praisal and Julian
Recent revrews of infective endocarditis (IE) have documented changes in predisposing factors, etiology, and the clinical characteristics of this infection.’ .Altbough “‘atypical” or unusual manifestations of IE are often stressed, the majority of casesmay be diagnosed using clinical criteria and blood culture results, In the past several years, new diagnostic tests have been used in assessing patients with IE. While some of these tests may rovide clinically useful information, it is important to critically evaluate these techniques and to determine which patients would benefit from such studies. Blood cultures, positive in approximately 85 per cent of patients with IE, continue to be the most definitive study. Blood culture results wili be compared in terms of sensitivity and specificity to newer diagnostic techniques. t-as Infectious endocardikis and other intravascular infections such as mycotic aneurysms and infected arteriovenous fistulas are characterized by bacteremia which is continuous.’ In contrast, positive blood cultures persist for less than 38 minutes in patients who have a low inoculum of bacteria,: since organisms are effectively cleared by the reficuloendothelial system.’ The rapid removal of pathogenic bacteria from the blood has also been demonstrated when larger inocula are given to experimental animals.” The persisProm tne %wkm of Infectious Diseases,Department of Medicine, Montefiore Roapitai and Medical Center, and the Albert Einstein College of Medicine. Receiwd for publication Feb. 24: 1978. Eieprint requesm: Michael H. Miller, M.D., Department of Medicine. Division of Infectious Diseases, Montefiore Hospital and Medical Center, Bronx, N.U. 10467.
-de 1.2 :~~~~n~~i~~ tent bacteremia seen with IE ‘if3* ::I
which are constantly seeded into the blood from vegetations. Blood cultures in patient,.9 with endocarditis should therefore be drawn in a way that will not only document bacteremia, but aiso indicate its gersistence. The use of proper techniques in obtaining blood dttures
At Least three
cultures should be obtained over a period of hours to days in patients with suspected ~ndocarditis More than six blood cultures are rar-e;y necessarzy. The timing of the cultures will often depend on the severit;y of the illness and the a& for rapid institution of therapy. Alternative venepuncture sites should be meticulously prepared wi.th a 2 per cent iodine solution followed by ‘10 per cent alcohol to remove the iodine. Arterial samples offer no advantage over antecubital vein cultures.’ Several milliliters or” blood are inoculated into each of two liquid me&s; routine blood sets consist of an aerobic and an anaerobic bottle. The amount of blood to ie maculated is specified by each manufacturer. The aerobic bottle is under a partial vaeu7~m and should be routinely aerated after blood collection. culture
sets 8x-e generally
tion of aerobic and anaero subculturing and incubation for up t.o 21 days is necessary when cultures are negative, since IE occasionally
tionally fastidious organisms., Since the reported incidence of negative cuftures in patients with EE is about 15 per cent,’ modification of the procedure owtliced above may be indicated in some patient,s. In patients who have received antibiotics (a common cause of negative cultures), an effort sh0~11:i he made to
inactivate antibiotics which may have been carried over into the culture flask from the patient’s blood. The addition of a beta-lactamase (penicillinase) to the medium may be helpful in patients who have received penicillins or cephalosporins. Care should be taken not to overinoculate the blood culture bottle. Antibiotics in the blood will be diluted by the larger volume of liquid culture medium, decreasing their activity. The presence of cell-wall-deficient forms should be sought in patients who have received agents whose primary activity is on the cell wall. Such drugs include the penicillins, cephalosporins, and vancomycin. Since cell-wall-deficient forms of bacteria will not grow on ordinary media, a hypertonic medium such as broth with 10 per cent sucrose should be used in addition to the routine blood culture bottles. Organisms requiring special growth factors not present in standard media are sometimes seen on Gram stain from patients with IE. The use of enriched medium may permit the isolation of these organisms.” Although thioglycollate or other anaerobic blood culture media will usually support the growth of anaerobes, routine subculturing and the incubation of bottles for many days are especially important when anaerobic endocarditis is suspected. Patients with gastrointestinal disease or prosthetic valve endocarditis account for most cases of anaerobic IE. Fungal endocarditis is another important cause of culture negative endocarditis. Candida species are more often associated with positive cultures than other fungi such as histoplasma or aspergillus species. The fungemia associated with candida endocarditis may not be continuous and often many days are required for the isolation of this pathogen. The use of biphasic medium’ and the aeration of bottle9 facilitate the isolation of these pathogens. Routine aeration of one bottle may also facilitate the isolation of some bacteria such as pseudomonas species. Fungal endocarditis should be suspected in the presence of drug addiction, following prosthetic valve replacement and in patients with intravenous or urinary catheters who have received parenteral antibiotic therapy. The presence of large emboli in culture-negative IE also suggest a fungal etiology, and the histologic and bacteriologic examination of material removed at embolectomy may provide a diagnosis. The examination of peripheral leukocytes for
the presence of bacteria may be useful in some patients with IE.3 False-negative results, however, are not uncommon,10 and the differentiation of bacteria from artifacts may be difficult. Echocardiography
Echocardiography has been used in assessing patients with IE. Vegetations have been documented on the aortic, mitral, and tricuspid valves. The sensitivity of this procedure is related to the size of the vegetation. In some clinical settings, echocardiography is a useful diagnostic procedure. Patients with aortic insufficiency of unknown etiology may be diagnosed as having IE by the demonstration of vegetations on the aortic valves.” This technique may also be useful in patients with culture negative fungal endocarditis. The sensitivity of this procedure, however, in diagnosing patients with IE is relatively poor. In one study, only one-third of patients with clinically and bacteriologically documented IE had positive results.12 Echocardiography does not distinguish between active and inactive cases,” and false-positive results may occur.13 Echocardiography is also useful as a prognostic indicator and may identify patients who require surgical intervention. Individuals with IE who have vegetations large enough to be documented by this technique have a poor prognosis. These patients more frequently require surgery for congestive heart failure and have higher mortality rates than those without this finding.” There is also a strong association between the presence of vegetations on echocardiography and embolic phenomena.” Premature closure of the mitral valve in IE with acute aortic insufficiency is demonstrated by echocardiography and is associated with a poor prognosis.‘” This finding may indicate the need for early valve replacement. Echocardiography indicates the nature of the pre-existing cardiac lesion in up to one-half of cases.‘j It also may define the extent and nature of damage secondary to the infectious process.15 This and other information provided is important when surgical intervention is being considered. Cardiac
Cardiac catheterization of patients with IE may document unusual or clinically unsuspected intracardiac complications, define the extent and
.?~nodynamic significance of valve damage, or identify the infected valve. In patients with active endocarditis, quantitasive differerbces in bacterial counts done on samples obtained through catheters from sites Qroximal and drstal to the suspected lesion may indicate the site of infection. This technique may be most useful in right-sided endocarditis where murmurs indicating tricuspid or pulmonary valvulitis are often absent.‘” In patients with endocarditis who deteriorate despite medical therapy, immediate valve replacement may be indicated. Cardiac catheterization with cineangiography has been useful in these patients in demonstrating complications such as mycotic aneurysms or ventricular septal defects.17 Patients with residual valvular damage may also benefit from catheterization prior to surgery. A retrospective study of 19 patients with bacteriologically inactive endocarditis was recently reported by Mills and associates.‘* In this study, catheterization with cineangiography was performed to clarify an uncertain diagnosis or to confirm a diagnosis suspected on clinical grounds. Direct inspection at the time of cardiac surgery or pathologic examination was used to document the anatomical diagnoses. Catheterization was often useful when the diagnosis was unclear. Three patients were thought to have combined mitral and aortic insufficiency. The severity of each lesion could be determined in two, and the third patient was shown not to have mitral insuflkkncy. The clinical diagnosis of mitral stenosis ir, two patients was shown by catheterization to be incorrect. The relative contribution of valvular insufficiency to heart failure was determined in two patients, one with emphysema, and another with pericarditis. Two serious complications resulted from these studies. One patient developed pulmonary edema and another a fatal arrhythmia. Bacterial vegetations were not demonstrated in any patient by cineangiography and four patients had false-positive tests indicating valvular insufficiency, In patients with clear-cut mitral insufficiency, catheterization data provided little additional information. Paravalvular lesions (five mycotic aneurysms and one fistulous tract) were present in six patients. Cineangiography demonstrated only three of these defects. These authors conclude that cardiac catheterization is helpful when
sever& vaives are involve$ with 1niec.2 .x:2., whS1: :* paravslvular lesion is present, or to determine the
relative contribution heart failure.
Serologic tests used in the assessment; of patients with IE can be divided in’u those which suggest a particular etiologic agent, oi’ rnpocardial involvement, and those tests whkh show a heightened immunologic state. Seroiogic tests may be useful in diagnosis of cultT2re-negative endocarditis and in following cbe FOWSI) of therapy. Rheumatoid factor (RF) is present in the blood of approximately 50 per cent of patients with IE in whom symptoms have beeai present far six weeks or more. RF is an IgM direc-te:il against the Fc portion of EgG and its presence may interfere with IgG mediated opsonizatior? of bacteria. The presence of RF correlates with active disease and Eiters fall rapidly with adequate therapy. The presence of glomer~~lo~e~b~~~~s due to the deposition of immune complexes h4~ been found with IE of a number of bacterial etiologies. A recent paper documenting the presence of eirculating immune complexes (CIC) in patients with IE is of considerable interest.!” The $ssible diagnostic value of this test in cult.ure-negative endocarditis has been stressed. In this study ‘$2 per cent of cases with HE had circulating immune complexes as compared to 80 t.o 40 per cent of control groups. Moreover, the patients with CB’C unrelated to endocarditis had lower titers than those with endocarditis. As wish RF. .~iters of CIC are related to duration of disease.Aitho~gh titers do diminish with adequate therapy, persistent CIC levels do not necessarily indicate a pool therapeutic response. The sensitivity of this test. was better than that of the simpler measurement of complement levels, the latter being decreased in only 41 per cent of cases of IE, Tests which measure CIC have potentid. usefuulness in culture-negative endocarditis, but these tests are difkult to perform and are noz availAle in most laboratories. Tests used for the determination of specific etiologic agents in.clude those which demcmstrate the presence of an antibody direet,iy, such as ~rn.a~~~~~ci~~tat~o~ tests and complement fixation tests.
Staphylococcus aureus cell walls contain the antigenic moiety ribitol teichoic acid. The determination of an antibody response to teichoic acid using immunoprecipitation tests such as counterimmunoelectrophoresis (CIE) or double diffusion in agar may be useful in patients with IE due to this organism. CIE is more rapid and sensitive than agar diffusion and has been proposed as an aid to early diagnosis of this infection.2o The latter is relatively sensitive and more specific than the CIE. These tests have most potential usefulness in patients who have received antibiotics active against Staphylococcus aureus. In some studies, antibodies to teichoic acid may be found in as many as 90 per cent of patients with IE due to this organism. There is a correlation with adequate therapeutic response and fall in titer. A number of problems exist with this diagnostic test. Teichoic acid antibodies may be found in uninfected drug addicts, and the presence of antibodies does not necessarily indicate endocarditis in patients with staphylococcal sepsis.21 False-positives occur in some patients with IE due to a streptococcal species.*O Furthermore, the absence of a standardized, commercially available antigen limits the availability of this test. Serologic tests may also be useful in cases of culture-negative fungal endocarditis. In patients with Candida endocarditis blood cultures will be positive in 50 to 75 per cent of cases. Serologic tests include immunoprecipitation and agglutination.?? The usefulness of these serologic tests has been questioned, since significant titers may occur in noninvasive disease, and false-negatives may occur in invasiv,e candida infection. In patients in whom the clinical diagnosis of endocarditis due to candida is suspected, serologic tests may give additional supportive evidence, especially when combined with echocardiography. Serologic studies available for the diagnosis of less common fungal etiologies such as aspergillus or histoplasma species are of limited use. As with candida infections, a single high titer or a changing titer may be helpful in certain circumstances. Coxiella burneti, the agent of Q fever, is an unusual cause of infective endocarditis and may be suspected in patients with culture-negative disease where there is a history of animal contact.’ An increase in the complement-fixing antibody titer is required to diagnose this infec-
tion. Similarly, Brucella species may cause culture-negative endocarditis in patients with animal exposure and may be diagnosed serologitally. The presence of antiheart antibodies measured by indirect immunofluorescence has been reported in nine out of 13 (62 per cent) patients with subacute endocarditis.“3 Antibody titers were associated with congestive heart failure and titers fell with adequate therapy. Antiheart antibodies may be seen in a variety of cardiac disorders and this test is unlikely to be useful in diagnosing or following patients with endocarditis. Gallium
The radiopharmaceutical Gallium 67 citrate localizes in areas of inflammation and in many neoplasms. Scintigraphy with gallium may be helpful in localizing occult infective foci such as intra-abdominal abscesses.This diagnostic procedure has recently been evaluated in ten patients with acute bacterial endocarditis and in an additional patient with a myocardial abscess.24Scanning demonstrated accumulation of the isotope within the heart in six of the IE cases and in the single patient with a myocardial abscess. The resolution of this procedure is not sufficient to determine which valve is infected, and there is a delay of at least 48 hours before scans become positive. With 40 per cent false-negative results, the sensitivity of this procedure is considerably lessthan blood cultures. The potential usefulness of gallium scans in patients with subacute infective endocarditis or culture-negative endocarditis has not been determined. Electrocardiography
The relative importance of the electrocardiogram (ECG) in the assessmentof patients with IE has recently been stressed.Z5However, there has been no comprehensive study of ECG’s in patients with this infection. ECG changes are not diagnostic of endocarditis and often consist of partial or complete heart blocks and premature ventricular contractions indicating myocarditis or the involvement of the conduction system with infection or inflammation. The anatomical relation of the non-coronary cusp of the aortic valve and the mitral annulus with the conduction system accounts for the frequency of conduction abnormalities and the type of the conduction
abnormality may have some localizing value.“’ One recent study correlated pathologic findings with EGG abnormalities in 24 patients with IE involving the aortic valve.‘” Eighteen of 24 patients with aortic valve endocarditis had prolonged P-R intervals unrelated to digitalis. Four developed complete heart block. Deep infection with aneurysm formation was present in 16 of these 18 patients. Four patients who developed left bundle branch block with normal P-R intervals had aneurysms of the intraventricular septum. Four of 24 patients had evidence of a myocardial infarction with multifocal ventricular ectopic beats, and two of these had coronary artery emboli on postmortem examination. It is important to obtain serial EGG’s in patients with the diagnosis of infective endocarditis. Electrocardiographic evidence of an infarction or heart block is associated with a poor prognosis. New conduction defects indicate abscess or aneurysm formation and may suggest the need for surgical int,ervention.
22 1. 2.
Weinstein, L., and Rubin, R. H.: Infective endocarditis-1973, Prog. Cardiovasc. Dis. 16:239, 1973. Beeson, P. B., Brannon, E. S., and Warren, J. V.: Observations on the sites of removal of bacteria from the patients with bacterial endocarditis. J. Exp. :9, 1945. ie Frock, J. L., Ellis, C. A., Turchik, J. B., and Weinstein,
Goshi, EC., Cl&f, L. E., ar,d Norman, 6. 4.: &u&es on the pathogenesis of staphylococcal infection. VI. Mechanism of immunity conferred by anri-alpha hemolysin, Bull. Sohns Hopkins Hosp. ‘F12:31, 1963. Cannady, P. B., and Sanford, d, P.: Negative biood cultures in infective endocarditis: a review, South. Med. 3. 69:1420, 1976. Cayeux, P., Acar, J. F.; and Chabbert, U. A.: Bacterial persistence in streptococcal en&card&is due to thiolrequiring mutants, J. Pnfect. Dis. 4 24:24?, 19’71. Roberts, G. D., and Washington, J. A.: Detection of fungi in blood cultures, J, Chn. Microbial. 1:3C9, 19’75. Roberts, G. D., Morstmeier, C., Hali. iif., arid Wasbington, J. A.: Recovery of yeast from vented blood culture bottles, 3. Clin. Microbic& 2:18, 1976. Fowers,
The rational use of techniques introduced in the past several years for assessing patients with suspected or proven IE requires careful patient selection. With the exception of cardiac catheterization, these tests are noninvasive and therefore not associated with significant morbidity. The general availability of many of these tests is limited, and the sensitivity and/or specificity may be less than more conventional studies. Serologic studies measuring circulating immune complexes, teichoic acid antibodies, and antiheart antibodies often require the sending of samples to reference laboratories. Gallium scans, cardiac catheterization, and echocardiography may require the transfer of patients to hospitals with facilities for such studies. Despite these lim.itations, the use of one or more of these tests in individual patients may provide information crucial to the diagnosis or management of patients with infective endocarditis.
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Rubinstein, E., Noriega, E. R., Simberkoff, M. S., Holzman, R., and Rahal, J. J.: Fungal endocarditis: Analysis of 24 cases and review of the literature, Medicine 54:331, 1975.