The Role of Two-Dimensional Echocardiography in the Diagnosis of Ineffective Endocarditis Andrew J. Burger, M.D. Brenda Peart, M.D. Haytham Jabi, M.D. and C. Robert Touchon, M.D.
HUNTINGTON, WEST VIRGINIA
A bstract Two-dimensional echocardiography has had a significant impact on and is considered the technique of choice for the diagnosis and management of infective endocarditis. Over a thirty-six month period, 106 patients were evaluated by echocardiography for the possibility of endocarditis. The diagnosis of endocarditis was determined by strict clinical and laboratory criteria. All clinical histories, blood cultures, echocardiograms, and autopsy results were reviewed. Five echocardiograms were technically inadequate, resulting in a study population of 101 patients. The age of the patients ranged from forty-five days to eighty-eight years (mean fifty-seven years). The clinical manifestations of endocarditis included fever (83%), chills (60%), congestive heart failure (25%), and splenomegaly (18%). Twelve patients had preexisting valvular or congenital heart disease. Gram-positive cocci were the most common microorganisms. Complications included mitral regurgitation, subarachnoid hemorrhage, renal infarction, stroke, and a pulmonary embolus. The patients were divided into two groups: Group I consisted of 36 patients with definite vegetations by echocardiography, and Group II had 65 patients with no vegetations. In Group I, acute infective endocarditis was present in 35 patients, whereas only 4 patients had endocarditis in Group II. The sensitivity of two-dimensional echocardiography for detecting endocarditis was 90%. The specificity was 98%. The predictive accuracy for a positive test was 97%, and the predictive accuracy for a negative test was 94%. Thus, two-dimensional echocardiography appears to have a high sensitivity, specificity, and predictive value in the evaluation of patients with suspected endocarditis. From the Division of Cardiology, Department of Medicine, Marshall University School of Medicine and Veteran’s Administration Medical Center, Huntington, West Virginia Presented at the 38th Annual Meeting of the American College of Angiology, Atlanta, Georgia, October, 1990.
552
553 Introduction The direct noninvasive visualization of valvular vegetations by means of echocardiography has been an exciting development in the evaluation of patients with infective endocarditis. In 1973, Dillon’ and Spangled described for the first time echocardiographic manifestations of valvular vegetations. Subsequently, numerous other reports have confirmed the usefulness of this technique.’-&dquo; However, the reliability of two-dimensional echocardiography in the diagnosis of infective endocarditis requires careful assessment. Most older published data have been based on M-mode echocardiography, which is inferior to two-dimensional echocardiographic techniques, especially in visualizing certain cardiac structures such as the tricuspid or pulmonic valves. Furthermore, most of the published studies&dquo;-&dquo; have presented rather short series of patients ranging from 6 to 32. Only a few reports 11-21 of specific subgroups with endocarditis have evaluated larger numbers of patients. Our study was, therefore, undertaken to evaluate in a large group of patients the sensitivity, specificity, and predictive value of two-dimensional echocardiography in the diagnosis of infective endocarditis.
Materials and Methods Over a thirty-six month period, patients referred to our echocardiographic laboratories for the possibility of infective endocarditis were eligible for the study. The admission criteria included the following: (1) Well-documented clinical histories, (2) availability of blood cultures, and (3) technically acceptable two-dimensional echocardiograms. The clinical records of each patient were reviewed to determine the presence or absence of infective endocarditis by use of strict clinical and laboratory criteria.&dquo; Clinical evidence of endocarditis included one or more of the following: persistent and unexplained fever, new or changing cardiac murmur, peripheral stigmata of endocarditis (Roth spots, Janeway lesions, Osler’s nodes, or conjunctival petechiae), or splenomegaly. Laboratory evidence included leukocytosis and one or more positive blood cultures with no other documented source of infection. If antibiotics were given before blood cultures and the cultures were negative, the patient was considered to have culture-negative endocarditis if overwhelming clinical and laboratory evidence were present, the entire hospital course was compatible with the diagnosis, and the usual antibiotic therapy for endocarditis was given. The patients were followed up for a minimum of at least three months to determine long-term outcome. Two-dimensional echocardiographic studies were performed in the standard fashion using commercially available echocardiographic equipment with a 3 mHz or 3.5 mHz transducer. The patients were examined in both the supine and left lateral position, and the heart was visualized from all available echocardiographic windows. Two-dimensional echocardiograms were recorded on a videotape for later analysis in real time, slow motion, and stop frame formats. All echocardiograms were reviewed by a blinded observer for the presence or absence of vegetations. A cardiac vegetation was defined as a heterogeneous, irregular, shaggy, mobile, echo-dense mass on a valve leaflet or cardiac structure. The sensitivity, specificity, predictive accuracy for a positive test, and the predictive accuracy for a negative test were calculated by use of standard formulas. Sensitivity =
554
TP/(TP + FN); specificity = TN/(TN + FP); predictive accuracy of a positive test = TP/(TP + FP); predictive accuracy of a negative test TN/(TN + FN), where TP true positive test, TN true negative test, FP false-positive test, and FN false-negative test. =
=
=
=
=
Results
patients who underwent the 3,406 two-dimensional echocardiographic studies performed at our institution over a thirty-six month period, 106 patients were eligible for the study. Five patients’ echocardiograms were technically inadequate, resulting in a study population of 101 patients. The age of the patients ranged from forty-five days to eighty-eight years; the mean age of the group was fifty-seven years. The following clinical manifestations of infective endocarditis were present: fever (83030), intermittent chills (60070), congestive heart failure (25~70), and splenomegaly (18%). Peripheral embolization (7~/0) and conjunctival petechiae (3%) were rare. Preexisting valvular or congenital heart disease was present in 12 patients. Five patients had aortic stenosis, 2 had mitral stenosis, and 1 had mitral valve prolapse. Prosthetic mitral and aortic valves were present in 2 different patients. Two patients had ventricular septal defects. Left-sided heart valves were most commonly affected by infective endocarditis. Vegetations were present on the mitral valve in 64% of the cases, on the aortic valve in 250, and on the tricuspid valve in 11070 . The pulmonic valve was not affected in our series. From the
Gram-positive cocci (Table I).
were
the most Bateriologic
common
microorganism involved
in endocarditis
TABLE I Cause of Endocarditis
’
Staphylococcal species were present in approximately 50% of the cases. Streptococcus was a close second, involving 43 ~lo of the cases. Diptheroids and Candida albicans were rare occurrences.
The
following clinical complications of infective endocarditis occurred. Three patients developed mitral regurgitation. One patient suffered a subarachnoid hemorrhage secondary to a ruptured mycotic aneurysm. There was 1 patient with a renal infarction, 1 with multiple cerebrovascular accidents, and 1 with pulmonary emboli. TABLE II
Correlation
o, f the Diagnosis of Endocarditis with Two Dimensional Echocardiographic Results
555 divided into two groups (Table II). Group I was composed of 36 patients who had definite vegetations visualized by two-dimensional echocardiography. Figure 1 demonstrates a typical echocardiogram of a valvular vegetation. Group II had 65 patients with no vegetations. In Group I, blood cultures were positive in 30 patients. Five additional patients, who had been treated with antibiotics before blood cultures were drawn, were diagnosed and treated as culture-negative endocarditis. In Group II, 57 of 65 patients had negative blood cultures. In those patients with positive blood cultures, another etiology for bacteremia (eg; urinary tract infection) was found in 4 patients; only short-term antibiotics were given to these patients with favorable long-term results. The remaining 4 patients had infective endocarditis not detected by two-dimensional echocardiography. There were 7 deaths in Group 1. In 6 of the 7 patients, autopsies were performed, which confirmed vegetations in all 6. In Group II, 9 deaths occurred from causes other than infective endocarditis. Three patients died of pneumonia, 2 of hepatorenal syndrome, 3 from sepsis, and 1 from a ruptured dissecting aortic aneurysm. Two autopsies were performed in this group; one showed a small 1.5 mm vegetation on the anterior leaflet of the mitral valve. The
patients
were
TABLE III Statistical Analysis
The
sensitivity, specificity, predictive accuracy for a positive test, and the predictive accuracy for a negative test were calculated according to standard formulas (Table III). The sensitivity of two-dimensional echocardiography for detecting the infective endocarditis was 90°~0 ; the specificity was 98%. The predictive accuracy for a positive test was 97 °~o and the predictive accuracy for a negative test was 94~70 . Discussion
The development of echocardiography has had a significant impact on the diagnosis and management of patients with infective endocarditis. Two-dimensional echocardiography is felt to be the technique of choice in the identification and characterization of intracardiac masses or vegetations .20 The determination of the usefulness of a diagnostic test depends not only on its sensitivity and specificity but also on the implications of false-positive and false-negative results.~‘ The purpose of our study was to evaluate the reliability and accuracy of two-dimensional echocardiography in detecting vegetations of infective endocarditis in a large general patient population with the clinical suspicion of the diagnosis. We reviewed 101 patients, who were referred to our echocardiographic laboratories for evaluation of possible endocarditis. Our study population consisted almost exclusively of patients without prosthetic valves (except for 2 patients). The sensitivity and specificity of two-dimensional echocardiography for detecting infective endocarditis were 90% and 98070, respectively. The predictive accuracy of a positive test was 97%, and the predictive value of a negative echocardiogram was 94 % .
556
FIG. 1. A two-dimensional echocardiogram demonstrating large vegetations on both mitral valve leaflets. A. Parasternal long-axis view. B. Parasternal short-axis view. C. and D. Apical four-chamber views in diastole and systole. The arrows indicate vegetations.
sensitivity and specificity of our study appear to be higher than expected when compared with the majority of previous reports. We think, however, that our results are more representative of the true sensitivity and specificity of two-dimensional echocardiography in the detection of endocarditis. Several factors may explain these differences. First, although many studies have been published on echocardiography in the diag9,10,19,25-30 used only M-mode nosis of infective endocarditis, earlier investigations echocardiography, which is much less sensitive and specific than two-dimensional echocardiography. Other reports14,15 have attempted to draw conclusions about the efficacy of echocardiography while lumping together the results of M-mode and two-dimensional The
557 studies. Our study utilized two-dimensional echocardiography, which is superior in detecting valvular vegetations when compared with M-mode echocardiography, and we expected, therefore, to have a higher sensitivity and specificity than older reports had. Second, in investigations using two-dimensional echocardiography, the detection rate for vegetations by this technique has ranged from a low of 43 07o to a high of 100070 .34 This variability may be related to the study size and patient populations (or subgroups), and these factors have made the interpretation and generalization of the data difficult.35 For example, numerous reports in infective endocarditis in intravenous drug abuserS23,24,31-33,36-38,40 have reviewed the microorganisms involved, the effects of vegetation size, results of medical therapy, complication rates, need for surgery, and ultimate clinical outcome. However, the variable sensitivity rate in reports of endocarditis involving drug abusers may be due to several factors. Previous episodes of endocartitis may interfere with subsequent echocardiographic evaluations, since vegetative lesions can result in fibrosis, scarring, and calcifications of valvular structures, which may hide small vegetations.34 Patients may present earlier in the course of their illness before large vegetation can develop and thus make it more difficult to detect the vegetations. Finally, the sensitivity of two-dimensional echocardiography in drug addicts with infective endocarditis is affected by the heterogeneity of this population with respect to the infecting microorganism(s), site and number of valves involved, and vegetation size.24’38 The higher sensitivity of our series may be related to the fact that our study had a small proportion of intravenous drug addicts. Third, the sensitivity of two-dimensional echocardiography in detecting endocarditis may also be affected by the presence of artificial heart valves or preexisting valvular disease. A study group with a higher proportion of patients with prosthetic valves (both porcine and mechanical) would be expected to have a lower sensitivity. Prosthetic valves decrease the diagnostic accuracy of echocardiography, because the degenerative changes in porcine valves or the echo density of mechanical valves make it difficult to identify the additional echoes produced by possible vegetations.2o,41,42 The same conclusion may also be applied to a population of patients who have a higher proportion of preexisting valvular disease. Myxomatous degeneration, fibrosis, or calcification of valvular structures and spontaneous rupture of chordae tendineae may hide or mimic vegetative endocarditis.2o,21,32,34,36,42 Thus, the high sensitivity of our study may be related in part to the small number of patients with artificial heart valves and preexisting valvular disease. Two-dimensional echocardiography is not, however, a perfect test for the detection of vegetations in infective endocarditis. Owing to difficulties in visualizing some portions of the heart and detecting small vegetations, it is impossible to exclude with absolute certainty the diagnosis of endocarditis on the basis of echocardiography alone. 20,24,32 The infective process may be interstitial and destructive rather than vegetative and therefore difficult to detect by echocardiographic methods. Technical limitations may also contribute to the inability of two-dimensional echocardiography to detect valvular or endocardial vegetations in certain situations. The physical characteristics of a particular lesion as determined by its size, shape, composition, density, and type of infecting organism may directly influence the quality of the echocardiogram.25 The quality of the study, the type of echocardiographic equipment, the timing of examination, the vegetation size, and the
558 intracardiac location may affect the detection of valvular vegetation detection by echocardiography. A vegetation may be more difficult to detect if it is less than 2 mm in size, if it is more than 7 cm away from the transducer, or if it is examined echocardiographically less than two weeks after the onset of symptoms.39 In our series, a small 1.5 mm vegetation on the mitral valve, which was not detected by echocardiography in 1 patient in Group II, was discovered at autopsy. The specificity of two-dimensional echocardiography in the detection of infective endocarditis has been consistently high (89070-100070) in previous reports .21 &dquo; The specificity in our series (98070) compares favorably and is consistent with previous investigations. There are, however, several factors that might lower the specificity of two-dimensional echocardiography in patients with infective endocarditis. The densities on valves are not specific for vegetations. It may be difficult to differentiate bacterial vegetations from valvular abnormalities of preexisting valvular disease such as thickened and fibrotic leaflets secondary to rheumatic heart disease, myxomatous degeneration of mitral valve prolapse, calcifications of cardiac structures, nodules of collagen vascular disease, intracardiac masses, or even healed vegetations.2o’21’32’36 Finally, the predictive accuracy of two-dimensional echocardiography in patients with infective endocarditis has rarely been calculated. In our study, the predictive accuracy of a positive test was 970, and the predictive value of a negative test was 940. Thus, two-dimensional echocardiography appears to be a very useful clinical test in patients with possible infective endocarditis. When a cardiac vegetation is visualized on an echocardiographic examination, infective endocarditis is probably present. When an echocardiographic study yields normal findings infective endocarditis is most likely not present (although a normal-appearing echocardiogram cannot absolutely exclude infective endocarditis in any particular patient). Two-dimensional echocardiography is not only, therefore, a sensitive and specific technique but is a very accurate one as well. The results of our study compare favorably with more recent investigations utilizing mainly two-dimensional echocardiography in the evaluation of patients with possible infective endocarditis.2’ Conclusion Two-dimensional echocardiography is an excellent noninvasive technique for the evaluation of patients with suspected endocarditis. It is safe, reliable, and accurate. Twodimensional echocardiography appears to have a high sensitivity, specificity, and predictive value for the diagnosis of infective endocarditis on native heart valves. Andrew J. Burger, M.D. Marshall University School 1801 Sixth A venue Huntington, WV 25701
of Medicine
559
References JC, Feigenbaum H, Konecke LL, et al: Echocardiographic manifestations of valvular vegetations. Am J Med 86:698-704, 1973. 2. Spangler RD, Johnson ML, Holmes JH, et al: Echocardiographic demonstration of bacterial vege1. Dillon
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tations in active infective endocarditis. J Clin Ultrasound 1:126-128, 1973. Lee CC, Ganguly SN, Magnisalis K, et al: Detection of triscuspid valve vegetations by echocardiography. Chest 66:432-433, 1974. Gottlieb S, Khuddus SA, Balooki H, et al: Echocardiographic diagnosis of aortic valve vegetations in Candida endocarditis. Circulation 50:826-830, 1974. Martinez EC, Burch GE, Giles TD: Echocardiographic diagnosis of vegetative aortic valve endocarditis. Am J Cardiol 34:845-849, 1974. DeMaria AN, King JF, Salel AF, et al: Echocardiography and phonography of acute aortic regurgitation in bacterial endocarditis. Ann Intern Med 82:329-335, 1975. Wray TM: Echocardiographic manifestations of flail aortic valve leaflets in bacterial endocarditis. Circulation 51:832-835, 1975. Wray TM: The variable echocardiographic features in aortic valve endocarditis. Circulation 52:658-663,
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1975. 9. Roy P,
Tajik AJ, Qiuliani ER, et al: Spectrum of echocardiographic findings in bacterial endocarditis.
Circulation 53:474-482, 1976. 10. Wann LS, Dillon JC, Weyman AE, et al: Echocardiography in bacterial endocarditis. N Engl J Med 295:135-139, 1976. 11.Stafford A, Wann LS, Dillon JC, et al: Serial echocardiographic appearance of healing bacterial endocarditis. Am J Cardiol 44:754-760, 1979. 12. Chandraratna P, Aronow WS: Spectrum of echocardiographic findings in tricuspid valve endocarditis. Br Heart J 42:528-532, 1979. 13. Sheikh MU, Ali N, Covarrubias E, et al: Right sided infective endocarditis. Am J Med 66:283-287, 1979. 14. Wann LS, Hallam CC, Dillon JC, et al: Comparison of M-mode and cross-sectional echocardiography in infective endocarditis. Circulation 60:728-733,
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15. Mintz GS, Kotler MN, Segal BL, et al: Comparison of two dimensional and M-mode echocardiography in the evaluation of patients with infective endocarditis. Am J Cardiol 43:738-744, 1978. 16. Thompson KR, Nanda NC, Gramiak R: The reliability of echocardiography in the diagnosis of infective endocarditis. Radiology 125:473-476, 1977. 17. Gilbert BW, Haney RS, Crawford F, et al: Twodimensional echocardiographic assessment of vegetative endocarditis. Circulation 55:346-353, 1976. 18. Andy JJ, Sheikh MU, Ali N, et al: Echocardiographic observations in opiate addicts with infective endocarditis. Am J Cardiol 40:17-23, 1977. 19. Stewart JA, Silimperi D, Horris P, et al: Echocardiographic documentation of vegetative lesions in infective endocarditis. Circulation 61:374-380, 1980. 20. Donaldson RM, Westgate C, Bennett JG, et al: The
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34.
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role of echocardiography in suspected bacterial endocarditis. Eur Heart J Supplement C):53-57, 1984. Stafford WJ, Petch J, Radford DJ: Vegetations in infective endocarditis: Clinical relevance and diagnosis by cross sectional echocardiography. Br Heart J 53:310-313, 1985. Bain RJI, Geddes AM, Littler WA, et al: The clinical echocardiographic diagnosis of infective endocarditis. J Antimicrob Chemother 20 (Suppl A): 17-27, 1987. Bayer AS, Blomquist IK, Bello E, et al: Tricuspid valve endocarditis due to staphylococcus aureus: Correlation of two dimensional echocardiography with clinical outcome. Chest 93:247-253, 1988. Dubonis RW, Ginzton LE: Role of echocardiography in suspected infective endocarditis in intravenous drug abusers. Am J Cardiol 58:649-650, 1986. Davis RS, Strom JA, Frishman W, et al: The demonstration of vegetations by echocardiography in bacterial endocarditis. Am J Med 69:57-63, 1980. Andy JJ, Sheikh MV, Ali N, et al: Echocardiographic observations in opiate addicts with active infective endocarditis. Am J Cardiol 40:17-23, 1977. Young JB, Welton DW, Quinones MA, et al: Prognostic significance of valvular vegetations indentified by M-mode echocardiography in infective endocarditis. Circulation 58 : II-42, 1978. Gura GM, Tajik AJ, Seward JB: Correlation of initial echocardiographic findings with outcome in patients with bacterial endocarditis. Circulation 58 : II-232, 1978. Pratt C, Whitcomb C, Meumann AM, et al: Relationship of vegetation on echocardiography to the clinical course and systemic emboli in endocarditis. Circulation 58 : II-41, 1978. Sheikl MV, Covarrubias EA, Ali N, et al: M-mode echocardiographic observations during and after healing of active bacterial endocarditis limited to the mitral valve. Am Heart J 101:37-45, 1981. Buda AJ, Zotz RJ, LeMire MS, et al: Prognostic significance of vegetations detected by two-dimensional echocardiography in infective endocarditis. Am Heart J 112:1291-1296, 1986. Kinney EL, Wright RJ: Aortic valve vegetation: Examples of overestimation and underestimation of disease by two dimensional echocardiography. Am Heart J 115:1248-1250, 1987. Herzog CA, Carson P, Michaud L, et al: Twodimensional echocardiographic imaging of left ventricular mural vegetations. Am Heart J 115:684-686, 1988. O’Brien JT, Geiser EA: Infective endocarditis and echocardiography. Am Heart J 108:386-394, 1984. Tak T, Rahimtoola SH, Kumar A, et al: Value of digital image processing of two-dimensional echocardiograms in differentiating active from chronic vegetations of infective endocarditis. Circulation 78:116-123, 1988. Lutas EM, Roberts RB, Devereux RB, et al: Relation between the presence of echocardiographic vegetations and the complication rate in infective endocarditis. Am Heart J 112:107-113, 1986.
560 37. Narenthiran S: Echocardiography in subacute bacterial endocarditis. Ceylon Med J 30:125-129, 1985.
38. Robbins MJ, Frater RWM, Seiro R, et al: Influence of vegetation size on clinical outcome of right-sided infective endocarditis. Am J Med 80 : 165-171, 1986. 39. Amsterdam EA: Value and limitations of echocardiography in endocarditis. Cardiology 71:229-231, 1984. 40. Manolis AS, Melita H: Echocardiographic and clinical correlates in drug addicts with infective en-
docarditis : Implications of vegetation size. Arch Intern Med 148:2461-2465, 1988. 41. Eilbott EJ, Steignigel RT: Infective endocarditis Board Review 5:97-118, 1988. 42. Gottdiener JA: Echocardiography in the diagnosis of a cardiac mass: Are we seeing too much or too little? Chicago, Illinois, Year Book Medical Publishers, Inc. pp 447-465, 1985. 43. Tape TG, Panzer RJ: Echocardiography, endocarditis, and clinical information bias. J Gen Int Med 1:300-304, 1986.
HUNTINGTON, WEST VIRGINIA
A bstract Two-dimensional echocardiography has had a significant impact on and is considered the technique of choice for the diagnosis and management of infective endocarditis. Over a thirty-six month period, 106 patients were evaluated by echocardiography for the possibility of endocarditis. The diagnosis of endocarditis was determined by strict clinical and laboratory criteria. All clinical histories, blood cultures, echocardiograms, and autopsy results were reviewed. Five echocardiograms were technically inadequate, resulting in a study population of 101 patients. The age of the patients ranged from forty-five days to eighty-eight years (mean fifty-seven years). The clinical manifestations of endocarditis included fever (83%), chills (60%), congestive heart failure (25%), and splenomegaly (18%). Twelve patients had preexisting valvular or congenital heart disease. Gram-positive cocci were the most common microorganisms. Complications included mitral regurgitation, subarachnoid hemorrhage, renal infarction, stroke, and a pulmonary embolus. The patients were divided into two groups: Group I consisted of 36 patients with definite vegetations by echocardiography, and Group II had 65 patients with no vegetations. In Group I, acute infective endocarditis was present in 35 patients, whereas only 4 patients had endocarditis in Group II. The sensitivity of two-dimensional echocardiography for detecting endocarditis was 90%. The specificity was 98%. The predictive accuracy for a positive test was 97%, and the predictive accuracy for a negative test was 94%. Thus, two-dimensional echocardiography appears to have a high sensitivity, specificity, and predictive value in the evaluation of patients with suspected endocarditis. From the Division of Cardiology, Department of Medicine, Marshall University School of Medicine and Veteran’s Administration Medical Center, Huntington, West Virginia Presented at the 38th Annual Meeting of the American College of Angiology, Atlanta, Georgia, October, 1990.
552
553 Introduction The direct noninvasive visualization of valvular vegetations by means of echocardiography has been an exciting development in the evaluation of patients with infective endocarditis. In 1973, Dillon’ and Spangled described for the first time echocardiographic manifestations of valvular vegetations. Subsequently, numerous other reports have confirmed the usefulness of this technique.’-&dquo; However, the reliability of two-dimensional echocardiography in the diagnosis of infective endocarditis requires careful assessment. Most older published data have been based on M-mode echocardiography, which is inferior to two-dimensional echocardiographic techniques, especially in visualizing certain cardiac structures such as the tricuspid or pulmonic valves. Furthermore, most of the published studies&dquo;-&dquo; have presented rather short series of patients ranging from 6 to 32. Only a few reports 11-21 of specific subgroups with endocarditis have evaluated larger numbers of patients. Our study was, therefore, undertaken to evaluate in a large group of patients the sensitivity, specificity, and predictive value of two-dimensional echocardiography in the diagnosis of infective endocarditis.
Materials and Methods Over a thirty-six month period, patients referred to our echocardiographic laboratories for the possibility of infective endocarditis were eligible for the study. The admission criteria included the following: (1) Well-documented clinical histories, (2) availability of blood cultures, and (3) technically acceptable two-dimensional echocardiograms. The clinical records of each patient were reviewed to determine the presence or absence of infective endocarditis by use of strict clinical and laboratory criteria.&dquo; Clinical evidence of endocarditis included one or more of the following: persistent and unexplained fever, new or changing cardiac murmur, peripheral stigmata of endocarditis (Roth spots, Janeway lesions, Osler’s nodes, or conjunctival petechiae), or splenomegaly. Laboratory evidence included leukocytosis and one or more positive blood cultures with no other documented source of infection. If antibiotics were given before blood cultures and the cultures were negative, the patient was considered to have culture-negative endocarditis if overwhelming clinical and laboratory evidence were present, the entire hospital course was compatible with the diagnosis, and the usual antibiotic therapy for endocarditis was given. The patients were followed up for a minimum of at least three months to determine long-term outcome. Two-dimensional echocardiographic studies were performed in the standard fashion using commercially available echocardiographic equipment with a 3 mHz or 3.5 mHz transducer. The patients were examined in both the supine and left lateral position, and the heart was visualized from all available echocardiographic windows. Two-dimensional echocardiograms were recorded on a videotape for later analysis in real time, slow motion, and stop frame formats. All echocardiograms were reviewed by a blinded observer for the presence or absence of vegetations. A cardiac vegetation was defined as a heterogeneous, irregular, shaggy, mobile, echo-dense mass on a valve leaflet or cardiac structure. The sensitivity, specificity, predictive accuracy for a positive test, and the predictive accuracy for a negative test were calculated by use of standard formulas. Sensitivity =
554
TP/(TP + FN); specificity = TN/(TN + FP); predictive accuracy of a positive test = TP/(TP + FP); predictive accuracy of a negative test TN/(TN + FN), where TP true positive test, TN true negative test, FP false-positive test, and FN false-negative test. =
=
=
=
=
Results
patients who underwent the 3,406 two-dimensional echocardiographic studies performed at our institution over a thirty-six month period, 106 patients were eligible for the study. Five patients’ echocardiograms were technically inadequate, resulting in a study population of 101 patients. The age of the patients ranged from forty-five days to eighty-eight years; the mean age of the group was fifty-seven years. The following clinical manifestations of infective endocarditis were present: fever (83030), intermittent chills (60070), congestive heart failure (25~70), and splenomegaly (18%). Peripheral embolization (7~/0) and conjunctival petechiae (3%) were rare. Preexisting valvular or congenital heart disease was present in 12 patients. Five patients had aortic stenosis, 2 had mitral stenosis, and 1 had mitral valve prolapse. Prosthetic mitral and aortic valves were present in 2 different patients. Two patients had ventricular septal defects. Left-sided heart valves were most commonly affected by infective endocarditis. Vegetations were present on the mitral valve in 64% of the cases, on the aortic valve in 250, and on the tricuspid valve in 11070 . The pulmonic valve was not affected in our series. From the
Gram-positive cocci (Table I).
were
the most Bateriologic
common
microorganism involved
in endocarditis
TABLE I Cause of Endocarditis
’
Staphylococcal species were present in approximately 50% of the cases. Streptococcus was a close second, involving 43 ~lo of the cases. Diptheroids and Candida albicans were rare occurrences.
The
following clinical complications of infective endocarditis occurred. Three patients developed mitral regurgitation. One patient suffered a subarachnoid hemorrhage secondary to a ruptured mycotic aneurysm. There was 1 patient with a renal infarction, 1 with multiple cerebrovascular accidents, and 1 with pulmonary emboli. TABLE II
Correlation
o, f the Diagnosis of Endocarditis with Two Dimensional Echocardiographic Results
555 divided into two groups (Table II). Group I was composed of 36 patients who had definite vegetations visualized by two-dimensional echocardiography. Figure 1 demonstrates a typical echocardiogram of a valvular vegetation. Group II had 65 patients with no vegetations. In Group I, blood cultures were positive in 30 patients. Five additional patients, who had been treated with antibiotics before blood cultures were drawn, were diagnosed and treated as culture-negative endocarditis. In Group II, 57 of 65 patients had negative blood cultures. In those patients with positive blood cultures, another etiology for bacteremia (eg; urinary tract infection) was found in 4 patients; only short-term antibiotics were given to these patients with favorable long-term results. The remaining 4 patients had infective endocarditis not detected by two-dimensional echocardiography. There were 7 deaths in Group 1. In 6 of the 7 patients, autopsies were performed, which confirmed vegetations in all 6. In Group II, 9 deaths occurred from causes other than infective endocarditis. Three patients died of pneumonia, 2 of hepatorenal syndrome, 3 from sepsis, and 1 from a ruptured dissecting aortic aneurysm. Two autopsies were performed in this group; one showed a small 1.5 mm vegetation on the anterior leaflet of the mitral valve. The
patients
were
TABLE III Statistical Analysis
The
sensitivity, specificity, predictive accuracy for a positive test, and the predictive accuracy for a negative test were calculated according to standard formulas (Table III). The sensitivity of two-dimensional echocardiography for detecting the infective endocarditis was 90°~0 ; the specificity was 98%. The predictive accuracy for a positive test was 97 °~o and the predictive accuracy for a negative test was 94~70 . Discussion
The development of echocardiography has had a significant impact on the diagnosis and management of patients with infective endocarditis. Two-dimensional echocardiography is felt to be the technique of choice in the identification and characterization of intracardiac masses or vegetations .20 The determination of the usefulness of a diagnostic test depends not only on its sensitivity and specificity but also on the implications of false-positive and false-negative results.~‘ The purpose of our study was to evaluate the reliability and accuracy of two-dimensional echocardiography in detecting vegetations of infective endocarditis in a large general patient population with the clinical suspicion of the diagnosis. We reviewed 101 patients, who were referred to our echocardiographic laboratories for evaluation of possible endocarditis. Our study population consisted almost exclusively of patients without prosthetic valves (except for 2 patients). The sensitivity and specificity of two-dimensional echocardiography for detecting infective endocarditis were 90% and 98070, respectively. The predictive accuracy of a positive test was 97%, and the predictive value of a negative echocardiogram was 94 % .
556
FIG. 1. A two-dimensional echocardiogram demonstrating large vegetations on both mitral valve leaflets. A. Parasternal long-axis view. B. Parasternal short-axis view. C. and D. Apical four-chamber views in diastole and systole. The arrows indicate vegetations.
sensitivity and specificity of our study appear to be higher than expected when compared with the majority of previous reports. We think, however, that our results are more representative of the true sensitivity and specificity of two-dimensional echocardiography in the detection of endocarditis. Several factors may explain these differences. First, although many studies have been published on echocardiography in the diag9,10,19,25-30 used only M-mode nosis of infective endocarditis, earlier investigations echocardiography, which is much less sensitive and specific than two-dimensional echocardiography. Other reports14,15 have attempted to draw conclusions about the efficacy of echocardiography while lumping together the results of M-mode and two-dimensional The
557 studies. Our study utilized two-dimensional echocardiography, which is superior in detecting valvular vegetations when compared with M-mode echocardiography, and we expected, therefore, to have a higher sensitivity and specificity than older reports had. Second, in investigations using two-dimensional echocardiography, the detection rate for vegetations by this technique has ranged from a low of 43 07o to a high of 100070 .34 This variability may be related to the study size and patient populations (or subgroups), and these factors have made the interpretation and generalization of the data difficult.35 For example, numerous reports in infective endocarditis in intravenous drug abuserS23,24,31-33,36-38,40 have reviewed the microorganisms involved, the effects of vegetation size, results of medical therapy, complication rates, need for surgery, and ultimate clinical outcome. However, the variable sensitivity rate in reports of endocarditis involving drug abusers may be due to several factors. Previous episodes of endocartitis may interfere with subsequent echocardiographic evaluations, since vegetative lesions can result in fibrosis, scarring, and calcifications of valvular structures, which may hide small vegetations.34 Patients may present earlier in the course of their illness before large vegetation can develop and thus make it more difficult to detect the vegetations. Finally, the sensitivity of two-dimensional echocardiography in drug addicts with infective endocarditis is affected by the heterogeneity of this population with respect to the infecting microorganism(s), site and number of valves involved, and vegetation size.24’38 The higher sensitivity of our series may be related to the fact that our study had a small proportion of intravenous drug addicts. Third, the sensitivity of two-dimensional echocardiography in detecting endocarditis may also be affected by the presence of artificial heart valves or preexisting valvular disease. A study group with a higher proportion of patients with prosthetic valves (both porcine and mechanical) would be expected to have a lower sensitivity. Prosthetic valves decrease the diagnostic accuracy of echocardiography, because the degenerative changes in porcine valves or the echo density of mechanical valves make it difficult to identify the additional echoes produced by possible vegetations.2o,41,42 The same conclusion may also be applied to a population of patients who have a higher proportion of preexisting valvular disease. Myxomatous degeneration, fibrosis, or calcification of valvular structures and spontaneous rupture of chordae tendineae may hide or mimic vegetative endocarditis.2o,21,32,34,36,42 Thus, the high sensitivity of our study may be related in part to the small number of patients with artificial heart valves and preexisting valvular disease. Two-dimensional echocardiography is not, however, a perfect test for the detection of vegetations in infective endocarditis. Owing to difficulties in visualizing some portions of the heart and detecting small vegetations, it is impossible to exclude with absolute certainty the diagnosis of endocarditis on the basis of echocardiography alone. 20,24,32 The infective process may be interstitial and destructive rather than vegetative and therefore difficult to detect by echocardiographic methods. Technical limitations may also contribute to the inability of two-dimensional echocardiography to detect valvular or endocardial vegetations in certain situations. The physical characteristics of a particular lesion as determined by its size, shape, composition, density, and type of infecting organism may directly influence the quality of the echocardiogram.25 The quality of the study, the type of echocardiographic equipment, the timing of examination, the vegetation size, and the
558 intracardiac location may affect the detection of valvular vegetation detection by echocardiography. A vegetation may be more difficult to detect if it is less than 2 mm in size, if it is more than 7 cm away from the transducer, or if it is examined echocardiographically less than two weeks after the onset of symptoms.39 In our series, a small 1.5 mm vegetation on the mitral valve, which was not detected by echocardiography in 1 patient in Group II, was discovered at autopsy. The specificity of two-dimensional echocardiography in the detection of infective endocarditis has been consistently high (89070-100070) in previous reports .21 &dquo; The specificity in our series (98070) compares favorably and is consistent with previous investigations. There are, however, several factors that might lower the specificity of two-dimensional echocardiography in patients with infective endocarditis. The densities on valves are not specific for vegetations. It may be difficult to differentiate bacterial vegetations from valvular abnormalities of preexisting valvular disease such as thickened and fibrotic leaflets secondary to rheumatic heart disease, myxomatous degeneration of mitral valve prolapse, calcifications of cardiac structures, nodules of collagen vascular disease, intracardiac masses, or even healed vegetations.2o’21’32’36 Finally, the predictive accuracy of two-dimensional echocardiography in patients with infective endocarditis has rarely been calculated. In our study, the predictive accuracy of a positive test was 970, and the predictive value of a negative test was 940. Thus, two-dimensional echocardiography appears to be a very useful clinical test in patients with possible infective endocarditis. When a cardiac vegetation is visualized on an echocardiographic examination, infective endocarditis is probably present. When an echocardiographic study yields normal findings infective endocarditis is most likely not present (although a normal-appearing echocardiogram cannot absolutely exclude infective endocarditis in any particular patient). Two-dimensional echocardiography is not only, therefore, a sensitive and specific technique but is a very accurate one as well. The results of our study compare favorably with more recent investigations utilizing mainly two-dimensional echocardiography in the evaluation of patients with possible infective endocarditis.2’ Conclusion Two-dimensional echocardiography is an excellent noninvasive technique for the evaluation of patients with suspected endocarditis. It is safe, reliable, and accurate. Twodimensional echocardiography appears to have a high sensitivity, specificity, and predictive value for the diagnosis of infective endocarditis on native heart valves. Andrew J. Burger, M.D. Marshall University School 1801 Sixth A venue Huntington, WV 25701
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