive and well a year later, with no recurrence of endocarditis.
Clinical Diagnosis
Acute bacterial endocarditis due to S. anginosus (S. milleri group), with myocardial abscess.
Pathological Discussion
Dr. Stuart L. Houser: The trileaflet aortic valve was thickened and had focal areas of calcification27 (Figure 2A). Vegetations were present that contained fibrin, platelets, neutrophils, and invading colonies of bacteria, findings that are characteristic of acute bacterial endocarditis (Figure 2B). The organisms were gram-positive cocci, consistent with the S. anginosus (S. milleri group) cultured in the patient's blood.
Figure 2. Resected Aortic Valve.
An aortic-valve leaflet (Panel A) is thickened and contains blue areas of dystrophic calcification (hematoxylin and eosin). There is acute endocarditis (Panel B), with neutrophils and gram-positive bacteria (Brown–Hopps stain).
This patient's aortic-root abscess indicated tissue destruction by a virulent organism. In a study of the pathogenesis of abscess formation in infections by S. milleri, Wanahita et al.28 observed that S. milleri stimulated neutrophil migration to a lesser extent than other viridans streptococci and than Staphylococcus aureus and survived better within human neutrophils.
Dr. Chae: The patient's chest pain, positive troponin levels, and electrocardiographic changes on admission have several possible causes. Because of her known coronary artery disease, she may have had subendocardial ischemia in the setting of increased physiological demand from her infection. Alternatively, if the aortic-root abscess had already formed, her acute presentation could have been due to infectious perimyocarditis. There are several complications of endocarditis that may result in coronary ischemia. Rarely, an aortic-root abscess can cause coronary-artery compression.29 The most commonly described complication is septic coronary embolism. This occurs in 22 to 50 percent of cases of endocarditis; whereas the majority (up to 65 percent) involve the central nervous system, other major arterial beds may be involved, including the coronary arteries.30 Septic emboli are more frequent with mitral-valve infections (25 percent) than with aortic-valve infections (10 percent), and with other organisms (such as S. aureus and candida species) than with S. milleri.30 In streptococcal endocarditis, larger vegetations are more likely to embolize, whereas with staphylococcal or fungal endocarditis, the risk is independent of vegetation size.31 Another rare complication is the formation of a mycotic coronary aneurysm with in situ thrombosis and embolization,32 although this type of aneurysm most commonly involves the intracranial arteries.30
This case illustrates the need for continued vigilance by clinicians with respect to the diagnosis of endocarditis and its possible complications.
Anatomical Diagnosis
Acute bacterial endocarditis with aortic-root abscess, due to infection by S. anginosus (S. milleri group).
Source Information
From the Division of Infectious Diseases, Beth Israel Deaconess Medical Center (A.W.K.); the Divisions of Cardiac Surgery (D.F.T.), and Cardiology (C.U.C., N.A.A.), and the Department of Pathology (S.L.H.), Massachusetts General Hospital; and the Departments of Surgery (D.F.T.), Medicine (C.U.C., A.W.K., N.A.A.), and Pathology (S.L.H.), Harvard Medical School — all in Boston.
References
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Related Letters:
Case 29-2004: A Woman with Acute Onset of Chest Pain and Fever
Medford A. R.L., Chae C.(Adolf W. Karchmer, M.D., )
Dr. Claudia U. Chae: A 75-year-old woman was admitted to the hospital because of chest pain. One week before admission she had had an illness characterized by fever, headache, nausea, malaise, and anorexia. On the night before admission, she awoke with a sensation of heaviness in her chest, dyspnea, and sweating, without nausea, vomiting, palpitations, or syncope. There was no improvement with the administration of sublingual nitroglycerin. She was admitted to the hospital.
The patient had had exertional chest pain for several years, which had been treated and controlled with sublingual nitroglycerin. Forty months before admission, a cardiac ultrasonographic study showed mild aortic stenosis. Eleven months before admission, she had had a non–Q-wave myocardial infarction. Cardiac catheterization revealed 65 percent stenosis of the proximal right coronary artery and severe stenosis of a circumflex obtuse marginal branch; percutaneous transluminal coronary angioplasty was performed, with stent placement. A cardiac ultrasonographic examination disclosed aortic stenosis with a valve area of 1 cm2 and a mean gradient of 28 mm Hg; the left ventricular systolic function was normal. On the day after the placement of the stent, the patient had episodes of tachycardia associated with dizziness; an electrophysiological study showed an easily inducible typical atrioventricular nodal tachycardia, and radiofrequency ablation was performed.
The patient had a history of hypothyroidism and in the past had had a transient cerebral ischemic attack, which had been managed by performing a left carotid endarterectomy. Her medications were atenolol, lisinopril, fluvastatin, levothyroxine, promethazine, and aspirin. She drank alcohol occasionally and had smoked cigarettes in previous years. Her mother had had diabetes mellitus and heart disease, and her father had died at 67 years of age from a myocardial infarction.
On physical examination, the jugular venous pressure was normal. The temperature was 37°C, the heart rate 68 beats per minute, and the respiratory rate 16 breaths per minute. The blood pressure was 140/70 mm Hg. The carotid pulses were + bilaterally. The lungs were clear. A systolic murmur, grade 2 of 6, was heard at the right upper sternal border, radiating to both carotid arteries; no pericardial rub was detected. The abdomen was unremarkable. There was no peripheral edema; the femoral pulses were + to ++ without bruits, and the pedal pulses were ++. No focal neurologic deficit was detected.
The urine was positive for protein (++), ketones (+++), and bilirubin (+); the sediment contained 50 to 100 white cells, 3 to 5 red cells, and moderate amounts of bacteria per high-power field. The levels of urea nitrogen, creatinine, conjugated and total bilirubin, phosphorus, magnesium, electrolytes, aspartate aminotransferase, alanine aminotransferase, amylase, lipase, creatine kinase, and creatine kinase MB were all normal. Other laboratory values are shown in Table 1 and Table 2.
Table 1. Hematologic Laboratory Data.
Table 2. Blood Chemical Values.
An electrocardiogram showed a normal rhythm at a rate of 78 beats per minute and right bundle-branch block with left anterior hemiblock; repeated tracings revealed normal rhythm and right bundle-branch block, with ST-segment depression of 0.5 mm inferiorly and as much as 1 mm in leads V4 through V6. A chest radiograph showed cardiomegaly; the mediastinal contour was within normal limits, and the lungs were clear.
Specimens of blood and urine were obtained for culture, and levofloxacin was begun as treatment for a possible urinary tract infection. The patient was treated with aspirin, beta-blockers, nitrates, and morphine in the emergency room, and her initial chest pain resolved over the course of four hours. She had recurrent chest pain on the first hospital day and two further episodes on the fourth hospital day; the patient reported that the pain resembled the angina she had had in the past, and it appeared to respond to treatment with nitrates. The troponin T level was elevated, at 0.21 ng per milliliter, on admission; it decreased to 0.17 ng per milliliter on the next day, was 0.19 ng per milliliter on the fourth hospital day, and then subsequently declined. The levels of creatine kinase and creatine kinase MB remained normal. Minidose heparin was injected for prophylaxis against deep venous thrombosis.
Twelve hours after admission, the temperature rose to 38.5°C, and a planned cardiac catheterization was aborted. The temperature rose daily thereafter to between 38.4 and 39.3°C, accompanied by shaking chills. Chest radiographs revealed that the heart and mediastinum were normal; there was mild atelectasis in the right lower lobe but no evidence of pneumonia. On the third hospital day, computed tomographic (CT) scanning of the abdomen and pelvis revealed no abnormalities.
On the fifth hospital day, two of the six cultures of blood drawn on the second hospital day yielded gram-positive cocci in pairs and short chains, which were later identified as Streptococcus anginosus (S. milleri group). Treatment with vancomycin was begun. A transthoracic ultrasonographic study disclosed valvular aortic stenosis with calcification of all three leaflets. An echolucent area, 2.3 cm by 0.92 cm, was present anterior to the right coronary cusp (Figure 1A and Video Clip 1 in the Supplementary Appendix, available with the full text of this article at www.nejm.org), and several small mobile echodensities on the atrial and ventricular side of the cusps were seen (Figure 1B and Video Clip 2 in the Supplementary Appendix). The peak transaortic gradient was 36 mm Hg and the mean gradient 20 mm Hg. There was moderate aortic regurgitation as visualized on Doppler ultrasonography. There was symmetrical left ventricular hypertrophy; the size and systolic function of the left ventricular cavity were normal. CT scanning of the brain revealed no abnormalities. Treatment with intravenous gentamicin and vancomycin was begun, and levofloxacin was discontinued.
Figure 1. Echocardiograms.
A parasternal, long-axis view (Panel A) from the transthoracic echocardiogram shows a lucent area adjacent to the aortic root, indicating an abscess of 2.3 cm by 0.92 cm (arrows). A color Doppler study (Panel B) shows a jet of aortic regurgitation (yellow-orange) and aortic insufficiency (blue). A transesophageal echocardiographic view of the aortic-valve leaflets (Panel C) demonstrates a shaggy thickening consistent with valvular vegetations (arrows). A transesophageal echocardiogram view of the aortic-valve leaflets as highlighted in a color-flow Doppler study (Panel D) shows evidence of aortic insufficiency. LA denotes left atrium, Ao aorta, and AoV aortic valve.
On the sixth hospital day, a transesophageal cardiac ultrasonographic study disclosed thickening of the aortic root and a hypoechoic area anterior to the aortic valve. Mobile, hyperechoic masses consistent with vegetations were present on the right coronary cusp; the largest measured 0.75 cm by 0.46 cm and was attached to the right aortic leaflet (Figure 1C and Video Clip 3 in the Supplementary Appendix). No evidence of leaflet perforation or fistula formation was detected. There was Doppler evidence of moderate aortic regurgitation (Figure 1D and Video Clip 4 in the Supplementary Appendix). Left ventricular size and systolic function were normal. There was a small pericardial effusion with evidence of right atrial inversion during a major portion of the cardiac cycle, consistent with elevation of pericardial pressure. Another chest radiograph disclosed mild cardiomegaly with clear lungs. Penicillin G was substituted for vancomycin, in response to results of tests to determine the sensitivity of the organism. The spiking fevers and chills continued. The results of cultures of blood from the fifth and sixth hospital days were negative.
On the seventh hospital day, chest radiographs showed an enlarged cardiac silhouette and bilateral pleural effusions with associated atelectasis. The temperature rose to 39.3°C, with rigor.
Differential Diagnosis
Dr. Chae: This 75-year-old woman with a history of coronary artery disease and aortic stenosis came to the hospital with chest pain of recent onset. The initial impression of the cardiology team was that she had unstable angina with a non–Q-wave myocardial infarction. As we were about to perform cardiac catheterization, she had a shaking chill, and fever developed. A chest radiograph showed no evidence of pneumonia. Our differential diagnosis at this point included subacute bacterial endocarditis, myopericarditis, and, possibly, cardiac ischemia due to increased physiological demand in the context of a febrile illness. On the fifth day, we received a report that two blood cultures were positive for gram-positive cocci, which were later identified as S. anginosus (S. milleri group). We then became very concerned about endocarditis, changed her antibiotic coverage, and obtained cardiac ultrasonographic studies.
May we see the imaging studies?
Dr. Nadeem A. Afridi: A transthoracic echocardiogram obtained in the parasternal long axis reveals a pericardial effusion and an echolucent space, consistent with an abscess cavity 2.3 cm by 0.92 cm, in the anterior aortic-root wall (Figure 1A and Video Clip 1 in the Supplementary Appendix). The aortic valve is thickened, with an attached substance suspected to be vegetations. Color Doppler visualization shows moderate-to-severe aortic regurgitation with no flow in the space, suggesting no direct communication between the abscess cavity and the aortic lumen (Figure 1B and Video Clip 2 in the Supplementary Appendix).
A transesophageal echocardiogram again shows the echolucent space with a mild pericardial effusion, suggesting a diagnosis of pericarditis in the setting of endocarditis. The valve leaflets are ragged and thickened and prolapse slightly into the outflow tract, affecting the integrity of the valve (Figure 1C and Video Clip 3 in the Supplementary Appendix) and inducing severe regurgitation (Figure 1D and Video Clip 4 in the Supplementary Appendix).
Dr. Chae: At this point, we knew that the patient had endocarditis; we believed she was receiving appropriate antibiotic therapy, and the blood cultures became negative. However, the findings on the transesophageal echocardiogram were highly worrisome, and on the seventh day, her fever spiked again, and a chest radiograph showed an enlarged cardiac silhouette. At this point, I sought urgent consultation from my colleagues in infectious diseases and cardiothoracic surgery, who had been involved in the patient's care since the first echocardiogram was performed. I would like to invite Dr. Karchmer to give us his thoughts on further evaluation and management of this case.
Dr. Adolf W. Karchmer: In a case such as this, the infectious-disease consultant needs to address several questions. What is the significance of the organism isolated from the patient's blood? Does this patient have endocarditis, and if so, what would be the optimal antimicrobial therapy? What is the meaning of the persistent fever and the echolucent area in the upper septum anterior to the right coronary cusp? What adjunctive therapy would be indicated and why, and when should it begin?
This patient's blood cultures grew S. anginosus, a member of the S. milleri group. This is the collective designation for three species, S. intermedius, S. constellatus, and S. anginosus. The organisms in this group are often -hemolytic, but occasionally they can be -hemolytic or nonhemolytic. They are found among the flora of the oral cavity and the gastrointestinal tract and are associated with abscesses and soft-tissue infections, which are often polymicrobial, in the abdominal cavity, lower respiratory tract, orofacial and sinus area, and skin. In addition, they can cause hematogenous, monomicrobial abscesses in the brain, liver, spleen, subdural space, and bone, and occasionally endocarditis.1
Does this patient have endocarditis? The modified Duke criteria2 require the presence of two major criteria or one major and three minor criteria to establish a definite clinical diagnosis of endocarditis (Table 3). This case illustrates the value of echocardiography in making the diagnosis of endocarditis. Because neither peripheral manifestations of endocarditis nor a diastolic murmur indicative of new aortic regurgitation was detected on physical examination, it remained unclear until echocardiography was performed whether the patient had S. milleri bacteremia and a focal extravascular infection or endocarditis. The echocardiographic findings and the positive blood cultures meet major criteria. If, for the sake of argument, the type of organism and the degree of bacteremia are not considered sufficient for a major criterion to be met, the bacteremia would meet a minor criterion. In the latter case, the patient's findings would satisfy three minor criteria: bacteremia, a predisposing condition (aortic stenosis), and persistent fever; the echocardiographic findings would constitute a major criterion. Thus, by the Duke criteria, the patient had definite endocarditis.
Table 3. Modified Duke Criteria for Endocarditis.
Is S. anginosus a probable cause of this patient's endocarditis? Viridans streptococci cause 30 to 50 percent of episodes of native-valve endocarditis,3,4 and the S. milleri group probably accounts for 1 to 2 percent of cases overall. A study of infective endocarditis caused by organisms of the S. milleri group5 found that in 25 percent of the cases there were extracardiac suppurative foci of infection, 14 percent had intracardiac abscesses, and 90 percent had valvular regurgitation. These cardiac findings are similar to those in the patient under discussion.
Organisms of the S. milleri group are generally susceptible to penicillin, but they may be relatively penicillin-insensitive (with a minimal inhibitory concentration of more than 0.1 μg per milliliter).6,7 All of the organisms in the S. milleri group are susceptible to vancomycin. As was done in this case, I would initiate therapy with vancomycin, establish the MIC of penicillin, and — if the isolate were susceptible — treat the infection with high-dose penicillin in the range of 16 to 24 million U daily. It is reasonable to add gentamicin, an aminoglycoside, to penicillin treatment in an attempt to enhance the bactericidal activity of penicillin, as long as the organism is not highly resistant to aminoglycosides. If the organism had been relatively resistant to penicillin, treatment with the combination of penicillin and gentamicin or with vancomycin should be considered.
This patient's fever persisted after three days of adequate therapy. Without complications, the time to defervescence in cases of endocarditis due to viridans streptococci is usually three days; fever persists for more than five days in only 10 percent of cases, and all patients should be afebrile by day 7.8 Fever that persists after more than seven days of appropriate antimicrobial therapy has been associated with increased mortality.8
In the context of persistent fever, there are several possibilities to consider: extensive intracardiac infection (intracardiac abscess accounts for 33 to 46 percent of such infections), embolic complications (15 to 20 percent), and drug hypersensitivity (approximately 20 percent). Nosocomial events, such as catheter-related bacteremia, diarrhea induced by Clostridium difficile, or pulmonary emboli, can cause persistent fever, as can extracardiac foci of infection, such as splenic abscesses, renal abscesses, and abscesses in other areas that might require drainage or special attention.9,10 The latter would be an important consideration in this patient with S. milleri endocarditis. We also should be concerned about inadequate therapy, either because the organism is resistant or because the initial microbiologic data were not accurate.
Abscesses are more common with infection of the aortic valve than with infection of other valves, and may be associated with new regurgitation, pericarditis, and conduction abnormalities.11,12,13,14 Conduction abnormalities were present in this patient but were preexisting and not progressive; however, the transthoracic echocardiogram showed an abscess. Transesophageal echocardiography is markedly more sensitive than transthoracic echocardiography for demonstrating intracardiac abscesses, with sensitivity rates of 87 to 100 percent and 28 to 36 percent, respectively.15,16 The echocardiogram revealed a newly dysfunctional aortic valve, continued normal left ventricular function, a perivalvular abscess, and a pericardial effusion with right atrial inversion during a substantial portion of the cardiac cycle. A chest radiograph suggested an increase in cardiomegaly or a pericardial effusion and bilateral pleural effusions. Taken together, these findings suggest an urgent need for cardiac surgery to débride the abscess and restore aortic-valve function.
Can this surgery be performed during active endocarditis? Three recent studies show that for patients with active native-valve or prosthetic-valve endocarditis who were operated on during the course of antibiotic therapy — often with recent positive cultures of blood or material from the site of infection — there was relatively low operative mortality.17,18,19 Recurrent endocarditis was infrequent. The timing of surgical intervention is very important. It is the patient's preoperative hemodynamic status that predicts postoperative mortality rates (not the duration of preoperative antibiotic therapy), and this should be the chief consideration in scheduling surgery. Delaying surgery when there is increasing ventricular decompensation may lead to an increase in the rate of mortality. Intracardiac abscesses are rarely cured by antibiotic therapy, particularly in the context of persistent fever, and delay may allow more tissue destruction by uncontrolled infection. This patient's abscess could rupture into the pericardial space or form an intracardiac fistula, or the aortic regurgitation could worsen. Finally, there is risk of an embolic complication.
In summary, this patient had intracardiac disease that would not respond to antimicrobial therapy, and the responsible organism, the S. milleri group, can cause infection in other sites, such as the liver and brain. Although surgery carries a small risk of death and of recurrent endocarditis, at this point I would recommend urgent cardiac surgical intervention.
Discussion of Management
Dr. Chae: I asked Dr. Torchiana to discuss how the decision was made whether and when to take this patient to surgery.
Dr. David F. Torchiana: Most patients with native-valve endocarditis are treated with antimicrobial therapy and do not need surgery.20,21 Surgery is most clearly indicated when there has been destruction of tissue by infection and when valvular insufficiency and congestive heart failure develop. Other possible indications for surgery in endocarditis are a resistant organism, persistent sepsis, extension of infection beyond the valve, and recurrent emboli. The term "complicated endocarditis" has been used to differentiate those cases in which one or more of these criteria are present.21 This patient had only modest aortic insufficiency, with little, if any, congestive heart failure. The infecting streptococcal organism was relatively sensitive, but she had extensive infection into the myocardium and persistent sepsis.
With a case of acute endocarditis and valvular insufficiency, the temptation is to treat with antibiotics and delay surgery if the patient's condition can be managed safely in the interim. Gaining control of acute sepsis renders surgery and cardiopulmonary bypass less hazardous. Sterilization of the field may reduce the risk of recurrent infection, especially if foreign material such as a valve prosthesis will be introduced. A sterilized field will have better tissue integrity, particularly if three or four weeks of antibiotic therapy can be instituted before surgery, allowing time for scarring and fibrosis to develop, which helps the valve sutures to hold.
There are pitfalls in delaying surgery, however, and vigilant follow-up is needed if this strategy is undertaken. Patients with aortic insufficiency, particularly younger patients, may appear to tolerate a severe valve lesion with relatively little evidence of clinical compromise, but their status may in reality be quite precarious. Recurrent emboli may be difficult to detect, particularly visceral emboli or central nervous system emboli in patients who already have an altered mental status. These issues must be kept in mind when following a patient with endocarditis, and they must be factored into decisions on the timing of surgery. As a general principle, patients with complicated endocarditis do better with surgery than without it, and delay makes no sense if the patient's health is deteriorating. In this patient, because of the extensive myocardial infection and persistent sepsis, I thought that surgery was indicated.
Once we decided that this patient would probably require surgery, a decision needed to be made whether to perform coronary angiography. In this case, the patient had two indications for coronary angiography. The first was known coronary artery disease and a prior coronary intervention. Obviously, the potential for new or progressive occlusive disease made coronary angiography beneficial in surgical planning. Second, this patient had an aortic-root abscess; knowledge of the relative size and course of the coronary arteries can be helpful in planning a complex aortic-root reconstruction. In the absence of risk factors for coronary disease and in younger patients, echocardiography is sufficient preoperative imaging. The necessity of administering a contrast agent to an already sick patient and the risk of causing embolization of aortic-valve vegetations are relative contraindications to angiography. Newer techniques for noninvasive coronary imaging, such as CT or magnetic resonance angiography, may have a role in management in the future. In this patient, we opted to do preoperative coronary angiography, which disclosed a 40 percent stenosis of the left main coronary artery and a 50 percent stenosis of the proximal right coronary artery.
The principles of valve surgery in endocarditis have changed relatively little since the first reported surgery in 1965.22 Infected tissue should be thoroughly débrided and cultured. There is no clear advantage in terms of the risk of recurrent infection with either mechanical or tissue prostheses.18,23,24,25 The lack of a need for anticoagulant treatment may make a tissue prosthesis a safer choice early on in complicated cases, in sick patients, and in intravenous-drug users in whom noncompliance increases the risks associated with warfarin.
The choice of prosthesis for patients with endocarditis is based on the same criteria as are used in the absence of infection. Valves that can be repaired should be repaired. When replacement is necessary, tissue valves are used in older patients and mechanical prostheses in younger patients. In cases of complicated infection of the aortic root, such as this, implantation of an aortic homograft (a nonviable, cryopreserved human aortic root) appears to be associated with better early results and a lower risk of recurrent infection.26 Both the pliability of the homograft tissue and the fact that the infected field is radically excluded from the bloodstream in this procedure probably contribute to its success rate in spite of the greater associated technical complexity.
At surgery, we found a large aortic-root abscess extending from the left main artery around to the origin of the right coronary artery, with purulent destruction of part of the interventricular septum. Because of the extent of tissue destruction, we used a homograft for root replacement. The left main coronary artery was reimplanted. The origin of the right coronary artery was surrounded by inflammatory tissue and induration, which precluded mobilization. This vessel was ligated proximally and bypassed with a saphenous-vein graft. The patient recovered uneventfully, was discharged on the sixth postoperative day, and went on to complete a six-week course of intravenous antibiotics. She is alive and well a year later, with no recurrence of endocarditis.
Clinical Diagnosis
Acute bacterial endocarditis due to S. anginosus (S. milleri group), with myocardial abscess.
Pathological Discussion
Dr. Stuart L. Houser: The trileaflet aortic valve was thickened and had focal areas of calcification27 (Figure 2A). Vegetations were present that contained fibrin, platelets, neutrophils, and invading colonies of bacteria, findings that are characteristic of acute bacterial endocarditis (Figure 2B). The organisms were gram-positive cocci, consistent with the S. anginosus (S. milleri group) cultured in the patient's blood.
Figure 2. Resected Aortic Valve.
An aortic-valve leaflet (Panel A) is thickened and contains blue areas of dystrophic calcification (hematoxylin and eosin). There is acute endocarditis (Panel B), with neutrophils and gram-positive bacteria (Brown–Hopps stain).
This patient's aortic-root abscess indicated tissue destruction by a virulent organism. In a study of the pathogenesis of abscess formation in infections by S. milleri, Wanahita et al.28 observed that S. milleri stimulated neutrophil migration to a lesser extent than other viridans streptococci and than Staphylococcus aureus and survived better within human neutrophils.
Dr. Chae: The patient's chest pain, positive troponin levels, and electrocardiographic changes on admission have several possible causes. Because of her known coronary artery disease, she may have had subendocardial ischemia in the setting of increased physiological demand from her infection. Alternatively, if the aortic-root abscess had already formed, her acute presentation could have been due to infectious perimyocarditis. There are several complications of endocarditis that may result in coronary ischemia. Rarely, an aortic-root abscess can cause coronary-artery compression.29 The most commonly described complication is septic coronary embolism. This occurs in 22 to 50 percent of cases of endocarditis; whereas the majority (up to 65 percent) involve the central nervous system, other major arterial beds may be involved, including the coronary arteries.30 Septic emboli are more frequent with mitral-valve infections (25 percent) than with aortic-valve infections (10 percent), and with other organisms (such as S. aureus and candida species) than with S. milleri.30 In streptococcal endocarditis, larger vegetations are more likely to embolize, whereas with staphylococcal or fungal endocarditis, the risk is independent of vegetation size.31 Another rare complication is the formation of a mycotic coronary aneurysm with in situ thrombosis and embolization,32 although this type of aneurysm most commonly involves the intracranial arteries.30
This case illustrates the need for continued vigilance by clinicians with respect to the diagnosis of endocarditis and its possible complications.
Anatomical Diagnosis
Acute bacterial endocarditis with aortic-root abscess, due to infection by S. anginosus (S. milleri group).
Source Information
From the Division of Infectious Diseases, Beth Israel Deaconess Medical Center (A.W.K.); the Divisions of Cardiac Surgery (D.F.T.), and Cardiology (C.U.C., N.A.A.), and the Department of Pathology (S.L.H.), Massachusetts General Hospital; and the Departments of Surgery (D.F.T.), Medicine (C.U.C., A.W.K., N.A.A.), and Pathology (S.L.H.), Harvard Medical School — all in Boston.
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Related Letters:
Case 29-2004: A Woman with Acute Onset of Chest Pain and Fever
Medford A. R.L., Chae C.(Adolf W. Karchmer, M.D., )