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Overuse of Transthoracic Echocardiography in the Diagnosis of Native Valve Endocarditis
Janaki C. Kuruppu, MD;
Mary Corretti, MD;
Philip Mackowiak, MD;
Mary-Claire Roghmann, MD, MS
Arch Intern Med. 2002;162:1715-1720.
ABSTRACT
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Background Infective endocarditis (IE) is a diagnostic challenge due to its variable
presentation and nonspecific clinical findings. The use of transthoracic echocardiography
(TTE) has greatly improved the ability to diagnose IE early, and therefore
reduce high mortality and morbidity rates. However, reliance on TTE to exclude
IE may lead to overuse of this technology in patients with a low pretest probability
of IE.
Methods Prospective observational study of all patients referred for TTE to
diagnose IE. Clinical factors were used to determine likelihood of IE based
on the Von Reyn criteria, and the resulting diagnostic probabilities were
correlated with abnormal TTE findings as well as duration of antibiotic therapy.
Results One hundred eleven TTEs performed on 98 patients were included in the
analysis. Over 70% of TTEs were obtained in patients in whom the diagnosis
of IE was rejected by Von Reyn criteria. Therapeutic
management (prolonged antibiotic administration) was associated significantly
with Von Reyn categorization, and not significantly affected by TTE results.
Conclusions Most TTEs are obtained in patients with a low pretest probability of
IE and do not contribute to therapeutic decision making. We propose a diagnostic
algorithm to direct the use of TTE to patients with intermediate or high pretest
probability of IE.
INTRODUCTION
INFECTIVE ENDOCARDITIS (IE) is a disease with high mortality, which
requires early diagnosis to give appropriate treatment. Early identification
of patients at risk for IE continues to present a challenge because clinical
findings can vary widely.1 To aid diagnosis,
formal criteria were published by Pelletier and Petersdorf2
in 1977. In 1981, Von Reyn et al3 modified
these criteria and proposed strict case definitions, generating 4 categories: definite (based on pathological findings), probable, possible, and rejected (see Appendix 1 of Von Reyn et al3).
During the 1980s, transthoracic echocardiography (TTE) became widely used
in the evaluation of valvular abnormalities, and the technology has since
gained sensitivity for identifying vegetations and valvular regurgitation.
In 1994, Durack et al4 proposed the addition
of TTE findings to the diagnostic criteria of endocarditis (referred to as
the Duke criteria) (see Appendixes 2 and 3 of Durack et al4).
In the ensuing years, several groups have confirmed the increased sensitivity
of the Duke criteria as compared with the older Von Reyn criteria. Most of
these later studies have been retrospective, and have used pathological specimens
or autopsy results to define the positive cases.5-15
Two prospective studies have compared the Duke and Von Reyn criteria.16-17 These studies have examined selected
patient populations with a high pretest probability of IE: all patients had
both TTE and transesophageal echocardiography (TEE) performed. Shapiro et
al17 noted that a "number of patients" who
were clinically classified as not having IE and had normal TTE findings were
treated with a prolonged course of antibiotics for "possible IE," indicating
that a negative TTE, even in patients with a low pretest probability of IE
clinically, may not provide clinicians with the reassurance to shorten the
course of empiric antibiotic treatment.
Generally, diagnostic tests are most useful in the evaluation and management
of patients with intermediate or high pretest likelihood of a given disease,
and are less useful in patients with a low pretest probability. Transthoracic
echocardiography, in the diagnosis of IE, is no exception.18-20
We suspected that many TTEs in our hospital are obtained to "rule out" IE
in patients with low pretest probability of IE. We conducted a prospective
observational study of all patients referred for TTE to rule out IE in a large,
urban, tertiary referral hospital (1) to determine the pretest likelihood
of IE and (2) to test the impact of TTE results on clinical management and
outcome.
METHODS
An "episode" is defined as a TTE performed to evaluate IE. All requests
for TTEs indicating a suspicion of IE (stated explicitly, "rule out vegetations,"
or history of intravenous drug use [IVDU] with fever) were reviewed between
December 1, 1998, and March 15, 1999. Patient charts were reviewed by one
of the authors (J.C.K.) to abstract clinical findings associated with IE.
Historical risk factors included IVDU, presence of an indwelling vascular
catheter, predisposing invasive procedure, human immunodeficiency virus status,
prior history of endocarditis or valve disease, and immunocompromise (other
than acquired immunodeficiency syndrome); clinical findings included fever,
cardiac murmur, petechiae, splinter hemorrhage, Roth spots, Janeway lesions,
Osler nodes, and suspected site of infection other than IE. Clinical findings
were included only if they were documented in the chart before or on the date
the TTE was ordered. Patients with prosthetic valves were excluded from this
study.
The following laboratory data were collected: white blood cell count,
band percentage, hematocrit, microscopic hematuria, number of blood cultures,
number of positive blood cultures, number of days for cultures to become positive,
organisms identified from positive cultures, positive cultures from sites
other than blood, and evidence of embolic phenomena on radiological studies.
In the case of blood culture results, we recorded whether the results of the
culture were available to the treating clinician at the time the TTE was ordered
(since cultures and TTEs were often requested on the same day that IE was
first suspected or considered).
Transthoracic echocardiography was performed at the University of Maryland
Adult Echo Lab, Baltimore, using a Sonos 5500 with harmonic imaging ultrasound
system (Agilent Technologies, Andover, Mass). Transthoracic echocardiograms
were read by 1 of 3 cardiologists blinded to the clinical information other
than the indication for requesting the TTE. Reported results were reviewed
for abnormal findings. All abnormal TTEs (vegetation, valve abnormality, moderate
or severe regurgitation, or perivalvular abscess) were reviewed by one of
us (M.C.) to confirm whether the TTE was diagnostic of IE.
Each episode was categorized by the Von Reyn criteria into probable,
possible, or rejected based on clinical data available (see Appendix 1 of
Von Reyn et al3). The Von Reyn criteria were
used because they are the most recently defined criteria that do not rely
on echocardiographic information to define likelihood of IE. Since the Von
Reyn criteria rely strongly on the presence and persistence of positive blood
cultures, the final results of blood cultures after 5 days of incubation were
used to calculate Von Reyn category, whether or not the results were available
to the treating clinician at the time the TTE was ordered.
Discharge diagnosis, clinical outcome, and length of antibiotic treatment
were obtained from dictated discharge summaries. When discharge summaries
were not available, the chart was reviewed again to obtain this information
from the progress notes or discharge instructions.
The primary objective was to compare clinical diagnosis of IE with TTE
results. We also looked at the association of both Von Reyn category and TTE
results with demographic variables, discharge diagnosis of endocarditis, and
duration of antibiotic therapy.
Statistical analysis was performed using Statview (Abacus Concepts Inc,
Berkeley, Calif). Categorical data were analyzed with the Fisher exact test,
and nominal data were analyzed with unpaired t tests.
All tests were performed at the 5% significance level, and used 2-tailed analysis.
RESULTS
One hundred twenty-eight TTE requests meeting the screening criteria
were selected for review, of which 17 were excluded: in 11, TTE was not done;
in 4, chart review revealed that the TTE request was erroneous or for an indication
other than IE; 1 patient was known to have IE with a preexisting valvular
vegetation; and 1 patient had a prosthetic valve. Thus, 111 TTEs were included
in the analysis.
DESCRIPTIVE ANALYSIS OF STUDY POPULATION
One hundred eleven TTEs, or episodes, occurred in 98 patients. The mean
age was 46 years (range, 15-82 years), and 61% were male. Seventy percent
were African American, 46% had a history of IVDU, and 31% were infected with
human immunodeficiency virus. In the latter, CD4 counts ranged widely (0-841/µL),
with a mean of 132/µL. Immunocompromised states other than human immunodeficiency
virus seropositivity, including diabetes mellitus, immunosuppressive therapy,
and neutropenia were present in 34 patients (35%). Ten patients had preexisting
valvular disease: 2 with rheumatic heart disease, 2 with nonrheumatic valvular
abnormalities, and 6 with a prior (remote) history of IE. No patient had a
documented history of mitral valve prolapse.
DESCRIPTIVE ANALYSIS OF VON REYN CRITERIA FACTORS
Table 1 and Table 2 list the association of clinical factors and outcomes with
either Von Reyn categorization or TTE findings, respectively.
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Table 1. Demographic Factors Associated With Von Reyn Categorization
and Echocardiographic Results*
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Table 2. Clinical Findings and Outcomes Associated With Von Reyn Categorization
and Echocardiographic Results*
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The factors that contributed to assigning each episode as probable,
possible, or rejected IE by Von Reyn criteria were as follows: persistently
positive blood cultures (46 episodes, 41%), cardiac murmur (42 episodes, 38%),
predisposing heart disease (10 episodes, 9%), fever (70 episodes, 68%), vascular
phenomena as evidenced by embolic phenomena on physical examination or by
radiography, or immunological phenomena (ie, Osler nodes and Roth spot) (32
episodes, 29%). These factors led to defining 22 episodes as probable (20%),
10 as possible (9%), and 79 as rejected (71%). Due to small numbers, the probable
and possible categories were combined, and the pooled category probable/possible
was compared in all analyses with the episodes that were rejected.
In 3 of 111 episodes, no blood cultures were obtained prior to getting
an echocardiogram. Of the 108 episodes with at least 1 blood culture, TTEs
were ordered in 29 instances before blood culture results were reported by
the clinical laboratory. In these cases, the TTE was ordered on the same day
that the blood cultures were drawn. Of these 29 episodes, 25 ultimately yielded
negative culture results.
Of the 44 blood cultures that met the Von Reyn definition of "persistently
positive," TTE was ordered after the culture results were available in 40
(91%). In contrast, culture results were available at the time of TTE in only
8 (28%) of 29 episodes in which the cultures ultimately showed no growth (91%
vs 28%; P<.001). In other words, in patients with
culture-proven bacteremia, TTEs were more likely to be ordered when positive
blood culture results were available, whereas in patients without bacteremia,
the TTE was more likely to be ordered before negative culture results were
known.
BIVARIATE ANALYSIS OF OTHER CLINICAL FACTORS WITH VON REYN CLASSIFICATION
Comparing the 32 probable/possible episodes with the 79 rejected episodes,
there were no differences between mean age, sex, race, human immunodeficiency
virus seropositivity, immunocompromised status, history of IVDU, presence
of indwelling vascular catheter, history of rheumatic heart disease or other
valvular abnormality, or prior invasive procedure. Episodes that fell in the
probable/possible category were strongly associated with presence of hematuria
(38% vs 4%; P<.001).
More than half (52%) of the TTEs were ordered within the first 3 days
of hospital stay, 11 at admission, 20 on the first day following admission,
17 on day 2, and 10 on day 3. Transthoracic echocardiograms ordered later
in the hospitalization were no more likely than those ordered in the first
3 days to reveal a pathological condition; however, those episodes in which
the TTE was performed later than 3 days into hospitalization were more likely
to fall into the probable/possible category than rejected (P = .03, Mann-Whitney test). Length of hospitalization showed no association
with likelihood of IE. Mortality was not significantly associated with Von
Reyn classification. Surprisingly, discharge diagnosis of IE was also not
associated with Von Reyn classification. Valve surgery was performed in 3
patients, none of whom were rejected by the Von Reyn classification (P = .02).
BIVARIATE ANALYSIS OF OTHER CLINICAL FACTORS WITH TTE RESULTS
Five of 111 TTEs showed valvular vegetations. In 2 additional TTEs,
valvular abnormalities other than vegetations were demonstrated, 1 showing
severe tricuspid regurgitation that was new compared with a prior TTE available
for that patient, and 1 showing an abnormality consistent with abscess adjacent
to the aortic valve. This latter case was the only abnormal TTE of the 7 that
fell into the rejected Von Reyn category. On review of prior TTEs obtained
in this patient, this abnormality had been seen on multiple occasions and
was unchanged for more than a year, and therefore did not represent active
IE. This patient was diagnosed as having pneumonia and Clostridium difficile colitis, and received 2 weeks of intravenous
antibiotics. Thus, 6 TTEs were diagnostic of IE.
COMPARISON OF VON REYN CLASSIFICATION WITH TTE RESULTS
Excluding the abnormal TTE result in the patient who had the stable
abnormality, 6 of 6 abnormal TTEs met Von Reyn criteria for probable/possible
(the Fisher exact test, P<.001). Twenty-six of
the 104 normal TTEs (25%) were in the probable/possible category, with the
remaining majority falling in the rejected category.
THE EFFECT OF VON REYN CLASSIFICATION AND TTE RESULTS ON DURATION OF
ANTIBIOTIC THERAPY
Data on antibiotic therapy duration were available in 99 of the 111
episodes, and these 99 episodes were analyzed for differences in mean number
of weeks of therapy based on either Von Reyn category or TTE results. Thirty-one
cases in the probable/possible category were treated for a mean ± SD
duration of 5.6 ± 3.0 weeks, and of these, 25 had normal findings on
TTE with a mean ± SD duration of antibiotics of 5.5 ± 3.2 weeks.
The 6 probable/possible cases with abnormal TTE findings were treated for
6.3 ± 2.3 weeks. Sixty-eight cases in the rejected category were treated
for 2.7 ± 1.9 weeks. Included in these 68 was the 1 abnormal TTE finding
that was not changed from prior studies, and this patient received antibiotics
for 2 weeks, stressing the importance of clinical findings over echocardiographic
results, and also indicating the need to review prior studies to confirm that
valvular abnormalities are changed. Figure
1 shows the relationship between antibiotic duration in weeks in
either the probable/possible or rejected Von Reyn categories, and the influence
of TTE results on duration in both groups. Duration of antibiotic therapy
(mean ± SD, 5.0 ± 3.0 weeks vs 2.0 ± 1.9 weeks; P<.001) and hospitalization (34 vs 18 days; P = .005) was significantly longer in the probable/possible category
compared with the rejected category (echocardiographic abnormalities did not
significantly affect duration of therapy [P = .03]).
Furthermore, a negative TTE did not correlate with shorter length of hospitalization
(20 [TTE abnormal] vs 23 [TTE normal] days; P = .69).
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Figure 1. Histogram showing that antibiotic
treatment was significantly prolonged in cases that met the criteria of probable or possible infective endocarditis
compared with cases that were rejected by the Von Reyn criteria
(P = .006, analysis of variance). Abnormal transthoracic
echocardiography results did not influence duration of antibiotic treatment
(P = .95 for transthoracic echocardiography results
alone and P = .55 in combination with Von Reyn category).
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DESCRIPTION OF PATIENTS DIAGNOSED CLINICALLY WITH IE
Twelve episodes resulted in a clinical diagnosis of IE. Nine of these
episodes grew Staphylococcus aureus in at least 1
blood culture; of the remaining 3 episodes, 1 grew viridans
Streptococcus, 1 grew Streptococcus intermedius,
and the last was culture negative (3 sets of blood cultures drawn); and the
diagnosis was based on the presence of a splenic infarct on a computed tomographic
scan. Nine of 12 met the Von Reyn definition of "persistently positive" blood
cultures, but only 6 of 12 fell into the probable/possible category. Five
of 12 had abnormalities on TTE. One patient was treated for only 2 weeks with
antibiotics, and the remaining 11 were treated for at least 4 weeks.
COMMENT
We conducted a prospective observational study to characterize the use
of TTE in the evaluation and management of IE in our hospital. Our main finding
is that a large proportion (>70%) of TTEs are ordered in patients with a low
pretest probability of IE by Von Reyn criteria. This percentage was much higher
than predicted at the outset of the study. Our finding is consistent with
that reported by Lindner et al21; however,
our study differs in that all adult patients referred with suspicion of IE
were included, and our hospital is located in an inner-city environment, where
the likelihood of IE may be higher than in a nonurban hospital.
We found that TTE results do not significantly affect duration of antibiotic
therapy. Rather, duration depended solely on clinical factors. This result
is also consistent with the results reported by Lindner et al,21
who found that clinical parameters were predictive of antibiotic course, and
were unaffected by either TTE or TEE. Ali et al22
also found in a retrospective review of 2750 serial TTEs that demonstration
of a vegetation in 15 of 20 cases had little effect on initiation of IE therapy
in patients with a low clinical suspicion of IE.
Lindner et al21 prospectively evaluated
105 patients with suspected endocarditis to assess the utility of either TTE
or TEE in the diagnosis of IE. They tested the impact of echocardiographic
findings on clinical management, and found that duration of antibiotic therapy
was dependent on clinical factors, and was not affected significantly by TTE
results, either TTE or TEE. They concluded that echocardiography is not useful
in the clinical management of cases with a low pretest probability of IE,
and is most useful in evaluating patients with an intermediate risk of IE.
Their study population came from a nonurban setting, and only 4 (4%) of their
patients had a history of IVDU, thus, their results may not be applicable
in an urban hospital. Their subjects also underwent both TTE and TEE, thereby
imposing a selection bias, since all subjects must be able and willing to
consent to an invasive procedure (TEE).
Heidenreich et al23 recently performed
a cost-effectiveness analysis based on previous clinical studies, and concluded
that patients with a pretest probability of IE that is less than 2% are optimally
treated empirically for bacteremia (with 10-14 days of intravenous antibiotics),
that patients with a pretest probability of greater than 60% should be treated
for IE no matter what the echocardiographic results are, and that patients
with pretest probability between 4% and 60% are best evaluated with TEE. This
wide margin reflects the importance of maintaining a low threshold of suspicion
for IE. Our study indicates that many TTEs are ordered in patients with a
low pretest probability. The challenge to clinicians is in quantifying the
pretest probability; how can one prospectively estimate the difference between
a less than 2% likelihood and a less than 4% likelihood? Patient characteristics
cited by Heidenreich et al23 to define a probability
of less than 2% were cases in which there was a firm alternate diagnosis or
resolution of endocarditis syndrome within 4 days (Duke "rejected IE" category)
or gram-negative bacteremia with clear noncardiac source of infection (Weinstein24). The Duke "rejected IE" category depends on 4 days
of clinical observation, implying that TTE should not be ordered until 4 days
have elapsed from the moment that IE was first suspected. Since our results
indicate that TTEs ordered after at least 3 days of hospitalization are less
likely to be low probability (ie, rejected by Von Reyn criteria) it is likely
that the number of TTEs would be substantially reduced by simply allowing
enough time for growth of cultures, and collecting additional clinical data
to assess the clinical likelihood of IE.
Since our survey demonstrates that a large number of TTEs are ordered
in the first 3 days of hospital stay, and blood culture results are not known
in many cases prior to obtaining a TTE, we propose the following algorithm
in the approach to the diagnosis of IE (Figure
2). In all patients suspected of having IE, 3 blood cultures should
be drawn from separate sites, with the first and last cultures separated temporally
by at least 1 hour. All cultures should be obtained before empiric antibiotic
therapy is started. Urinalysis should be obtained to document the presence
of microscopic hematuria, which has been shown in our study and by others
to increase the sensitivity of clinical assessment of IE.9, 25
Radiographic studies may aid in the documentation of embolic phenomena. If
hemodynamic compromise is present, a TTE is warranted at the outset to identify
the underlying cardiac status; however, in the hemodynamically stable patient,
TTE should be forestalled until the patient has received 4 days of appropriate
antibiotic therapy with routine monitoring and documentation of clinical course.
After 4 days of clinical observation and antibiotic therapy to cover likely
sources of infection and the availability of culture results, if IE is still
a diagnostic consideration, TTE should be used to identify valvular abnormalities
diagnostic of IE, and to assist in decision making regarding antibiotic duration
or surgical intervention. In our study population, using this diagnostic algorithm,
59 (53%) of 111 of the TTEs obtained would have been avoided, without loss
of diagnostic accuracy. Interestingly, of 13 patients who were considered
to have IE, clinically (as noted in discharge summaries), they were evenly
distributed between Von Reyn categories (6 in the probable/possible category
and 7 in the rejected category). None of the 7 cases in the rejected category
had positive findings on TTE.
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Figure 2. Proposed algorithm for diagnosis
of infective endocarditis (IE) based first on consideration of clinical presentation
and blood cultures, and proceeding to transthoracic echocardiography when
intermediate or high probability cases are suspected and an alternative diagnosis
is not made.
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The TTE should contribute to the diagnosis and/or management of IE in
at least 1 of the following ways: (1) to distinguish between bacteremia and
IE to shorten the course of antibiotic therapy; (2) to predict the risk of
complications of IE such as heart failure or emboli; and (3) to assess the
need for surgical intervention. Our results, with Lindner et al,21
demonstrate that antibiotic therapy is not altered by results of TTE. Others
have shown that echocardiographic findings do not predict risk of embolic
complications from IE26-27; however,
Goldman et al28 found TTE results to be predictive
of major complications such as development of heart failure, embolic episodes,
and need for surgery, particularly with vegetation involving the aortic valve
and measuring larger than 1.8 cm. In the latter study, presence of embolic
phenomena at admission was predictive of further embolic episodes, and in
our study, embolic phenomena were associated with abnormal TTEs; thus, it
may be more accurate to say that embolic episodes predict abnormal echocardiographic
findings, rather than the reverse. Thus, the main clinical utility of TTE
in the management of IE may lie in evaluating patients with a high or intermediate
clinical probability of IE to decide on surgical intervention or duration
of therapy.29
Despite significant advances in technology, diagnosis of IE remains
a clinical diagnosis, requiring collection and interpretation of clinical,
laboratory, and microbiological data. Transthoracic echocardiography in low-risk
patients does not add diagnostic information, and does not alter therapeutic
strategies. Based on our findings, TTE is overused in the diagnosis of IE,
primarily because it is obtained before all clinical information is available.
Echocardiography in the diagnosis and management of IE should be reserved
for patients with intermediate or high probability of IE, based on clinical
findings and positive blood culture results.
AUTHOR INFORMATION
Accepted for publication December 10, 2001.
We gratefully acknowledge Sheldon E. Greisman, MD, who graciously reviewed
the manuscript in preparation and helped clarify and focus the results and
discussion.
Corresponding author and reprints: Janaki C. Kuruppu, MD, Vaccine
Research Center, National Institutes of Health, 40 Convent Dr, Room 3612B,
Bethesda, MD 20892 (e-mail: jkuruppu{at}mail.nih.gov).
From the Vaccine Research Center, National Institutes of Health, Bethesda,
Md (Dr Kuruppu); and the Department of Medicine, University of Maryland (Drs
Corretti and Mackowiak), the Medical Care Clinical Center, Veterans Administration
Maryland Health Care System (Drs Mackowiak and Roghmann), and the Department
of Epidemiology and Preventive Medicine, University of Maryland (Dr Roghmann),
Baltimore.
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